Writing this paper was an intellectual exercise, and I want to say that I strongly advise people to talk to their doctors before exposing themselves to sunlight or other UVB or UVA sources, even casually. And, in my opinion, it is not wise to use UVB or UVA for therapeutic purposes of any kind. I obviously think that sun exposure would increase the risk of skin cancers. Another implication of the mechanisms I discuss in the paper is that UV exposure could produce actual brain damage, and there are reports of people with multiple sclerosis dying after sitting in the sun. I think it would be a terrible idea for people to use UV therapeutically. In fact, UV exposure could cause brainstem hemorrhages by inducing low-frequency, spontaneous firing of trigeminal ganglion neurons, innervating the skin of the face. The low-frequency firing rates that primary afferent neurons demonstrate within ~30 minutes of exposure to UV causes CGRP and substance P to be released in the spinal cord and trigeminal nucleus, in the brain, and this could cause perivascular mast cell degranulation and thereby increase vascular permeability and cause a hemorrhage, etc. A single UV exposure can cause ~1 Hz, asynchronous firing of sensory neurons and trigeminal ganglion and dorsal horn neurons that lasts 5-7 days. But CGRP has immunomodulatory effects and could act on astrocytes and microglia, upon its release in various parts of the brain, etc. Another implication is that UV could modify cerebral blood flow (either decreasing it or increasing it) by inducing one or another type of trigeminal root reflex, meaning efferent action potentials in fibers innervating the cerebral blood vessels. UV could also modify thalamic mast cell degranulation, potentially with damaging consequences.
But the mechanisms also imply that no blood-borne photoreceptors or bilirubin (as a photoreceptor, etc.) or mysterious capacity of UVA to reach the retina would be required for UVB or UVA to modify brain function in significant ways (modify the circadian rhythm, thermoregulation, etc.). Changes in the trigeminal system can affect neurotransmission in many parts of the brain, by polysynaptic pathways, and maybe this paper would stimulate some interest in basic research on photobiology or on actual, legitimate treatments for multiple sclerosis, etc. The immunosuppressive effects of UVB are really complex and can go wrong at multiple points along the cascade of events that result from UVB exposure, and the result could be a new type of lupus-like autoimmune disease in some people. It's not a valid immunomodulatory approach. But an implication of the mechanistic analysis might be that drugs modifying CGRP receptor activation could be useful for autoimmune diseases, etc. CGRP is also a very potent vasodilator and produces NOS-independent vasodilation, for example.
In any case, I don't like anti-intellectualism in the context of basic research, and I stand by the validity of my mechanistic discussion in this paper, from an intellectual standpoint. Maybe if more people were not so terrified of discussing some of these topics in a rigorous and objective manner, it would be possible to persuade more people of various public-health-type messages. Instead, the discussion degenerates into proclamations, etc. Again, this paper is not meant to suggest any rationale for doing anything. Maybe people with multiple sclerosis or the like will be more careful about sun exposure and realize that being aware of all the mechanisms can be useful, as far as protecting oneself from the brain damage that could conceivably result from sun exposure, particularly in someone in any kind of disease state.
A Review of the Effects of Cutaneous Exposure to Ultraviolet Radiation On Primary Afferent and Dorsal Horn Neurons: Mechanisms and Effects On Immune Function and Pain
Abstract
Background—Following the exposure of the skin to either ultraviolet B (UVB) or ultraviolet A (UVA) radiation, the immunological responses to cutaneously-administered protein antigens or small-molecule haptens can be suppressed systemically. UVB is known to cause sensory C-fibers to release the neuropeptides -calcitonin gene-related peptide (CGRP) and substance P (SP) into the skin, and the release of these neuropeptides contributes to UVB-induced systemic immunosuppression and UVB-induced increases in neurogenic blood flow (i.e. erythema). More specifically, CGRP released from the peripheral terminals of C-fibers, in response to UVB, acts on antigen-presenting cells (APC) migrating from or infiltrating into the skin and contributes to the UVB-induced production of interleukin-10 (IL-10) by these APC. Cutaneous UVB has also been shown to increase the CGRP and SP content in the dorsal horn (DH) of the spinal cord, and this apparent release of CGRP and SP has been suggested to mediate UVB-induced sunburn pain and hyperalgesia. The immunological consequences of CGRP released in the spinal cord has never been investigated but may be relevant for understanding the etiology of multiple sclerosis, which UVB exposure may protect against but also, conceivably, worsen the course of.
Key Conclusions—Researchers have found that ultraviolet radiation (UVR) can influence the electrophysiological activities of and phenotypic expression of proteins by neurons in deeper spinal cord or brain sites (i.e. those that do not receive direct synaptic inputs from C-type, primary afferent neurons). CGRP released in the spinal cord may induce immunosuppressive cytokine production by, or reduce the antigen-presenting/costimulatory capacity of, astrocytes, microglia, or dendritic cells in the CNS. UVR induces low-frequency spontaneous, asynchronous activity in C-fibers innervating the exposed skin and also causes DH neurons to exhibit increases in spontaneous activity. This spontaneous activity releases glutamate, CGRP, and SP in the DH and contributes to UVB-induced primary and secondary hyperalgesia. These neurogenic effects may also contribute to the UVB-induced suppression of pruritus. UVB produces biphasic increases in blood flow in the UV-irradiated skin, and researchers have previously proposed that only the second peak of blood flow is neurogenic (C-fiber-mediated). Numerous pieces of evidence argue against this conclusion and suggest that UVR produces two largely neurogenic phases of increased blood flow. The first peak of blood flow is likely to be both neurogenic and non-neurogenic but is unlikely to be purely non-neurogenic. UVB has been shown to reactivate the herpes simplex virus in the trigeminal ganglia and dorsal root ganglia (DRG), and this reactivation follows a bimodal timecourse. It is likely that UVR first depletes CGRP and SP from C-fibers in the skin and subsequently induces adaptive changes in the cell bodies of DRG neurons and DH neurons, which replenish CGRP and SP stores and produce the second neurogenic phase of erythema via axon reflexes and dorsal root reflexes. UVR has also been found to produce rewarding and pain-reducing effects on the CNS. These effects have generally been attributed to UVR-induced increases in plasma opioid peptides, but it is more likely that these effects occur via purely neurogenic pathways involving the DRG, DH, and supraspinal sites (including the striatum, amygdala, etc.). UVB-induced increases in hormonal vitamin D3 production may modify the C-fiber-mediated effects of UVB and UVA. Hormonal vitamin D3 may, in part, protect against MS by increasing NGF, GDNF, and the low-affinity neurotrophin receptor (p75NTR) in the CNS. A hormonal vitamin D3 analog has been shown to increase the CGRP content in the DRG in an NGF-dependent manner, and the actions of hormonal vitamin D3 may reduce UVB-induced hyperalgesia.
Introduction
Some of the immunosuppressive effects of ultraviolet B radiation (UVB) are thought to be protective against multiple sclerosis (MS) and other autoimmune diseases (McMichael and Hall, 1997). MS is an inflammatory, demyelinating disease of the CNS that is thought to result from an autoimmune response against components of myelin (Storch et al., 1998; Lucchinetti et al., 1996; Lassman et al., 2004). The disease process in MS is also characterized by the degeneration of axons (Trapp et al., 1998) and the loss of neurons (Bozzali et al., 2002; Owens, 2003), and the extent of disability, in people with MS, is closely and positively associated with the loss of axons (Lassman et al., 2004). The demyelination in MS is believed to be largely mediated by CNS-infiltrating T-helper (CD4+) lymphocytes with a pro-inflammatory, Th1, phenotype (Lassman et al., 2004), and UVB reliably suppresses Th1-cytokine production by CD4+ T-cells (Shreedhar et al., 1998) and antigen-presenting cells (APC) (Garssen et al., 1999; Toichi et al., 2002) in regional lymph nodes. The apparent UVB-induced protection against MS has mainly been explained in terms of the immunomodulatory actions of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] (Hayes, 2000), the hormonally active form of vitamin D3, and, to a lesser extent, -melanocyte stimulating hormone (-MSH) (Friedman, 2004). Increases in the concentrations of both -MSH and 1,25(OH)2D3 have been found to be induced, in the skin, in response to UVB exposure (Lehman et al., 2003; Funasaka et al., 2001).
The implicit assumption has been that any UVB-induced immunosuppressive effects within the CNS must be preceded by, and must also be a consequence of, immunosuppressive effects in regional lymph nodes (RLNs) that drain the UVB-irradiated skin. The UVB-induced elevation in plasma 25-hydroxyvitamin D3 [25(OH)D3] could, as noted by others, clearly produce immunological changes that would originate in the CNS (McCarty, 2006). Microglia, astrocytes, and other cell types can convert 25(OH)D3 into 1,25(OH)2D3 and respond to the newly-produced 1,25(OH)2D3 (Garcion et al., 2002), which can act in a paracrine or autocrine fashion (Garcion et al., 2002). Many, if not most, of the immunosuppressive effects of UVB are known, however, to result from the actions of mediators other than vitamin D3, mediators that include cis-urocanic acid (cis-UCA) (Holán et al., 1998; Sleijffers et al. , 2003) and numerous cytokines (Boonstra et al., 2000), or from changes that overlap in some ways with 1,25(OH)2D3-associated signalling (Lehmann et al., 2004). Although some researchers have discussed the relevance to multiple sclerosis of UVB-induced immunosuppression that is independent of 1,25(OH)2D3 (Chaudhuri, 2005; McMichael and Hall, 1997; Van der Mei et al., 2001), these discussions have frequently been narrowly focused on the effects of -MSH. The involvement of -MSH in UVB-induced immunosuppression is thought to be of somewhat secondary importance and has not been as clearly established as the involvement of other mediators (Shimizu and Streilein, 1994). Many of these immunosuppressive effects, effects that include the UVB-induced expansion of regulatory T-cell populations (Schwarz et al., 2004), have not been discussed, in detailed terms, in the context of multiple sclerosis. UVR has been shown to either prevent damage from EAE (Hauser et al., 1984) or worsen the outcome (Tsunoda et al., 2005), but the complex interactions of UVR with CNS immune privilege and EAE have not been adequately explored (Hauser et al., 1984; Tsunoda et al., 2005).
