Multiple Revisions of an Old Paper of Mine

I guess this is the end of this [(http://www.mediafire.com/?410jmzmrjjm); (http://hardcorephysiologyfun.blogspot.com/2009/06/folate-and-uvb-papers-in-pdf-format.html); (http://hardcorephysiologyfun.blogspot.com/2009/05/another-old-paper-of-mine.html); (http://hardcorephysiologyfun.blogspot.com/search/label/UVB)]. Maybe I'll try it elsewhere, at some point in the future. In any case, it wasn't really for my benefit that I did these, and it's not going to benefit me in the future. The dermatologists wouldn't like it, and the neurologists wouldn't like it, either. But the mechanisms are relevant to biology in general.


Multiple Sclerosis and Ultraviolet Radiation (UVR): Can UVR Exert Immunomodulatory Effects in the CNS Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?

Bains [1], in a recent and very interesting article, noted that excessively-direct exposure of the eyes to ultraviolet radiation (UVR) could cause optic neuritis and contribute to the development of multiple sclerosis (MS) in some people, and additional research lends credence to that hypothesis and sheds light on some mechanisms by which neurogenic effects of UVR could influence immunological processes in the brain. Cutaneous exposure to either ultraviolet B (UVB) or ultraviolet A (UVA) increases the concentrations of inflammatory mediators in the skin [2,3], and these mediators can then act on primary afferent neurons (PAN’s) innervating the skin and increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin [2,3] and also in the dorsal horn (DH) of the spinal cord [4,5]. Researchers have suggested that UVR may be able to modify brain function by direct or indirect, neurogenic mechanisms [6-13], and UVR could, by increasing the percentages of spontaneously-active PAN’s, either augment or suppress the immune and inflammatory responses of microglia and dendritic cells in the central nervous system (CNS).
UVR can increase the release of cytokines and neurotrophins and other mediators from keratinocytes and mast cells in the skin [14, 15], and these mediators can then depolarize and induce spontaneous action potentials (APs) in C-fibers [2,16,17] and A-fibers [16] innervating the exposed skin [2,16,17]. The APs are likely to be largely asynchronous [18], can begin as soon as 30 minutes after exposure [17] and persist for five days [2,16], and can occur at low frequencies of 0.8-1.25 Hz [2] or at comparable freqencies [16,17]. Thus, UVA-induced APs in trigeminal ganglion (TG) neurons may have contributed to the visual-evoked potentials measured in humans [19] and the rapid emergence of changes in the pineal gland [20] or suprachiasmatic nucleus [9] in hamsters or rats, respectively.

The release of neuropeptides into UVR-exposed skin is likely to occur through axon reflexes [21-23] or dorsal root reflexes. In an axon reflex, it is thought that an afferent (and, here, orthodromic) AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent (and, here, antidromic) direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber [24]. In a dorsal root reflex, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber [24]. The complex, UVR-induced changes in the expression, formation, and release of CGRP and SP, in the DH, are likely to result from changes in the patterns of orthodromic and antidromic APs that PAN’s, in the dorsal root ganglia (DRG) or TG, exhibit following UVR [3-5,25].

TG and DRG neurons are likely to serve as the primary inputs for the apparently-polysynaptic pathways by which UVR can alter neuronal activity in the CNS. UVR can cause neurons in the DH to fire spontaneously [26,27], to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission [26-29], and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS [5,6,9,10,30-35] in animals or humans. The apparent effects of UVB or UVA on the brain [6,9,10,32,35] have sometimes been blocked by ciliary ganglionectomy [10], optic nerve (ON) transection [7] or denervation [8], hypophysectomy [8,10], or orbital enucleation [6,9]. Despite the evidence suggesting that UVR induces APs in ON fibers [6-9], ocular UVB is known to reliably induce Herpes simplex virus reactivation in the TG [36] and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. [10] suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears [10,32] were likely to have been mediated by the activation of TG neurons, in the ophthalmic branch of the trigeminal nerve (V1), and also by neurons in the ciliary ganglion/ganglia (CG) [10], and, consistent with this, some neurons in the caudal trigeminal nucleus (Vc) project to the hypothalamus and receive monosynaptic inputs from TG neurons innervating the facial skin [37].

In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised [19,20], it is relevant that only ~ 2 percent of UVB reaches the lens in the intact eye and that almost all of the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor [38]. Sliney et al. [38] noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum [39], can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by excised ocular tissues [19,20]. The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses [19], but neither UVA nor UVB is likely to act directly on cells in the retina. Most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules [38], and any prolonged exposure of the eyes to direct UVR could damage corneal C-fibers or A-fibers, impact neurotransmission in the brain by atypical mechanisms, or, as noted by Bains [1], contribute to the development of optic neuritis.

The axons of many neurons in the TG or CG or accessory CG, in rats [40] and some mice [41] and also humans [42], extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON [41], just posterior to the globe, and it is possible that the ON denervation or transection or ciliary ganglionectomy procedures [6,8-10] damaged some axons of neurons in the CG, accessory CG, or TG. Most of the TG neurons that innervate the corneas are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, a subdivision of V1 [40], and many of the TG neurons pass through the CG without forming synapses [40].

The neurogenic release of CGRP in the skin contributes to UVB-induced systemic immunosuppression [25,43] and to visible-light-mediated immune privilege in the eyes [44], and the UVR-induced release of SP and CGRP in the CNS could act on microglia or dendritic cells and either promote tolerance to CNS-specific antigens, such as in people who do not have MS, or exacerbate the course of MS. Following UVR exposures to rodents, researchers could evaluate, with an eye to the relevance to MS, phenotypic changes in dendritic cells that migrate from the CNS to the cervical lymph nodes [45] or site-specific changes in microglial activation in the CNS.