The induction of DNA damage by UVB is, for example, one effect that is immunosuppressive (Garssen et al., 2000) and that could not be induced by vitamin D3 alone. The development of UVB-induced systemic immunosuppression requires, as one component of a cascade of changes, the formation of pyrimidine dimers in the skin and the migration of DNA-damaged cells to RLNs (Garssen et al., 2000). The UVB-induced formation of cyclopyrimidine dimers in KCs is, furthermore, involved in the UVB-induced increases in IL-10 output by KCs (Nishigori et al., 1996). The enhancement of DNA repair, in UV-irradiated skin, is also known to decrease the systemic immunosuppressive effects of UVB (Garssen et al., 2000). It is notable that 1,25(OH)2D3 and its analogs increase, in various cell types, the protein content of p21CIP1/KIP1/WAF1 (Gumireddy et al., 2003), a protein that induces cell cycle arrest and allows for DNA repair to occur (Weinberg et al., 2002). In the context of DNA damage, 1,25(OH)2D3 could therefore be expected to actually lessen the immunosuppressive effects of UVB.
Apart from the effects of 1,25(OH)2D3 in the CNS (Garcion et al., 2002), UVB-induced immunosuppression has also been investigated only in lymphoid organs that drain tissues outside the brain. The suppressor cells that appear in the spleen, following UVB-irradiation of the skin (Schwarz et al., 2004), may be partially the result of APC migrating from the CNS, and some of these suppressor cells may have been specific to CNS-associated antigens. This possibility has never been evaluated. The UVB-induced expansion of various populations of regulatory T-cells (Schwarz et al., 2004), which have the potential to induce antigen-nonspecific, IL-10-dependent, bystander suppression of other T-cells (Schwarz et al., 2004), and altered APC (Dumas et al., 2000) in RLNs could indeed, as proposed by others (Sharpe, 1986), gradually reinforce tolerance to myelin-associated antigens. These "skin-to-body-to-brain" changes could occur by the mechanisms previously described (Dumas et al., 2000; Sharpe, 1986) and are likely to contribute to UVB-induced neuroimmunomodulation. An example of this type of effect was the amelioration of lupus-associated neuropsychiatric symptoms, and the normalization of the uptake of 18F-2-fluoro-2-deoxyglucose in specific brain regions, by UVA-1 phototherapy in a patient with lupus (Menon et al., 2003). These changes were accompanied by improvements in the clinical lupus scores (Menon et al., 2003). Other studies have found UVA-1-induced reductions in systemic autoantibody titres in patients with lupus (Polderman et al., 2004), reductions that have sometimes been accompanied by improvements in cognitive functioning (McGrath Jr., 2005). Thus, it is reasonable to think that the reductions in autoantibody production occurred primarily in the blood, as a result of UVA-1-induced immunosuppressive changes in the skin, and produced, for example, secondary decreases in endothelial cell activation in cerebral blood vessels. It is also understandable that researchers have traditionally examined UVB-induced changes in T-cells and APC, in the spleen or the lymph nodes draining the skin, with reference to the skin. Given that the skin is used as the initiation and elicitation site for the examination of these protein antigen-specific or hapten-specific immune responses, the focus on skin-derived APC and skin-associated immunity is entirely appropriate. However, researchers have found that UVB can increase the expression of immediate early genes (Gillardon, Wiesner, and Zimmermann, 1992) and the concentrations of neuropeptides in the dorsal horn (DH) of the spinal cord (Gillardon, Schrock, and Morano, 1992). UVR can also influence the mRNA and protein contents of neuropeptides and immediate-early gene products in primary afferent neurons, both in the cell bodies in the dorsal root ganglia (DRG) (Gillardon et al., 1991) and the peripheral branches that innervate the UV-irradiated skin (Benrath et al., 1995; Eschenfelder et al., 1995). The changes in the DH, which occur through UVR-induced actions on DRG sensory C-fibers, could cause immunosuppressive changes to proceed in a "skin-to-brain-to-body" direction. Specifically, the UVB-induced increase in the content of the neuropeptide CGRP in the DH could contribute to the apparent protection against MS.
UVB-induced systemic immunosuppression is known to depend on the neurogenic release of the neuropeptide -calcitonin gene-related peptide (CGRP, or CGRP) into the skin (Kitazawa et al., 2000; Garssen et al., 1998; Hart et al., 2002; Khalil et al., 2001; Niizeki et al., 1997; Legat et al., 2004), but the UVB-induced changes in the CGRP content in the DH and DRG have primarily been viewed in the context of UVB-induced hyperalgesia (Gillardon et al., 1991; Gillardon, Wiesner, and Zimmermann, 1992; Gillardon, Schrock, and Morano, 1992). CGRP that is released from the epidermal or dermal terminals of C-type afferent nociceptive fibers is known to exert, by direct and indirect mechanisms, immunosuppressive effects on APC in the skin (Kitazawa et al., 2000; Niizeki et al., 1997). However, the immunosuppressive implications of the UVB-induced increases in CGRP levels in the spinal cord remain unexplored.
In the context of MS, it is noteworthy that the increased CGRP concentrations, following UVB, in the vicinity of both the peripheral terminals (in the skin) and central terminals (in the DH) of DRG neurons may be partially dependent on NGF. UVB has been shown to increase the expression and release of NGF by keratinocytes (Gillardon et al., 1995) and modify the abundance of NGF receptors on keratinocytes (Bull et al., 1998) and epidermal nerve terminals (Bull et al., 1998). Researchers have also hypothesized that the increased retrograde axonal transport of NGF, from the skin to the cell bodies of DRG neurons, contributes to the UVB-induced increases in CGRP levels in the DH (Gillardon et al., 1995). Although this may be the case, other mechanisms could also be important. The release of NGF from KC, perhaps in concert with the UVB-induced changes in the p75NTR content on the peripheral branches of DRG neurons (Bull et al., 1998), could, by increasing the firing rate of DRG neurons, augment CGRP release, from the central terminals of DRG neurons, or produce phenotypic changes in the cell bodies of DRG neurons. UVR is known to induce C-fibers (Andreev et al., 1994; Eschenfelder et al., 1995; Szolcsányi, 1987) and DH neurons (Urban et al., 1993; Chapman and Dickenson, 1994) to fire, spontaneously, at low-frequencies, and the orthodromic action potentials in C-type, DRG axons are therefore the most obvious "cause" of the UVB-induced release of CGRP from the central terminals of those DRG neurons. The broader question, which will be explored in this paper, is which factors, induced by UVB in the skin, are responsible for the spontaneous action potentials and which factors may help replenish the stores of CGRP, at the central and peripheral terminals of DRG neurons, that are depleted by the UVB-induced, spontaneous activity. KC-derived NGF could exert these effects without undergoing axonal transport to the DRG. NGF, induced in the skin by inflammatory stimuli other than UVR, is known to contribute to spontaneous activity in C-fibers (Djouhri et al., 2001). In addition, exogenous NGF can exert rapid effects on C-fibers, such as the sensitization of C-fibers to capsaicin, that could contribute to hyperalgesia and spontaneous activity (Mendell et al., 2002). Some indirect evidence supports the notion that NGF participates in the UVB-induced increases in C-fiber activity (Khalil et al., 2001), but a UVB-induced increase in the axonal transport of NGF is more hypothetical.
The damage induced by experimental autoimmune encephalomyelitis (EAE) has been found to be less severe after the intracerebroventricular (i.c.v.) injection of exogenous NGF (Triaca et al., 2005) and more severe in rats either autoimmunized against NGF or injected with an anti-NGF antibody. In EAE, an NGF antibody augmented the infiltration of the CNS by pro-inflammatory cells of the immune system (Micera et al., 2000) and appeared to act on progenitor cells participating in the repair of damaged areas (Triaca et al., 2005). The expression and release of CGRP by DRG neurons and B-cells is increased by NGF (Bracci-Laudiero et al., 2002), and many of the anti-inflammatory effects of NGF may be secondary to this CGRP (Bracci-Laudiero et al., 2002). From the standpoint of UVR, the ongoing release of CGRP in the dorsal horn may be accompanied by the release of BDNF. This is because BDNF is known to be co-released with CGRP and SP from the central terminals, in the DH, of C-type, DRG neurons (Malcangio et al., 2003). CGRP has been shown to decrease the severity of experimental autoimmune diabetes (EAD) (Sun et al., 2003) and experimental autoimmune retinitis (Kezuka et al., 2004) and to exert numerous immunosuppressive effects on dendritic cells (Carucci et al., 2000), monocytes (Fox et al., 1997), and T-cells (Boudard et al., 1991). Vitamin D3 could also contribute to the UVB-induced increases in NGF and CGRP. 1,25(OH)2D3, the hormonal form of vitamin D3, and its analogs have been shown to increase the expression of NGF and the abundance of the NGF protein in various cell types, including DRG neurons (Riaz et al., 1999). In addition, the VDR is expressed in lamina I-II of the spinal cord (Stumpf et al., 1988). Thus, 1,25(OH)2D3, produced locally in the skin, or in an autocrine or paracrine fashion in the peripheral or central nervous system, may contribute to the UVR-induced effects on DRG and DH neurons.
This paper will discuss the mechanisms and immunological implications of the UVB-induced increases in the CGRP content of the spinal cord. Specifically, the increased storage and release of CGRP could produce immunosuppressive effects, in the CNS, that would be protective against multiple sclerosis. The UVB-induced increases in CGRP could decrease the release of pro-inflammatory cytokines by Th1 cells, infiltrating the spinal cord, or suppress the antigen-presenting capacity of microglia and infiltrating monocytes. In the DH, UVB-induced release of neuropeptides may also induce the migration, from the CNS, of dendritic cells that are deficient, either because of immaturity and premature migration or because of phenotypic changes induced by CGRP, in their costimulatory capacity. It is also noteworthy that UVR has been shown to exert antihyperalgesic effects in the context of chronic pain (Kaur et al., 2005b) and to produce reinforcing or reward-associated effects on humans (Gambichler et al., 2002a; Feldman et al., 2004; Kaur, Liguori, and Fleischer et al., 2006; Kaur, Liguori, and Lang et al., 2006; Zeller et al., 2006). The supposed rewarding effect of UVR has, however, never been discussed in the context of the known effects of UVR on DRG and DH neurons. There is evidence that UVB can induce the release of -MSH, from the pituitary, via a kind of neurogenic cascade involving the activation of TG neurons, fibers that innervate the cornea and comprise part of the ophthalmic branch of the trigeminal nerve, ciliary ganglion (CG) neurons, and hypothalamic neurons (Hiramoto et al., 2003). In view of these findings, it is possible that the spino-trigemino-parabrachio-amygdaloid and spinohypothalamic pathways may be involved in both the hyperalgesic and antihyperalgesic effects of UVR. The relevance of these possibilities to immune deviation (i.e. immune privilege), across multiple brain regions, will also be briefly discussed. Finally,1,25(OH)2D3, produced locally in the skin or in the DRG and spinal cord from 25(OH)D3 in the systemic circulation, may modify the effects of UVR on CGRP and on the spinal cord. The oral administration of CB1093, a vitamin D analogue, has been found to increase, in an NGF-dependent manner, the CGRP content in sciatic nerve segments of rats (Riaz et al., 1999).
Effects of UVB On Cutaneous Sensory Fibers and the Firing Rates of DRG Neurons
Exposure to UVB increases the content of CGRP alone (Seike et al., 2002) or both CGRP and SP (Legat et al., 2002; Legat et al., 2004) in cutaneous sensory nerve fibers and causes the release of these neuropeptides into the skin (Niizeki et al., 1997). The dermis and basal layer of the epidermis are innervated by the peripheral axons of primary afferent neurons (PANs), whose cell bodies are in the dorsal root ganglia (DRG) (Burbach et al., 2001; Schulze et al., 1997; Reilly et al., 1997). Approximately one million nerve fibers innervate the skin (Krogstad, 1999). UVB has been found to increase the percentages of epidermal nerve fibers that are immunoreactive for CGRP (Legat et al., 2004) and to induce the release of CGRP from nerve terminals into the epidermis (Legat et al., 2004) and the dermis (Niizeki et al., 1997). Researchers have found increases in the release of CGRP from epidermal and dermal afferent fibers, as indicated by an elevated concentration in the skin, that appear as soon as two hours after a single exposure to UVB (Gillardon et al., 1995) and persist for up to seven days (Legat et al., 2004) after the end of a course of multiple exposures. Single exposures to UVB have been shown to increase the content of CGRP in cutaneous fibers at 24 hours (Seike et al., 2002) post-irradiation. Similarly, twelve exposures to UVB over the course of a month roughly tripled the percentage of epidermal fibers containing CGRP (Legat et al., 2004). This peak in CGRP in response to chronic UVB occurred 24 hours after the final UVB treatment (Legat et al., 2004). Although Gillardon et al. (1995) found that UVB transiently reduced the concentration of CGRP in the skin of rats, this decrease was attributed to the UVB-induced release of CGRP from cutaneous nerve fibers (Gillardon et al., 1995). The timecourse of this decrease in CGRP, which emerged as soon as two hours post-irradiation (Gillardon et al., 1995) and began to rebound after 24 hours, has been interpreted as a transient depletion of stored CGRP from epidermal sensory nerve terminals (Gillardon et al., 1995). In the ears of rats exposed to UVB for four weeks, with three low-dose exposures per week, Legat et al. (2002) found data consistent with an adaptive increase in the storage of CGRP per sensory fiber in the epidermis and dermis. Seike et al. (2002) also found an increase in CGRP content within nerve fibers innervating the upper dermis and epidermis at 24 hours after single UVB exposures. These increases became proportionally more pronounced, increasing in a dose-dependent fashion, as the dose of UVB was increased from 0.3 to 0.5 J/cm2, although the increase in the CGRP content appeared to plateau as the dose was increased from 0.5 to 0.7 J/cm2 (Seike et al., 2002). Legat et al. (2002) suggested that the long-term increases in CGRP storage and release, which have been shown to appear after 24 hours and may persist for seven days after the final UVB exposure, are due to the anterograde transport of newly-expressed CGRP from the DRG.
The baseline firing rates and firing thresholds of both thinly-myelinated A-type fibers and unmyelinated C-fibers are sensitive to UV exposure (Andreev et al., 1994) and are likely to be most directly involved in the UVR-induced changes in CGRP content and release. Eschenfelder et al. (1995) found that exposure to a combination of UVB and UVA caused over 35 percent of high-threshold mechanoreceptive C-fibers in the saphenous nerve to exhibit a low-frequency (0.8-1.25 Hz), spontaneous firing pattern. This type of firing pattern, which can occur in the context of UVR exposure and other models of peripheral inflammation, is spontaneous in the sense that endogenous, physiological factors or conditions have become capable of inducing a receptor potential and, thereby, eliciting an orthodromic action potential. The firing of C-fibers at frequencies between 0.1 and 1 Hz, for example, does not produce a sensation of pain (Lynn and Shakhanbeh, 1988; Gybels et al., 1979), may produce a sensation of itch (Torebjörk, 1974), and does produce vasodilation (Lynn and Shakhanbeh, 1988). This spontaneous activity had begun at 24 hours postirradiation, had peaked after 72 hours, and was still slightly increased, above baseline, after 96 hours (Eschenfelder et al., 1995). In rabbits whose shaved ears were exposed to UVR, Szolcsányi (1987) found that polymodal nociceptive C-fibers innervating the irradiated skin of the ear developed a low-frequency pattern of activity. This background activity, at 6.64 impulses per minute or an arithmetic mean of roughly 0.1 Hz, was measurable within five hours post-irradiation in the vast majority of the C-fibers analyzed, although one of the fibers had begun to exhibit activity as soon as 30 minutes after UVR (Szolcsányi, 1987). When bradykinin was administered into the greater auricular artery of UVR-pretreated rabbits, Szolcsányi (1987) found an increase, compared with nonirradiated controls, in the total number of impulses and the "duration" of bradykinin-induced spontaneous activity in polymodal nociceptive C-fibers. These results indicate that UVR can rapidly produce both spontaneous depolarization of C-fibers and sensitization to a given concentration of a substance, such as bradykinin, that is known to induce depolarization. These concepts will subsequently be discussed in more detail. All of the fibers analyzed by Szolcsányi (1987) were fibers of the greater auricular nerve, whose cell bodies are in the cervical DRG in humans. Andreev et al. (1994) found, similarly, that UVR exposure to the rat hindpaw caused C- and A-type fibers of the saphenous nerve to exhibit low-frequency (6-108 discharges per minute, or an arithmetic mean of 0.1-1.8 Hz), spontaneous activity. This ongoing activity, measured at five days post-irradiation, was reduced by the application of morphine and other opioid receptor ligands (Andreev et al., 1994). As discussed below, other anti-hyperalgesic drugs have been shown to influence the UVR-induced sensitization of nociceptive and mechanoreceptive fibers.
Effects of UVB on Neurons in the DRG and DH
In addition to producing changes in sensory fibers in the skin, UVB has been shown to influence the expression of CGRP in the cell bodies of neurons in the DRG (Gillardon et al., 1991) and the content of CGRP in the DH of the spinal cord (Gillardon et al., 1992). Hindpaw exposure to UVB has been shown to decrease the expression of CGRP mRNA in the L3 and L4 DRG (Gillardon et al., 1991) and increase the protein content of CGRP in the medial portion of the superficial dorsal horn (i.e. laminae II-IV), in the L4-L5 lumbar segments (Gillardon et al., 1992). These changes, which were maximal at roughly the same times at which the UVB-induced erythemal skin responses were maximal, were measured in the DRG at 48 hours post-UVB (Gillardon et al., 1991) and, in the DH, from 24 to 96 hours post-UVB (Gillardon et al., 1992). The concentration of CGRP in the DH had increased to 150-160 percent of controls at the first measurement, taken at 24 hours post-UVB, and was still somewhat elevated at both 48 and 96 hours post-UVB (Gillardon et al., 1992). Compared with non-irradiated rats, the UVB-irradiated rats showed both an increase in CGRP and a relative decrement in a higher-molecular-weight CGRP "precursor" (roughly 14.4 kDa) (Gillardon et al., 1992). The increase in CGRP was therefore suggested to have been, in part, a result of the UVB-induced proteolysis of CGRP precursor peptides (Gillardon et al., 1992). The findings may also have resulted from a relative increase in the translation of CGRP, given that CGRP peptides are encoded by mRNA splice variants of mRNA transcripts of the calcitonin (CT) gene.