References

[1] Bains W. Exposure of the eyes to near-horizon sunshine may be a trigger for multiple sclerosis. Med Hypotheses 2009, doi:10.1016/j.mehy.2009.09.054
[2] Eschenfelder CC, Benrath J, Zimmermann M, Gillardon F. Involvement of substance P in ultraviolet irradiation-induced inflammation in rat skin. Eur J Neurosci 1995;7(7):1520-6.
[3] Legat FJ, Griesbacher T, Schicho R, et al. Repeated subinflammatory ultraviolet B irradiation increases substance P and calcitonin gene-related peptide content and augments mustard oil-induced neurogenic inflammation in the skin of rats. Neurosci Lett 2002;329(3):309-13.
[4] Gillardon F, Schrock H, Morano I, Zimmermann M. Long-term increase in CGRP levels in rat spinal dorsal horn following skin ultraviolet irradiation. A mechanism of sunburn pain? Ann N Y Acad Sci 1992;657:493-6.
[5] Polgar E, Szucs P, Urban L, Nagy I. Alterations of substance P immunoreactivity in lumbar and thoracic segments of rat spinal cord in ultraviolet irradiation induced hyperalgesia of the hindpaw. Brain Res 1998;786(1-2):248-51.
[6] Amir S and Robinson B. Fos expression in rat visual cortex induced by ocular input of ultraviolet light. Brain Res 1996;716(1-2):213-8.
[7] Hiramoto K, Mashita Y, Katada T, Konishi H, Sugiura M, Hayakawa R. Immunosuppression by ultraviolet B rays via eyes in mice. Arch Dermatol Res 1997;289(12):709-11.
[8] Inoue M, Hiramoto K, Park A, Sato EF. UV-Irradiation down-regulates immune functions and causes fatigue by photo-optico-neuronal network: lessons from iNOS-knockout mice. Neurochem Res 2004;29(8):1582.
[9] Amir S and Robinson B. Ultraviolet light entrains rodent suprachiasmatic nucleus pacemaker. Neuroscience 1995;69(4):1005-11.
[10] Hiramoto K, Yanagihara N, Sato EF, Inoue M. Ultraviolet B irradiation of the eye activates a nitric oxide-dependent hypothalamopituitary proopiomelanocortin pathway and modulates functions of alpha-melanocyte-stimulating hormone-responsive cells. J Invest Dermatol 2003;120(1):123-7.
[11] Ericsson AD, Dora J, Cao S. Melanocytes: morphological basis for an exteroceptive sensory system for monitoring ultraviolet radiation. Physiol Chem Phys Med NMR 2003;35(1):27-42.
[12] Taylor SL, Kaur M, LoSicco K, et al. Pilot Study of the Effect of Ultraviolet Light on Pain and Mood in Fibromyalgia Syndrome. The Journal of Alternative and Complementary Medicine 2009;15(1):15-23.
[13] Rogers SC, Shuster S, Marks JM, Penny RJ, Thody AJ. The effects of photochemotherapy on endocrine secretion in patients with psoriasis. Acta Derm Venereol 1981;61(4):350-2.
[14] Saade NE, Farhat O, Rahal O, Safieh-Garabedian B, Le Bars D, Jabbur SJ. Ultraviolet-induced localized inflammatory hyperalgesia in awake rats and the role of sensory and sympathetic innervation of the skin. Brain Behav Immun 2008;22(2):245-56.
[15] Streilein JW, Alard P, Niizeki H. Neural influences on induction of contact hypersensitivity. Ann N Y Acad Sci 1999;885:196-208.
[16] Andreev N, Urban L, Dray A. Opioids suppress spontaneous activity of polymodal nociceptors in rat paw skin induced by ultraviolet irradiation. Neuroscience 1994;58(4):793-8.
[17] Szolcsanyi J. Selective responsiveness of polymodal nociceptors of the rabbit ear to capsaicin, bradykinin and ultra-violet irradiation. J Physiol 1987;388:9-23.
[18] Ikeda H, Stark J, Fischer H, et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 2006;312(5780):1659-62.
[19] Brainard GC, Beacham S, Sanford BE, Hanifin JP, Streletz L, Sliney D. Near ultraviolet radiation elicits visual evoked potentials in children. Clin Neurophysiol 1999;110(3):379-83.
[20] Brainard GC, Podolin PL, Leivy SW, Rollag MD, Cole C, Barker FM. Near-ultraviolet radiation suppresses pineal melatonin content. Endocrinology 1986;119(5):2201-5.
[21] Benrath J, Gillardon F, Zimmermann M. Differential time courses of skin blood flow and hyperalgesia in the human sunburn reaction following ultraviolet irradiation of the skin. Eur J Pain 2001;5(2):155-67.
[22] Eisenbarth H, Rukwied R, Petersen M, Schmelz M. Sensitization to bradykinin B1 and B2 receptor activation in UV-B irradiated human skin. Pain 2004;110(1-2):197-204.
[23] Koppert W, Brueckl V, Weidner C, Schmelz M. Mechanically induced axon reflex and hyperalgesia in human UV-B burn are reduced by systemic lidocaine. Eur J Pain 2004;8(3):237-44.
[24] Willis WD, Jr. Dorsal root potentials and dorsal root reflexes: a double-edged sword. Exp Brain Res 1999;124(4):395-421.
[25] Gillardon F, Moll I, Michel S, Benrath J, Weihe E, Zimmermann M. Calcitonin gene-related peptide and nitric oxide are involved in ultraviolet radiation-induced immunosuppression. Eur J Pharmacol 1995;293(4):395-400.
[26] Chapman V and Dickenson AH. Enhanced responses of rat dorsal horn neurons after UV irradiation of the hindpaw; roles of the NMDA receptor. Neurosci Lett 1994;176(1):41-4.
[27] Urban L, Perkins MN, Campbell E, Dray A. Activity of deep dorsal horn neurons in the anaesthetized rat during hyperalgesia of the hindpaw induced by ultraviolet irradiation. Neuroscience 1993;57(1):167-72.
[28] Boxall SJ, Berthele A, Tolle TR, Zieglgansberger W, Urban L. mGluR activation reveals a tonic NMDA component in inflammatory hyperalgesia. Neuroreport 1998;9(6):1201-3.
[29] Thompson SW, Dray A, Urban L. Injury-induced plasticity of spinal reflex activity: NK1 neurokinin receptor activation and enhanced A- and C-fiber mediated responses in the rat spinal cord in vitro. J Neurosci 1994;14(6):3672-87.
[30] Boxall SJ, Berthele A, Laurie DJ, et al. Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation. Neuroscience 1998;82(2):591-602.
[31] Davis CL, Naeem S, Phagoo SB, Campbell EA, Urban L, Burgess GM. B1 bradykinin receptors and sensory neurones. Br J Pharmacol 1996;118(6):1469-76.
[32] Hiramoto K. Ultraviolet A irradiation of the eye activates a nitric oxide-dependent hypothalamo-pituitary pro-opiomelanocortin pathway and modulates the functions of Langerhans cells. J Dermatol 2009;36(6):335-45.
[33] Gillardon F, Wiesner RJ, Zimmermann M. Expression of the junD proto-oncogene in the rat spinal cord and skin following noxious cutaneous ultraviolet irradiation. Neurosci Lett 1992;136(1):87-90.
[34] Seifert F, Jungfer I, Schmelz M, Maihofner C. Representation of UV-B-induced thermal and mechanical hyperalgesia in the human brain: a functional MRI study. Hum Brain Mapp 2008;29(12):1327-42.
[35] Zawilska JB, Rosiak J, Nowak JZ. Effects of near-ultraviolet light on the nocturnal serotonin N-acetyltransferase activity of rat pineal gland. Neurosci Lett 1998;243(1-3):49-52.
[36] Shimeld C, Easty DL, Hill TJ. Reactivation of herpes simplex virus type 1 in the mouse trigeminal ganglion: an in vivo study of virus antigen and cytokines. J Virol 1999;73(3):1767-73.
[37] Malick A and Burstein R. Cells of origin of the trigeminohypothalamic tract in the rat. J Comp Neurol 1998;400(1):125-44.
[38] Sliney D. Ultraviolet radiation effects upon the eye: Problems of dosimetry. Radiat Prot Dosimet 1997;72(3-4):197-206.
[39] Van den Berg TJ. Quantal and visual efficiency of fluorescence in the lens of the human eye. Invest Ophthalmol Vis Sci 1993;34(13):3566-73.
[40] Kuchiiwa S, Kuchiiwa T, Suzuki T. Comparative anatomy of the accessory ciliary ganglion in mammals. Anat Embryol 1989;180(2):199-205.
[41] Nowak E, Kuder T, Szczurkowski A, Kuchinka J. Anatomical and histological data on the ciliary ganglion in the Egyptian spiny mouse (Acomys cahirinus Desmarest). Folia Morphol 2004;63(3):267-72.
[42] Natori Y and Rhoton AL, Jr. Transcranial approach to the orbit: microsurgical anatomy. J Neurosurg 1994;81(1):78-86.
[43] Garssen J, Buckley TL, Van Loveren H. A role for neuropeptides in UVB-induced systemic immunosuppression. Photochem Photobiol 1998;68(2):205-10.
[44] Streilein JW, Okamoto S, Sano Y, Taylor AW. Neural control of ocular immune privilege. Ann N Y Acad Sci 2000;917:297-306.
[45] Hatterer E, Davoust N, Didier-Bazes M, et al. How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood 2006;107(2):806-12.