The effects of low-dose, daily UVB exposure on CGRP release, together with the suppressive effects of UVB on sensory fiber CGRP content in people with psoriasis, are consistent with a longer-term, adaptive decrease in neurogenic inflammation. Legat et al. (2002) found that four weeks of low-dose UVB exposures, given at three times per week, increased the content of CGRP per nerve fiber. However, as noted by the authors, this increase was not accompanied by ongoing, persistent inflammation and edema in the exposed skin (Legat et al. 2002). The authors noted that UVB may, after repeated exposures, decrease the release of CGRP from nerve fibers innervating the exposed skin (Legat et al., 2002). In patients with different subtypes of psoriasis or eczema, UVB decreased the numbers of nerve fibers containing CGRP and also decreased the overall density of nerve fibers (i.e. including those that did not contain CGRP) (Wallengren and Sundler, 2004). Given that the remaining nerve fibers were thicker, Wallengren and Sundler (2004) suggested that UVB had remodeled, rather than produced degeneration in, the sensory innervation of the epidermis and dermis. Wallengren and Sundler (2004) noted that histamine, and the mast cells releasing it, can activate sensory fibers but can also lead to desensitization and neuropeptide depletion in sensory fibers. It was also found that UVB reduced itch and inflammation in the skin of patients (Wallengren and Sundler, 2004), a finding that is consistent with the known antipruritic effects of UVB (Gilchrest et al., 1979; Lim et al., 1997; Holme and Mills, 2001; Kaptanoglu and Oskay, 2003). The suppression of itch was attributed to the UVB-induced changes in cutaneous sensory fibers (Wallengren and Sundler, 2004). Although UVB has been shown to inhibit both the weal and flare responses that are produced by mast cell-derived histamine (Fjellner and Hägermark, 1982), Wallengren and Sundler (2004) noted that UVB often suppresses pruritus in people who have not responded to antihistamines. Consistent with this assessment, Holme and Mills (2001) found that UVB reduced pruritus in a woman whose pruritis had not responded to antihistamines. Interestingly, the woman had also responded to, but had not been able to tolerate, transcutaneous electrical nerve stimulation (Holme and Mills, 2001). Kaptanoglu and Oskay (2003) also found UVB to be effective as an antipruritic in a person who was no longer responding to antihistamines. Together with other findings, which will be discussed in a subsequent section, it should become clear, as noted by Wallengren and Sundler (2004), that the UVB-induced suppression of the weal and flare, components of the so-called axon reflex, cannot be easily attributed to a process such as histamine tachyphylaxis (Wallengren and Sundler, 2004). The relative "histamine-independence" of the UVB-induced antipruritic effects may, for example, result from the central suppression of itch (i.e. in the spinal cord). When UVB is administered to only part of the body surface, the suppression of pruritus is known to be "systemic" and generalized accross the entire body surface (i.e. extending to unexposed sites) (Gilchrest et al., 1979).
UVR has also been shown to influence the concentration of substance P (SP) and the activation of one of its receptors, the neurokinin-1 receptor (NK1R), in the dorsal horn (Polgár et al., 1998; and Thompson et al., 1994). When the spinal cords of rats were removed one day after the unilateral exposure of the rats' (right) hindpaws to UVA, Polgár et al. (1998) found that the substance P content was reduced bilaterally in the L4-L5 lumbar segments and was increased, mainly in the contralateral spinal cord, within the T6-T8 thoracic segments. The distribution of SP in the irradiated rats' spinal cords was compared with the distribution found in non-irradiated controls, rather than the distribution that would have been found prior to irradiation in the experimental group (Polgár et al., 1998). The roughly 50 percent decreases in immunoreactive SP in the lumbar DH were similar on both the ipsilateral side, which contained the central branches of DRG neurons innervating and providing afferent inputs from the irradiated skin, and contralateral side and were found in laminae I and II, in deeper laminae of the DH, and in the lateral spinal nucleus (LSN) (Polgár et al., 1998). In the thoracic segments, the increased SP was more pronounced on the contralateral side than on the ipsilateral side and was most striking, both contralaterally and ipsilaterally, in laminae II and III (Polgár et al., 1998). In view of these results, Polgár et al. (1998) suggested that UVA had increased the production of SP in both the lumbar and thoracic segments of the DH but had, additionally, increased the release of SP in only certain areas. The bilateral decrease of SP in the L4-L5 lumbar DH was viewed as evidence of a UVR-induced increase in SP production and release (Polgár et al., 1998), presumably by L4-L5 DRG neurons that received afferent inputs from the ipsilateral hindpaw and entered the ipsilateral dorsal horn at the L4-L5 segments.
It should be noted that the decrease in SP content in the LSN, in the lumbar spinal cord (Polgár et al., 1998), suggests that UVR can modify the activities of neurons in supraspinal sites, such as the periaqueductal gray matter (PAG). Assuming the decrease in SP content in the LSN was due to an increase in SP release from neurons in the LSN, as proposed by Polgár et al. (1998), the release of SP could have occurred from either descending or ascending pathways (Jiang et al., 1999). Electrophysiological studies suggest that LSN neurons, specifically those that project to supraspinal sites and deliver afferent APs to those supraspinal sites, do not receive direct synaptic inputs from DRG fibers entering the spinal cord (Jiang et al., 1999). The ascending LSN neurons are nonetheless activated, in a polysynaptic manner via intervening, DH interneurons, by stimulation of dorsal root fibers (Jiang et al., 1999). LSN neurons project directly to, and form synapses with, neurons in the PAG (Harmann et al., 1988), thalamus (Battaglia and Rustioni, 1992), hypothalamus (Burstein et al., 1987), and amygdala (Burstein and Potrebic, 1993). The afferent activities of these LSN neurons are, in turn, modified, in the lumbar spinal cord, by mediators released from descending axons of neurons in the raphe nuclei and the PAG (Carlton et al., 1985; Masson et al., 1991). An example of a supraspinal pathway that may be activated by UVR is shown in Fig. 4.
The UVR-induced upregulation of the neurokinin-1 receptor (NK1-R) responsiveness of DH neurons (Thompson et al., 1994) is also consistent with an acute increase in SP-mediated effects. The UVR-induced augmentation of NMDA-R responsiveness in the DH (Thompson et al., 1994; ) also suggests that SP release is acutely increased in response to UVR, given that SP is co-released into the DH, from PAFs, with glutamate (Millan, 1999, Section 10.3). The UVR-induced release of SP in the DH could, in fact, be expected to simultaneously produce an acute decrease in SP content, as found by Polgár et al. (1998), and an increase in the responsiveness of DH neurons to NK1-R and NMDA-R activation. The NK1-R is rapidly internalized in response to SP binding, and the NK1-R is also known to also be redistributed to the plasma membrane after the degradation of SP (Millan, 1999, Section 10.3.2.2). The activation of NK1-Rs and NK2-Rs is nonetheless thought to be more important for the initiation of central sensitization than for its prolongation (Millan, 1999, Section 10.3.2.2). The activation of NK1-Rs by SP produces slow depolarization of DH neurons but can increase the fast and more sustained depolarization induced by NMDA-R activation (Millan, 1999, Section 10.3.2.2; Boxall et al., 1998b). Thus, the release of SP by UVR could account for the findings that UVR augments NMDA-R-mediated activation of DH neurons (Thompson et al., 1994; Thompson et al., 1995; Boxall et al., 1998b). For example, the binding of SP to the NK1-R can, by activating the PLC-IP3-DAG cascade, indirectly enhance the increase in intracellular calcium ([Ca2+]i) that is produced by NMDA-R activation (Millan, 1999, Section 10.3.2.2). Additionally, Boxall et al. (1998b) found evidence that NMDA-R activation, induced in the L5 DH by hindpaw UVR, can exert a "primary" role in sensitizing DH neurons to signals that produce slow depolarization. Hindpaw UVR augmented the depolarization of L5 spinal neurons that had been induced by the administration, intrathecally, of an mGluR1/mGluR5 agonist (Boxall et al., 1998b). This increased responsiveness was largely abrogated by the concurrent administration of an NMDA-R antagonist (Boxall et al., 1998b). The activation of group I mGluRs, such as by the mixed mGluR1/mGluR5 agonist that was used in UVR-treated rodents, generally produces the same slow depolarization of DH neurons and gradual elevation of [Ca2+]i that NK1R activation produces, thereby augmenting the sensitization of DH neurons and contributing to hyperalgesia (Boxall et al., 1998b; Millan, 1999, Section 10.3.2.3). Given that hindpaw UVR enhanced the responsiveness of DH neurons to mGluR1/mGluR5 activation at higher doses of the agonist but did not change the EC50 responses to the agonist, Boxall et al., (1998b) suggested that UVR had probably not upregulated the total numbers of binding sites on the DH neurons. The results of the study implied that hindpaw UVR can, as suggested by the authors (Boxall et al., 1998b), increase NMDA-R-mediated transmission in the spinal cord and thereby increase the mGluR1/mGluR5 responsiveness of DH neurons. More specifically, the authors noted that mGluR1/mGluR5 activation could serve to maintain the activation of NMDA-Rs by phosphorylating the receptors and augmenting protein kinase C (PKC) activation, in much the same way as NK1 receptor activation can augment NMDA-R responses in a PKC-dependent fashion (Boxall et al., 1998b). In contrast, agonists at mGluR3, the mRNA of which was increased by UVA in the DH (Boxall et al., 1998), have been shown to produce antinociceptive effects (Millan, 1999, Section 10.3.2.3). UVR might therefore induce both nociceptive and antinociceptive responses in the spinal cord, and the nociception that occurs through slow depolarization, as in response to CGRP or SP or mGluR receptor activation, is likely to interact with fast (i.e. ionotropic), NMDA/kainate/AMPA-R-mediated, glutamatergic transmission.