Does Ultraviolet Radiation Regulate Brain Function and Circadian Neuroendocrine Rhythms Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?

Recently, Brajac et al. [1] noted that the sensory innervation of the skin may influence the development of psoriatic plaques and that stress-activated signalling in the central nervous system (CNS) may interact with melanocytes and with the disease process in psoriasis. The research on the effects of cutaneous exposure to ultraviolet B (UVB) or ultraviolet A (UVA) on primary afferent neurons (PAN’s) innervating the skin may shed light on the mechanisms by which changes in the skin could interact with processes in the CNS. Ultraviolet radiation (UVR) can increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin [2,3] and also in the dorsal horn (DH) of the spinal cord [4,5]. Researchers have suggested that UVR may be able to modify brain function by altering neurotransmission in the optic nerve (ON) [6-9], the ophthalmic branch of the trigeminal nerve (V1) [10], or by incompletely-defined mechanisms [11,12], potentially related to changes in the levels of biogenic amine neurotransmitters or neuropeptides [13] or in the activities of PAN’s [11]. UVR could influence the thermoregulatory and neuroendocrine aspects of circadian rhythms and influence other processes in the CNS, such as the immune responses of microglia and dendritic cells, by increasing the percentages of spontaneously-active PAN’s and thereby altering the release of CGRP, SP, and glutamate at different sites in the CNS.

UVR can induce spontaneous action potentials (AP’s) in C-fibers [2,14,15] and A-fibers [14] innervating the exposed skin [2,14,15]. These sensory fibers (SF’s), which are the peripheral branches of PAN’s in the dorsal root ganglion/ganglia (DRG) and trigeminal ganglion/ganglia (TG), develop graded receptor potentials, which are analogous to excitatory postsynaptic potentials (EPSP’s), and AP’s in response to their rapid depolarization by cytokines and NGF and other mediators [16] that are released from keratinocytes and mast cells [17] in UV-exposed skin. The AP’s in PAN’s can begin as soon as 30 minutes after exposure [15] and persist for five days [2,14] or longer. Spontaneous AP’s in SF’s are likely to be largely asynchronous [18], and UVR-induced AP’s in SF’s have occurred at frequencies of 0.8-1.25 Hz [2] or 6.64 AP’s per minute (an arithmetic mean of 0.1 Hz) [15] or 6-108 AP’s per minute (~0.1-1.8 Hz) [14]. Thus, UVA-induced AP’s in TG neurons may have contributed to the visual-evoked potentials measured in humans [19] and rapid emergence of changes in the pineal gland [20] and suprachiasmatic nucleus [7].

The release of neuropeptides into UVR-exposed skin is likely to occur through axon reflexes (AXR) [21-23] or dorsal root reflexes (DRR’s). In an AXR, it is thought that an afferent (and, here, orthodromic) AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent (and, here, antidromic) direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber [24]. In a DRR, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber [24].

The AP’s in SF’s are likely to first deplete and subsequently increase the levels of CGRP and SP in both the skin and DH. UVR is thought to induce the release and depletion of CGRP and SP from cutaneous SF’s, during the first several hours after exposure in rats [25], and to then induce adaptive increases in the anterograde transport of those neuropeptides, from the cell bodies to the peripheral terminals of PAN’s, and in the formation of new CGRP and SP in PAN’s [3]. The increases in CGRP and SP in the DH have also been attributed to adaptive increases in the formation and storage of CGRP and SP in the central branches of PAN’s, in response to the release of those neuropeptides [4,5]. Those increases in CGRP and SP may also result from adaptive decreases, over the long term [3] or short term [4], in the rates of release of CGRP and SP from the peripheral or central terminals, respectively, of PAN’s [3,4]. For example, the UVR-induced increases in the firing rates of DH projection neurons could activate neurons in supraspinal sites that produce descending inhibition of nociceptive transmission in the DH.

TG and DRG neurons are likely to serve as the primary inputs for the polysynaptic pathways activated by UVR. UVR can cause neurons in the DH to fire spontaneously [26, 27], to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission [26-29], and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS [5-7, 10, 30-35] in animals or humans. The apparent effects of UVB or UVA on the brain, as indicated by increases in plasma ACTH or -MSH [10, 32] or in IEG expression [6, 7] or pineal NAT activity [35], have sometimes been blocked by ciliary ganglionectomy [10], ON transection [8] or denervation [9], hypophysectomy [9, 10], or orbital enucleation [6, 7]. Despite the evidence suggesting that UVR induces AP’s in ON fibers [6-9], ocular UVB is known to reliably induce HSV reactivation in the TG [36] and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. [10] suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears were likely to have been mediated by the activation of TG neurons, in V1, and also by neurons in the ciliary ganglion/ganglia (CG) [10]. These effects were more pronounced after exposure to the eyes alone than after exposure to the ears alone [10, 32], and this could be explained by the exceptionally-dense trigeminal innervation of the corneas [37]. Additionally, corneal inflammation can increase plasma ACTH by inducing the SP-mediated activation of neurons in the Vc [38], and the UVR-induced increases in plasma ACTH [32] or -MSH [10] in mice could be explained in terms of UVR-induced changes in the firing rates or firing patterns of neurons in the Vc. Some Vc neurons project to the hypothalamus [39] and receive monosynaptic inputs from TG neurons innervating the facial skin [39]. Ocular UVB exposure, in mice that had not been infected with HSV-1, also increased the concentrations of some cytokines in satellite cells in the TG and in cells in the dorsal root entry zone of the Vc [36].