It is more difficult, however, to definitively account for the UVA-induced changes in SP content on the contralateral side of the DH. Polgár et al. (1998) implicitly suggested that the UVB-induced activation of primary afferent fibers entering and terminating in the ipsilateral lumbar spinal cord could have induced the depletion of SP from primary afferent fibers terminating in, or at least passing through, the contralateral L4-L5 DH. This is plausible and has been referred to as "volume transmission," whereby mediators are released locally but exert actions distant from the site at which the mediators have been released from (Millan, 1999, Sections 4.7 and 10.3.2.3). The contralateral changes could also have been mediated by the excitation or disinhibition of commissural interneurons, which are abundant in the spinal cord (Sugimoto et al., 1990). Neurons receiving inputs from ipsilateral DRG fibers in the superficial laminae of the DH have been shown to cross the dorsal commissure and influence the contralateral DH in a nearly symmetrical manner (Koltzenberg et al., 1999). Thus, in response to UVR, SP released ipsilaterally in the L4-L5 DH would not have had to diffuse across the midline and induce SP release from primary afferent terminals in the contralateral L4-L5 DH.
Other researchers have found that unilateral exposures to UVR can induce bilateral changes in spinal neurons or peripheral, nociceptive fibers. Thompson et al. (1994) found bilateral thermal and mechanical hyperalgesia on the hindpaws of rats that had been given unilateral, hindpaw UVA. The thermal and mechanical sensitivities were less pronounced on the contralateral hindpaws than the ipsilateral paws, but the timecourses for the changes were similar on both hindpaws (Thompson et al., 1994). Boxall et al. (1998) also found that unilateral UVA exposure to the rat hindpaw produced mechanical hyperalgesia and allodynia on both hindpaws. The peaks of hyperalgesia and allodynia in both hindpaws, measured at 24 hours postirradiation, occurred at roughly the same time that bilateral increases in the mGluR3 mRNA content were found in the lumbar dorsal horn (Boxall et al., 1998). At 24 hours post-UVA, the increase in mGluR3 mRNA was highest in laminae II-IV and lamina I of the L5 lumbar segment but was also found in laminae IV-VII (Boxall et al., 1998). The increases were restricted to laminae I-IV by 48 hours postirradiation, when the sensitivities to mechanical stimuli had begun to normalize (Boxall et al., 1998). Similarly, Gillardon et al. (1992) found that UVB exposed unilaterally to rats' hindpaws increased the concentration of junD mRNA in both the ipsilateral and contralateral sides of the lumbar spinal cord. The junD mRNA content at six hours post-UVB was increased to roughly eight times the level found in non-irradiated rats, an increase that was more or less coincident with the neurogenic vasodilation, or flare, and plasma extravasation that UVB had induced in the irradiated skin (Gillardon et al., 1992).
UVR-induced changes in B1 bradykinin receptor (B1-R) responsiveness have also been found in association with hyperalgesia on the contralateral (non-irradiated) hindpaws of rats (Perkins & Kelly, 1993b). Perkins & Kelly (1993b) found that, compared to controls, unilateral UVA increased the thermal hyperalgesia induced in both the ipsilateral and contralateral hindpaws by an intravenously-injected B1 bradykinin receptor (B1-R) agonist. In the absence of treatment with the B1-R agonist, thermal hyperalgesia was only significant on the UV-irradiated (ipsilateral) hindpaw and was still present, following its peak at 48 hours post-UVA, at 96 hours post-UVA (Perkins & Kelly, 1993b). Gougat et al. (2004) found that the thermal hyperalgesia induced by unilateral hindpaw UVA, which could be reduced by up to 85 percent by a small-molecule B1-R antagonist, was only significant on the irradiated side at 48 hours post-UVA. Although the same half-duration dose of UVA (6,210 mJ/cm2) used by both groups of investigators might account for the absence (Gougat et al., 2004) or "subclinical" character (Perkins & Kelly, 1993b) of the observed contralateral hyperalgesia, Perkins & Kelly (1993b) found that the hyperalgesia measured on the contralateral hindpaw was highest at 24 hours post-UVA and had decreased by 48 hours post-UVA. Given this earlier disappearance of BK-R hyperresponsiveness on the contralateral side, contralateral hyperalgesia may have developed in the animals studied by Gougat et al. (2004) and subsided by the 48 hour time point at which the B1-R antagonist was administered.
UVR has also been shown to induce spontaneous activity in, and increases in the excitability of, DH neurons (Urban et al., 1993; Chapman and Dickenson, 1994). In general, the spontaneous activity in DH neurons is induced by C-fiber activity but soon becomes independent of changes in C-fiber activity. In other words, the timecourse of the increases in spontaneous C-fiber activity, induced by UVR exposure, should not be assumed to parallel the increases in the firing rates of DH neurons. Szolcsányi (1987) measured spontaneous APs in PMN C-fibers that began at 30 minutes post-UVR and were well-developed across the interval of 2.5-5 hours post-UVR, but the timecourse of C-fiber activity has not been analyzed across the entire, up-to-7-day timecourse of UVR-induced hyperalgesia and blood flow increases. Eschenfelder et al. (1995) began analyzing the spontaneous APs in C-fibers, which were found to occur at 0.8-1.25 Hz, at 24 hours post-UVB and took daily measurements on each of the four subsequent days. The percentage of C-fibers showing spontaneous activity was highest at 72 hours post-UVB and declined almost to baseline by 5 days post-UVB, but the changes in the activities of C-fibers were not monitored over the first 24 hours following UVB (Eschenfelder et al., 1995). Urban et al. (1993) found that the spontaneous activity of WDR neurons, in the DH, was largely independent of C-fiber inputs at 5-7 days post-UVR, as indicated by the nonsignificant effect of dorsal rhizotomy on WDR neuron activity, but was even somewhat independent, albeit nonsignificantly, over the 1-3 day, post-UVB interval. Thus, the activities of DH neurons do not simply parallel, temporally, the activities of C-fibers. There is also some evidence that the UVR-induced changes in the spontaneous firing rates of DH neurons does not correlate, and may even vary inversely, with the excitability of DH neurons. For example, Chapman and Dickenson (1994) found that the UV-induced augmentation of one form of C-fiber wind-up, which involves measuring the excitability of DH neurons and is thought to reflect central sensitization, increased between 3 and 5 days post-UVR but was accompanied by a nonsignificant decrease in the mean frequency, from 2.5 to 1.86 Hz, of the spontaneous APs in DH neurons in the L1-L3 segments. Similarly, Chapman and Dickenson (1994) measured UVR-induced electrophysiological changes, in the DH, that were consistent with allodynia and that were disconnected from artificially-induced changes in C-fiber activity. Consistent with allodynia, Chapman and Dickenson found decreased thresholds in A fibers innervating the UV-irradiated hindpaw and increased numbers of action potentials induced in WDR neurons in response to a fixed-duration, three-times-threshold stimulation of A fibers. However, the firing of WDR neurons was not significantly augmented, compared to non-irradiated controls, in response to peripheral stimulation of C-fibers (Chapman and Dickenson, 1994). These results indicate that, in the context of central sensitization, the firing rates of DH neurons may increase or decrease in ways that do not reliably correlate with changes in spontaneous C-fiber activity.
From a practical standpoint, it should also be evident that the time post-UVR cannot be used to predict the degree to which UVR-induced hyperalgesia is peripherally-mediated or centrally-mediated. Thompson et al. (1994) found that hindpaw UVR produced an augmentation of A-wind-up, an electrophysiological change that is consistent with allodynia, in the hemisected spinal cords of rats at 24 hours post-UVR. Nociceptive responses that are consistent with central sensitization can therefore be established, in response to UVR exposure, rather quickly. Other results, apart from the effects of UVR, shed light on the capacity for C-fiber activity to rapidly induce central sensitization. Klede et al. (2003) found that 1 Hz stimulation of high-threshold, mechanically-insensitive C-fibers produced punctante SMHA and allodynia that were both centrally-mediated, but only the allodynia was clearly dependent on ongoing C-fiber stimulation. Although the results of Chapman and Dickenson (1994) imply that UVR-induced allodynia can become partially independent of C-fiber activity, the emergence of both allodynia and punctate SMHA after only 30 minutes of C-fiber stimulation (Klede et al., 2003) highlights the rapidity with which central sensitization can emerge and become, particularly in the case of punctate SMHA, partially independent of C-fiber activity.