In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised [19, 20], it is also relevant that, in the intact eye, only ~ 2 percent of UVB reaches the lens and that the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor [40]. Sliney et al. [40] noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum [41], can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by excised ocular tissues [19, 20]. The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses [19], but neither UVA nor UVB is likely to act directly on cells in the retina. It should be noted that most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules [40], and any prolonged exposure of the eyes to direct UVR could damage corneal SF’s and impact neurotransmission in the brain by atypical mechanisms.

The axons of many neurons in the TG or CG or accessory CG, in rats [42] and some mice [43] and also humans [44], extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON [43], just posterior to the globe, and it is possible that the ON denervation or transection or ciliary ganglionectomy procedures [6, 7, 9, 10] damaged some axons of neurons in the CG, accessory CG, or TG. Most of the TG neurons that innervate the corneas are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, a subdivision of V1 [42], and many of the TG neurons pass through the CG without forming synapses [42].

UVR exposure could influence circadian neuroendocrine rhythms and other processes in the brain, including immune privilege, by inducing low-frequency AP’s in TG and DRG neurons and thereby inducing changes in the firing patterns of neurons in the Vc or DH, and these mechanisms could be relevant to the interpretation of research suggesting that changes in sun exposure may influence the risk of developing multiple sclerosis or various cancers. Researchers could expand upon the fMRI research in UVR-exposed humans [34] or examine the changes in the CNS, in rodents, in more detail and over longer periods of time.