Bradykinin and Early, UVB-Induced Action Potentials in C-fibers
Other evidence suggests that BK exerts direct effects on nociceptive PAFs, and these effects may contribute to the early induction by UVR of spontaneous activity in C-fibers. In the UVB-irradiated skin of humans, Eisenbarth et al. (2004) found that the neurogenic, axon reflex-associated vasodilation was enhanced, compared to controls, in response to the localized perfusion of B1-R and B2-R agonists into the irradiated skin. While the B1-R agonist-induced, subjective pain ratings were also enhanced at the perfusion site, the vasodilation induced by the BK-R agonists at the infusion site was not augmented by UVB (Eisenbarth et al., 2004). By inserting microdialysis catheters intracutaneously (i.e. intradermally) into the irradiated skin, Eisenbarth et al. (2004) were able to assess BK-R-induced vasodilation at both the site of BK-R agonist perfusion and the skin surrounding the perfusion site. Both sites of analysis were within the boundary of the irradiated skin, and the experiments were performed at 24 hours post-UVB (Eisenbarth et al., 2004). UVB evidently induced an increase in the B1-R or B2-R responsiveness of C-fibers or augmented the release of other C-fiber-activating mediators from KC within the perfusion site. The absence of local vasodilation largely excludes a UVB-induced increase in the responsiveness of ETC or SMC to the direct actions of BK. If UVB had induced BK-R hyperresponsiveness in both C-fibers and ETC or SMC, the BK-R agonists would be expected to have produced non-neurogenic vasodilation at the perfusion site and neurogenically-mediated vasodilation in the skin at which the flare was induced. It is noteworthy that vasodilation both within and surrounding the irradiated skin could be explained by axon reflexes induced by UVB, and Eisenbarth et al. (2004) was, therefore, evaluating the capacity of BK-R agonists to augment UVB-induced axon reflexes within the irradiated site (see Fig. 2). The effects of BK-R agonists that were unique to the UVB-irradiated subjects, and that were not found in non-irradiated controls, can be seen as "UVB-specific."
These and other results suggest that bradykinin may contribute to the spontaneous C-fiber activity induced by UVB. In rabbits whose ears had been exposed to UVR, Szolcsányi (1987) found that the administration of BK into the greater auricular artery produced a greater number and duration of spontaneous action potentials, compared to nonirradiated controls, in polymodal nociceptive C-fibers of the greater auricular nerve. In non-irradiated rabbits, bradykinin injected intra-arterially also induced "spontaneous" activity polymodal nociceptive C-fibers (Szolcsányi, 1987). In the context of the spontaneous APs that were measured in C- and A-fibers of the saphenous nerve at 5 days post-UVR, Andreev et al. (1994) noted that BK and other early mediators were unlikely to contribute directly to the activation of PAFs at such a late time point. As discussed below, however, the early activation of C-fibers by BK and other mediators may be necessary for C-fiber activity to be sustained by UVR-induced, late-phase mediators. For example, authors have proposed that NGF may sustain the release of CGRP and SP from C-fibers (Khalil et al., 2002) or be responsible for the ongoing APs in C-fibers at 5 days post-UVR (Andreev et al., 1994).
Biphasic Increases in Blood Flow: Are The Effects of Prostaglandins Non-neurogenic or Just Non-Activating?
The difficulty arises in attempting to reconcile the rapidly-induced release of CGRP and SP in the irradiated site (Benrath et al., 1995) with the apparent capsaicin-insensitivity of the first 24 hours of UVB-induced erythema. Some investigators have found that UVB induces two phases of increased blood flow within the irradiated site (Benrath et al., 1995; Benrath et al., 2001), and the early and late peaks of erythema were attributed, respectively, to non-neurogenic and neurogenic mediators (Benrath et al., 2001). The early peak increase in blood flow occurred at 1 hour post-UVB in rats (Benrath et al., 1995) and 12 hours post-UVB in humans (Benrath et al., 2001), and the second peak occurred in rats at 24 hours (Benrath et al., 1995) and in humans at 36 hours (Benrath et al., 2001) post-UVB. When human skin was treated with topical capsaicin for four days and was exposed to UVB on the day after the final capsaicin treatment, there was no reduction in blood flow in the irradiated skin until 24 hours post-UVB (Benrath et al., 2001). In part because the first peak of erythema was insensitive to capsaicin pretreatment, which depletes SP and CGRP from C-fiber terminals, it was suggested that primarily the second phase of erythema was neurogenic (Benrath et al., 2001). This neurogenic SP and CGRP release was proposed to be mediated by axon reflexes (Benrath et al., 2001). Given that the UVB-induced increases in HA and prostaglandins have been found to decrease to pre-UVB concentrations within 18-24 hours post-UVB and that the administration of COX inhibitors have been shown to only inhibit erythema within the first 24-36 hours post-UVB, the early phase of erythema was attributed to the non-neurogenic, direct vasodilatory actions of PGs and HA (Benrath et al., 2001).
Although the early phase of UVB-induced erythema is likely to be partially non-neurogenic in origin, there is considerable evidence that neurogenic effects of UVB begin almost immediately after exposure. For example, the increase in blood flow to human skin that was up to 10 mm outside the irradiated border, a neurogenically-mediated effect, began, in the absence of capsaicin pretreatment, at 9 hours post-UVB (Benrath et al., 2001). This is a more telling result than the limited attenuation of the early erythema by capsaicin, in part because the effects of topical capsaicin are less predictable than intradermal capsaicin and are less reliable in humans than in rodents (Szallasi and Blumberg, 1999). For example, Munn et al. (1997) found that topical capsaicin did not alter SP immunoreactivity in the skin of humans. In contrast, intradermal capsaicin was found to produce a pronounced decrease in SP immunoreactivity and degeneration of SP-containing nerve fibers (Szallasi and Blumberg, 1999). Szallasi and Blumberg (1999) also noted that human skin is between 4 and 8 times less permeable to topical capsaicin than rat skin. Benrath et al. (2001) also noted that the topical capsaicin preparation that was used had previously been shown to be too low in potency to completely deplete the stores of neuropeptides from sensory fibers. It is conceivable that capsaicin partially depleted the SP and CGRP stores from C-fibers and that the UVB-induced increases in BK, PGE2, TNF-, IL-1, and other early mediators depleted the remaining stores, thereby explaining the monophasic increase in blood flow, as found by Benrath et al. (2001), in capsaicin-pretreated, UVB-exposed human skin.
The finding that capsaicin pretreatment did not attenuate the UVB-induced thermal hyperalgesia within the first 24 hours post-UVB (Benrath et al., 2001) could also be interpreted as evidence of an early neurogenic effect of UVB. At first glance, this might appear to be consistent with the view that predominantly non-neurogenic mechanisms occur during the first 24 hours. Although a nonsignificant attenuation of the UVB-induced thermal hyperalgesia (THA) was apparent only after a 24 hour delay in capsaicin pretreated skin, the UVB-induced THA increased monophasically over the first 24 hours in capsaicin-pretreated skin and did not begin after a 24 hour latent period (Benrath et al., 2001). An antihyperalgesic effect of capsaicin pretreatment began to emerge after the 24-hour point (Benrath et al., 2001), and this suggests that a minimal desensitization of C-fiber responses occurred in response to capsaicin. In other words, the capsaicin pretreatment may have blunted the CGRP release produced by early, neurogenically-acting mediators. As the CGRP and SP stores were being replenished over roughly the first 24 hours post-UVB, after having been partially depleted by topical capsaicin pretreatment, the newly-replenished CGRP and SP could have produced the monophasically-emerging hyperalgesic and vasodilatory effects found by Benrath et al. (2001). This could have caused the first 24 hours of UVB-induced changes to appear "non-neurogenic," when in fact the C-fibers would have been "running on empty" and have been acted upon by BK and other early mediators.
Although the UVB-induced increases in the concentrations of PGs and HA do return to baseline levels within 24-36 hours, their early effects on C-fibers may contribute to hyperalgesia and neurogenic vasodilation at later time points. Benrath et al. (2001) suggested that UVB-induced HA, PGs and other mediators may have contributed to THA and MHA, by sensitizing C-fibers, during the first 36 hours post-irradiation but that substance P and other C-fiber-derived neuromediators may have sustained the THA after that point. Similarly, Eschenfelder et al. (1995) suggested that HA and PGs induced transiently by UVB were likely to primarily influence the erythemal and edematous responses during the time period, namely the first 8-24 hours, their concentrations were elevated. UVB-induced PGE2 could conceivably have reduced the thresholds, in C-fibers, required for C-fiber-activating stimuli (i.e. heat) or substances to induce action potentials, and this PG-mediated effect could conceivably produce THA without inducing AR-mediated vasodilation. Prostaglandins are known to sensitize C-fibers to subthreshold depolarization without, themselves, inducing APs (Millan, 1999). It is known that COX inhibitors administered more than 24-36 hours post-UVB are ineffective in reducing the erythemal response, but COX inhibitors administered immediately after UVB produced relatively stable anti-erythemal effects over 48 hours (Eschenfelder et al., 1995). It was noted that UVB-induced PGE2 and PGF2 levels may remain elevated up to 48 hours post-irradiation (Eschenfelder et al., 1995), and this could support the suggestion that a mixture of neurogenic and non-neurogenic factors contribute to UVB-induced blood flow, in animals, at the 24-hour time point (Eschenfelder et al., 1995). But given that the anti-erythemal effect of early, COX-inhibitor treatment persisted past the 36 hour point, which corresponded to the more robustly neurogenic, late blood flow peak in humans (Benrath et al., 2001), it is possible that the early effects of PGs on C-fibers facilitate the later, sustained phase of neurogenic inflammation and vasodilation. PGs and HA were not suggested to have been the exclusive or obligatory mediators of the early vasodilatory and hyperalgesic effects (Benrath et al., 2001), and PGs and HA are not the only mediators that are rapidly induced by UVB and that could act on C-fibers. BK, for example, is induced by UVB in a matter of minutes (Kang-Rotondo et al., 1996) and is known to be able to induce action potentials, and not simply induce sensitization, in C-fibers (Banik et al., 2001). Andreev et al. (1994) suggested that the pro-inflammatory cytokines and NGF could have produced the spontaneous activities of C- and A-fibers that they had measured at five days post-UVB. Additionally, the neurogenic vasodilation that was evident in humans at 9 hours post-UVB (Benrath et al., 2001) is a reliable sign that C-fibers were being depolarized, not merely sensitized, and that APs were being induced in them.