References

(1) Brajac I, Kastelan M, Prpic-Massari L, Perisa D, Loncarek K, Malnar D. Melanocyte as a possible key cell in the pathogenesis of psoriasis vulgaris. Med Hypoth 2009;73(2):254-6.
(2) Eschenfelder CC, Benrath J, Zimmermann M, Gillardon F. Involvement of substance P in ultraviolet irradiation-induced inflammation in rat skin. Eur J Neurosci 1995;7(7):1520-6.
(3) Legat FJ, Griesbacher T, Schicho R, et al. Repeated subinflammatory ultraviolet B irradiation increases substance P and calcitonin gene-related peptide content and augments mustard oil-induced neurogenic inflammation in the skin of rats. Neurosci Lett 2002;329(3):309-13.
(4) Gillardon F, Schrock H, Morano I, Zimmermann M. Long-term increase in CGRP levels in rat spinal dorsal horn following skin ultraviolet irradiation. A mechanism of sunburn pain? Ann N Y Acad Sci 1992;657:493-6.
(5) Polgar E, Szucs P, Urban L, Nagy I. Alterations of substance P immunoreactivity in lumbar and thoracic segments of rat spinal cord in ultraviolet irradiation induced hyperalgesia of the hindpaw. Brain Res 1998;786(1-2):248-51.
(6) Amir S and Robinson B. Fos expression in rat visual cortex induced by ocular input of ultraviolet light. Brain Res 1996;716(1-2):213-8.
(7) Amir S and Robinson B. Ultraviolet light entrains rodent suprachiasmatic nucleus pacemaker. Neuroscience 1995;69(4):1005-11.
(8) Hiramoto K, Mashita Y, Katada T, Konishi H, Sugiura M, Hayakawa R. Immunosuppression by ultraviolet B rays via eyes in mice. Arch Dermatol Res 1997;289(12):709-11.
(9) Inoue M, Hiramoto K, Park A, Sato EF. UV-Irradiation down-regulates immune functions and causes fatigue by photo-optico-neuronal network: lessons from iNOS-knockout mice. Neurochem Res 2004;29(8):1582.
(10) Hiramoto K, Yanagihara N, Sato EF, Inoue M. Ultraviolet B irradiation of the eye activates a nitric oxide-dependent hypothalamopituitary proopiomelanocortin pathway and modulates functions of alpha-melanocyte-stimulating hormone-responsive cells. J Invest Dermatol 2003;120(1):123-7.
(11) Ericsson AD, Dora J, Cao S. Melanocytes: morphological basis for an exteroceptive sensory system for monitoring ultraviolet radiation. Physiol Chem Phys Med NMR 2003;35(1):27-42.
(12) Taylor SL, Kaur M, LoSicco K, et al. Pilot study of the effect of ultraviolet light on pain and mood in fibromyalgia syndrome. J Altern Complement Med 2009;15(1):15-23.
(13) Rogers SC, Shuster S, Marks JM, Penny RJ, Thody AJ. The effects of photochemotherapy on endocrine secretion in patients with psoriasis. Acta Derm Venereol 1981;61(4):350-2.
(14) Andreev N, Urban L, Dray A. Opioids suppress spontaneous activity of polymodal nociceptors in rat paw skin induced by ultraviolet irradiation. Neuroscience 1994;58(4):793-8.
(15) Szolcsanyi J. Selective responsiveness of polymodal nociceptors of the rabbit ear to capsaicin, bradykinin and ultra-violet irradiation. J Physiol 1987;388:9-23.
(16) Saade NE, Farhat O, Rahal O, Safieh-Garabedian B, Le Bars D, Jabbur SJ. Ultraviolet-induced localized inflammatory hyperalgesia in awake rats and the role of sensory and sympathetic innervation of the skin. Brain Behav Immun 2008;22(2):245-56.
(17) Streilein JW, Alard P, Niizeki H. Neural influences on induction of contact hypersensitivity. Ann N Y Acad Sci 1999;885:196-208.
(18) Ikeda H, Stark J, Fischer H, et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 2006;312(5780):1659-62.
(19) Brainard GC, Beacham S, Sanford BE, Hanifin JP, Streletz L, Sliney D. Near ultraviolet radiation elicits visual evoked potentials in children. Clin Neurophysiol 1999;110(3):379-83.
(20) Brainard GC, Podolin PL, Leivy SW, Rollag MD, Cole C, Barker FM. Near-ultraviolet radiation suppresses pineal melatonin content. Endocrinology 1986;119(5):2201-5.
(21) Benrath J, Gillardon F, Zimmermann M. Differential time courses of skin blood flow and hyperalgesia in the human sunburn reaction following ultraviolet irradiation of the skin. Eur J Pain 2001;5(2):155-67.
(22) Eisenbarth H, Rukwied R, Petersen M, Schmelz M. Sensitization to bradykinin B1 and B2 receptor activation in UV-B irradiated human skin. Pain 2004;110(1-2):197-204.
(23) Koppert W, Brueckl V, Weidner C, Schmelz M. Mechanically induced axon reflex and hyperalgesia in human UV-B burn are reduced by systemic lidocaine. Eur J Pain 2004;8(3):237-44.
(24) Willis WD, Jr. Dorsal root potentials and dorsal root reflexes: a double-edged sword. Exp Brain Res 1999;124(4):395-421.
(25) Gillardon F, Moll I, Michel S, Benrath J, Weihe E, Zimmermann M. Calcitonin gene-related peptide and nitric oxide are involved in ultraviolet radiation-induced immunosuppression. Eur J Pharmacol 1995;293(4):395-400.
(26) Chapman V and Dickenson AH. Enhanced responses of rat dorsal horn neurons after UV irradiation of the hindpaw; roles of the NMDA receptor. Neurosci Lett 1994;176(1):41-4.
(27) Urban L, Perkins MN, Campbell E, Dray A. Activity of deep dorsal horn neurons in the anaesthetized rat during hyperalgesia of the hindpaw induced by ultraviolet irradiation. Neuroscience 1993;57(1):167-72.
(28) Boxall SJ, Berthele A, Tolle TR, Zieglgansberger W, Urban L. mGluR activation reveals a tonic NMDA component in inflammatory hyperalgesia. Neuroreport 1998;9(6):1201-3.
(29) Thompson SW, Dray A, Urban L. Injury-induced plasticity of spinal reflex activity: NK1 neurokinin receptor activation and enhanced A- and C-fiber mediated responses in the rat spinal cord in vitro. J Neurosci 1994;14(6):3672-87.
(30) Boxall SJ, Berthele A, Laurie DJ, et al. Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation. Neuroscience 1998;82(2):591-602.
(31) Davis CL, Naeem S, Phagoo SB, Campbell EA, Urban L, Burgess GM. B1 bradykinin receptors and sensory neurones. Br J Pharmacol 1996;118(6):1469-76.
(32) Hiramoto K. Ultraviolet A irradiation of the eye activates a nitric oxide-dependent hypothalamo-pituitary pro-opiomelanocortin pathway and modulates the functions of Langerhans cells. J Dermatol 2009;36(6):335-45.
(33) Gillardon F, Wiesner RJ, Zimmermann M. Expression of the junD proto-oncogene in the rat spinal cord and skin following noxious cutaneous ultraviolet irradiation. Neurosci Lett 1992;136(1):87-90.
(34) Seifert F, Jungfer I, Schmelz M, Maihofner C. Representation of UV-B-induced thermal and mechanical hyperalgesia in the human brain: a functional MRI study. Hum Brain Mapp 2008;29(12):1327-42.
(35) Zawilska JB, Rosiak J, Nowak JZ. Effects of near-ultraviolet light on the nocturnal serotonin N-acetyltransferase activity of rat pineal gland. Neurosci Lett 1998;243(1-3):49-52.
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Does Ultraviolet Radiation Regulate Brain Function and Circadian Neuroendocrine Rhythms Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?