Following UVB+UVA exposure to the rat hindpaw, for example, the CGRP content of the skin decreased as soon as 2 hours post-UVR (Gillardon et al., 1995). The decrease in CGRP was nearly maximal by 6 hours post-UVB, was maximal by 12 hours post-UVB, and was starting to increase at 24 hours post-UVB (Gillardon et al., 1995). The authors suggested that UVB had depleted CGRP from the skin by inducing the release of CGRP from cutaneous nerve fibers (Gillardon et al., 1995). Although the early peak in blood flow occurred in rats at 1 hour post-UVB, the early increase had not declined, to a between-peak minimum, until 12 hours post-UVB (Benrath et al., 1995). In the same experiments, the s.c. (systemic) administration of the CGRP receptor antagonist CGRP(8-37), the NOS inhibitor L-NAME, or a combination of the two agents reduced UVB-induced blood flow as soon as 1 hour post-irradiation. The injection of the NK1-R antagonist, CP-96,345, at 1 hour post-UVB also reduced blood flow. Similarly, Eschenfelder et al. (1995) found that each of two SP receptor antagonists, administered separately and intradermally to UVA+UVB-exposed ears, decreased the resulting edema as soon as 6 hours post-irradiation and the erythemal response by 12 hours post-UVB.
When the bimodal qualities of UVR-induced herpesvirus reactivation are viewed in the context of the above controversy, UVR can be seen as inducing two phases of neurogenic changes. In experimental reactivation of HSV by UVB, for example, there is frequently a biphasic pattern to the reactivation and the appearance of lesions (Bernstein et al., 1997; Spruance and Kriesel, 2002; Burkhart and Burkhart, 2005). The first peak occurs at roughly 24 hours post-UVB and has been attributed to HSV reactivation in the skin (Burkhart and Burkhart, 2005). The second peak requires about four days, post-UVB, to occur in humans, and this has been attributed to the time required for anterograde axonal transport, as from the DRG or TG to the skin, of HSV proteins (Burkhart and Burkhart, 2005). The second neurogenic phase induced by UVB may, also in the context of CGRP release, be an "axonal transport phase," in which stores of CGRP and other proteins are transported from the cell bodies of DRG neurons to the peripheral terminals, in the skin via anterograde axonal transport, and the central terminals of DRG neurons. This second phase would replenish the depleted stores of CGRP and allow for other phenotypic changes to occur on DRG neurons.
Central Suppression of Itch by Pain, and Suppression of Both Itch and Pain by UVR
Given that UVB has been shown to suppress pathological itch (pruritus) and induce hyperalgesia, at least acutely, it is possible to view some of the effects of UVR in terms of the inverse relationship between itch and pain (Ikoma et al., 2003). Eisenbarth et al. (2004) found that activation of BK receptors, with the use of BK receptor agonists, did not produce itch sensation in UVB irradiated skin but did produce itch in nonirradiated controls. UVB irradiation did produce sensitization to the neurogenic effects, both in terms of the axon reflex flare and the hyperalgesia, of the BK agonists, and the authors suggested that UVB-induced hyperalgesia may have produced centrally-mediated suppression of itch (Eisenbarth et al., 2004). The generalized, inverse relationship between itch and pain is known to be tied to opiodergic effects (Ikoma et al., 2003), but it is necessary to specify the site at which the change in opiodergic signalling is occcurring. This is currently a difficult task in the context of the effects of UVR, given that the effects of UVR interact with peripheral opiodergic signalling but are also likely to affect spinally and supraspinally mediated opiodergic signalling.
Exposure to UVR has been shown to increase the expression of the proopiomelanocortin (POMC) gene and the production of -endorphin and -lipotropin by KC (Wintzen et al., 1996), and UVR also modifies the responsiveness of PAFs to opioid receptor ligands (Andreev et al., 1994). The interpretation of these findings has, however, been a source of significant confusion. In early research, exposures of large areas of skin to UVR were found to increase the plasma concentrations of -endorphin and other POMC-derived peptides (Levins et al., 1983). Given the large areas of UVR-exposed skin, the UVR-induced release of the peptides from KCs was thought to be extensive enough to increase the systemic concentrations of the peptides. Researchers have not consistently found changes in the concentrations of plasma opioid peptides in UVR-exposed humans (Wintzen et al., 2001; Gambichler et al., 2002b), and a number of relevant issues have not been addressed adequately. Some researchers have found reinforcing or reward-like effects of UVR and have explained the results in terms of an opioidergic effect (Kaur, Liguori, and Fleischer et al., 2006; Kaur, Liguori, and Lang et al., 2006). To the extent that an increase in the plasma concentration of -endorphin or another opioidergic peptide could contribute to these subjective effects, the opioid peptides would have to cross the blood-brain barrier and ultimately exert a generalized augmentation of -opioidergic activity in one or another supraspinal sites. An increase in plasma -endorphin would, most simply, not be a reliable indication of supraspinally-mediated antinociception. Apart from this issue, the increases in plasma opioids and POMC-derived mediators are more likely to be mediated by UVR-induced effects on the spinohypothalamic tract or on other neuronal populations that influence pituitary function. For example, the UVB-induced increase in plasma -MSH, following UVB exposure to the eyes alone, was found to be blocked by hypophysectomy or ciliary gangliectomy (Hiramoto et al., 2003). In addition, both the antipruritic effects of UVB and the effects of UVR on pain thresholds or C-fiber activity are broadly consistent with, at least in the short term, the antagonism of -opioidergic activity.
It is noteworthy that the notion of UVB as rewarding stimulus (Kaur, Liguori, and Fleischer et al., 2006; Kaur, Liguori, and Lang et al., 2006) is generally consistent with the augmentation of anti-nociceptive pathways and is clearly inconsistent with an escalation of centrally-mediated hyperalgesia. Researchers have found evidence that UVR can suppress pain for several hours after exposure (Kaur et al., 2005b) and that UVR can be used to prevent post-herpetic neuralgia (Jalali et al., 2006). While the investigation of UVR-induced antinociceptive and reward-associated effects is a valid avenue of research, one problem seems to be the assumption that the reward-associated effects must be primarily or exclusively opioidergic. This is not the case. Becerra et al. (2001) noted that ascending nociceptive pathways can themselves activate neurons in the ventral striatum and nucleus accumbens, meaning that nociceptive stimuli activate dopaminergically-mediated reward centers in the brain (Gear et al., 1999; Becerra et al., 2001). These effects could occur via the activation of spinothalamic tract neurons or by the direct activation of striatal neurons, given that neurons in the lateral dorsal horn of primates and rats are known to form direct synaptic connections with striatal neurons (Newman et al., 1996)
Gillardon et al. (1992) suggested, explicitly, that the apparent UVB-induced release of CGRP into the DH could both contribute to UVB-induced hyperalgesia and, implicitly, activate descending, -opioidergic, supraspinally-mediated, pathways. Although researchers have not investigated the involvement of specific supraspinal sites in the hyperalgesic or anti-hyperalgesic effects of UVB, it is likely that chronic treatment with UVB, particularly at high-doses, would activate and produce changes in neurons that exert descending influences on nocisponsive, DH neurons.
Although any UVR-induced changes in opioidergic activity in spinal or supraspinal neurons are poorly understood and are likely to be complex, UVR has produced changes in the responses of C-fibers to opioid-receptor (OR) ligands. Andreev et al. (1994) found that the application of either of two -OR agonists, morphine and DAGOL, or the -OR agonist, U-69593, to the peripheral terminals of C-fibers and A-fibers, in UV-irradiated skin, reduced the frequencies of spontaneous APs in the fibers. These reductions, measured at five days post-UVR, were naloxone-reversible (Andreev et al., 1994). These findings are relevant to a discussion of the supposed naltrexone-sensitivity of the addictive or reinforcing effects of UVR. Given that the peripheral, hyperalgesic effects of UVR are naloxone-sensitive, one would expect naloxone to disinhibit and essentially "unblind" the peripheral component of UVR-induced hyperalgesia. The naloxone would clearly be expected to amplify, both at the peripheral and spinal level, the hyperalgesic effects of ongoing UVR. Given that the behavior could be modified by merely the peripheral actions of systemically-administered naloxone, it is inappropriate to conclude that UVR produces some sort of mechanistically-nonspecific, opioidergically- and supraspinally-mediated reinforcing effect.
In the context of multiple sclerosis, it is noteworthy that IL-10, in addition to other mediators, are likely to contribute to both immunosuppressive and antihyperalgesic effects of UVR. The UVB-induced production of IL-10, by APC and other cells, is known to depend on UVB-induced CGRP release (Kitazawa et al., 2000). Given that exogenous IL-10 was found to counteract UVB-induced hyperalgesia (Saadé et al., 2000), it follows that UVB-induced endogenous IL-10 may also contribute to the supposed antihyperalgesic effects of chronic UVB. There is already some evidence that UVB can produce cytokine "cascades," in the cell bodies and central branches of trigeminal ganglion (TG) neurons, that parallel the pattern of UVB-induced cytokine production in the skin. Shimeld et al. (1999) found that UVB induced TNF- and IL-6 production, by satellite cells, in the TG of mock-inoculated mice (i.e. those that had not been infected with HSV). This transient inflammatory response is unlikely to persist, given that IL-6 knockout mice are known to have reduced IL-10 production in response to UVB (Nishimura et al., 1999). TNF-, induced in response to UVB-induced CGRP release, is also known to be required, via the TNF--induced migration of LC, for UVB-induced local immunosuppression (Niizeki et al., 1997). In addition, the UVB-induced synthesis of 1,25(OH)2D3 by KCs is known to be dependent on the UVB-induced increases in the TNF-a content in the skin (Lehman et al., 2004). A similar progression of TNF-- and IL-6-induced anti-inflammatory effects may occur in the spinal cord or other sites in the CNS.
Interactions With Vitamin D-Mediated Effects And Prospects For Further Research
Vitamin D may interact in a number of ways with the neurogenic effects of UVR. The oral administration of the vitamin D analogue CB1093, in a rat model of diabetic neuropathy, was found to increase, compared to untreated diabetic rats, the CGRP, substance P, and NGF protein concentrations in segments of the sciatic nerve (Riaz et al., 1999). In non-diabetic rats, compared to non-diabetic rats not treated with CB1093, the oral CB1093 also increased the content of CGRP and NGF in the sciatic nerve fibers, the NGF content in the soleus muscle, and the NGF mRNA in the skin from the hindlimb foot. The increases in CGRP were thought to be NGF-dependent and secondary to the CB1093-induced increase in the NGF protein content in the sciatic nerve fibers (Riaz et al., 1999).
VDR ligands are also known to induce GDNF and the low-affinity neurotrophin receptor (p75NTR) in various cell types found in the CNS, and these changes could modify the effects of UVR on the spinal cord. VDR ligands have been shown to induce the expression of the low-affinity neurotrophin receptor (p75NTR) in glioma cells (Naveilhan et al., 1996a), the expression and protein content of 75NTR in the developing brain (Eyles et al., 2003), and the p75NTR mRNA content of cultured oligodendrocytes and astrocytes (Baas et al., 2000). The p75NTR receptor binds all members of the neurotrophin family and, in concert with TrkA, is thought to be involved in the retrograde axonal transport, at least by L4 and L5 DRG neurons, of NGF (Delcroix et al., 1997). In the developing brains of rats whose mothers were depleted of dietary vitamin D3, the levels of p75NTR mRNA were reduced by 30 percent and the p75NTR protein content, in four separate brain regions, was almost completely depleted (Eyles et al., 2003). Maternal vitamin D3 depletion also reduced the concentration of the free NGF protein by 17 percent and the concentration of free GDNF by 25 percent (Eyles et al., 2003). Although VDR ligands do not appear to regulate the expression or protein content of BDNF, it is noteworthy that p75NTR is thought to be important for the trophic actions of BDNF. The induction of NGF and perhaps other neurotrophins by 1,25(OH)2D3 in the skin may also contribute to the effects of UVB on DRG neurons. Tacalcitol, a 1,25(OH)2D3 analog, has been shown to increase NGF expression the release of NGF by cultured human keratinocytes (Fukuoka et al., 2001). Fukuoka et al. (2001) suggested that VDR ligands may, by increasing neurotrophin expression in the skin, have potential in the treatment of peripheral neuropathy. It is interesting that GDNF has the potential to treat neuropathic pain (Sah et al., 2005), and GDNF has been found to upregulate CGRP expression by sensory neurons without inducing hyperalgesia (Ramer et al., 2003). 1,25(OH)2D3 has been shown to increase GDNF production by numerous cell types (Naveilhan et al., 1996b).
UVR has also been shown to modify the p75NTR content of sensory fibers (Bayerl et al., 1997; Moll et al., 1994), and these effects may or may not be partially dependent on UVB-induced 1,25(OH)2D3. For example, the p75NTR content in cutaneous nerve fibers was found to be reduced at 24 hours post-UVR in humans with UV-induced dermatitis (Bayerl et al., 1997) and also to be reduced in the dermal nerve fibers of normal humans at 48 hours post-UVB (Moll et al., 1994). The induction of NT-3 and NT-4/5 production in KCs exposed to UVB (Marconi et al., 2003), and the induction of NT-3 production in UVA-irradiated KCs (Marconi et al., 2003), are other effects of UVR that are strikingly similar to the effects of 1,25(OH)2D3 on neurotrophin production (Neveu et al., 1994). 1,25(OH)2D3 was found to upregulate NT-3 and NT-4 production by astrocytes (Neveu et al., 1994). Again, the effects of UVB and UVA on NT-3 are probably independent of 1,25(OH)2D3, but this does not preclude an effect of 1,25(OH)2D3 on KC neurotrophin production or on C-fibers in the skin. Given these remarkable similarities between the effects of VDR ligands and the effects of UVR on neurotrophin production, it is not unreasonable to suspect some local effects of UVB-induced 1,25(OH)2D3 on sensory fibers.
Interestingly, Plotnikoff and Quigley (2003) recently found that 93 percent of people who sought medical treatment for nonspecific, musculoskeletal pain were clinically deficient in vitamin D3. This was consistent with previous reports of muscle pain, occurring in conjunction with muscle weakness, in people with vitamin D3 deficiency (Plotnikoff and Quigley, 2003). Although the musculoskeletal pain in vitamin D3 deficiency was suggested to be secondary to the abnormalities in bone structure that are associated with vitamin D3 deficiency, the pain could also be the result of central sensitization and be explained in terms of the UVB-induced changes in DRG and DH neurons.
Conclusions
In summary, the UVR-induced release of CGRP in the spinal cord is likely to contribute to secondary hyperalgesia, to the antihyperalgesic effects of chronic UVR, to the suppression of pruritus by UVB, and to the reward-associated effects of UVR. CGRP released in the DH and in other spinal and supraspinal sites may also induce immunosuppressive and antihyperalgesic changes in astrocytes, microglia, or dendritic cells in the CNS. In the skin, prostaglandins are likely to sensitize C-fibers to the action-potential-inducing effects of histamine and bradykinin. The low-frequency spontaneous activity induced in C-fibers appears to induce central sensitization in DH neurons, and the firing rates of DH neurons appear to become independent of the firing rates of the C-type neurons that provide direct or indirect (i.e. converging, polysynaptic) inputs to the DH neurons. UVR-induced spontaneous activity in C-fibers has been shown to begin by 30 minutes post-irradiation, and this indicates that the timecourse alone cannot be used to distinguish between primary (peripheral) and secondary (peripheral and central) hyperalgesia. A closer examination of the timecourse, the times post-irradiation at which UVR-induced changes in the peripheral and central nervous systems occur, will nonetheless be important for future research examining changes in astrocytes or microglia. The abundance of evidence suggests that the UVR-induced changes in the CNS should be examined at time points as early as 0.5-2 hours post-irradiation and followed, at various time points, for at least five or more days post-irradiation. The immunological changes in the lymph nodes draining the CNS, such as in the posterior cervical triangle, may require considerably more time to appear.
With regard to multiple sclerosis and the generalized immunological effects of centrally-released CGRP, a number of additional conclusions follow from the experimental results discussed in this paper. First, the exposure of UVB or UVA to the eyes is likely to be especially perilous for individuals with multiple sclerosis. Although it is well known that essentially no UVB wavelengths penetrate deeper than the cornea and that little UVA penetrates deeper than the iris and lens (Sliney, 1997), the cornea is densely innervated by, for example, sensory fibers whose cell bodies are in the TG. The classical map of somatosensory "two-point discrimination" can be used as a crude indicator of the potential for direct, neurological damage induced by UVB or UVA exposure, and casual exposure of the face, and particularly the eyes, should probably be aggressively avoided by individuals with MS (i.e. given the potential, via polysynaptic changes induced by UVR through the TG, caudal trigeminal nucleus, and ciliary ganglia-to-Edinger-Westphal nucleus, for brainstem damage or neurovascular events and increases in BBB permeability). The effects of UVR on the CNS are likely to be especially potent following exposure to the eyes and, additionally, especially difficult to research, given that most sun-derived UVR reaches the surface of the eyes as diffuse UVB and UVA (i.e. after Rayleigh and Mie scattering by gases in the atmosphere of the Earth) (Sliney, 1997). Diffuse UVR would be exceptionally difficult to produce by artificial light sources, and the application of direct UVB or UVA from an artificial source would be potentially so damaging, not only to the eyes but also to the CNS, as to be unethical.
Notwithstanding these conclusions, it is possible that CGRP release, either related to or dependent on NGF trafficking from the skin, plays some role in the protection against MS among individuals younger than a certain age. Although UVR is unlikely to be useful in a therapeutic context, the involvement of NGF and CGRP in UVR-induced neuroimmunology could have implications for the use of vitamin D receptor analogs in MS. The NGF-inducing effects of VDR ligands have not previously been viewed as being relevant to the protection against MS, but the NGF-dependent augmentation, by VDR ligands, of CGRP production in the CNS is likely to have therapeutic implications for MS. Given that cutaneous UVR exposure is likely to exert complex, polysynaptic changes in the activities of various neuronal populations throughout the CNS, future research in rodents should focus on the synaptic actions, rather than increases in the plasma concentrations, of -MSH and other POMC-derived peptides.
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