Recently, Brajac et al. (13) noted that the sensory innervation of the skin may influence the development of psoriatic plaques and that stress-activated signalling in the central nervous system (CNS) may interact with melanocytes and with the disease process in psoriasis. The research on the effects of cutaneous exposure to ultraviolet B (UVB) or ultraviolet A (UVA) on primary afferent neurons (PAN’s) innervating the skin may shed light on the mechanisms by which changes in the skin could interact with processes in the CNS. Ultraviolet radiation (UVR) can increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin (21,39) and also in the dorsal horn (DH) of the spinal cord (26, 46). The increases in the DH are likely to result from increases in the release of CGRP and SP from the central terminals of PAN’s (27,48). Similarly, exposure of the facial skin to UVR is likely to induce the release of CGRP, SP, and glutamate in the trigeminal nucleus caudalis (Vc), in the brainstem (51). Researchers have suggested that UVR may be able to modify brain function by altering neurotransmission in the optic nerve (ON) (1,2,30,33), the ophthalmic branch of the trigeminal nerve (V1) (31), or by incompletely-defined mechanisms (20,57), potentially related to changes in the levels of biogenic amine neurotransmitters or neuropeptides (47) or in the activities of PAN’s (20). There is evidence that cutaneous UVR can influence peptidergic and glutamatergic transmission in the spinal cord (9,10,15,17,46,59,60,61) and brain (2,31) along polysynaptic pathways, and these effects are likely to result from prolonged increases in low-frequency, spontaneous action potentials (AP’s) induced in PAN’s, in the dorsal root ganglion/ganglia (DRG) and trigeminal ganglion/ganglia (TG), innervating the UV-irradiated skin (3,21,56). Those mechanisms (3,21,26,27,29,30,31) imply that the neuroendocrinological effects (12,29,31), increases in immediate-early gene (IEG) expression in the suprachiasmatic nucleus (SCN) and other sites in the brain (1,2), or decreases in pineal melatonin content (12) or serotonin N-acetyltransferase (NAT) activity (65), induced by UVR exposure to only the eyes (1,2,29,30,31) or ears (29,31), could have resulted from increases in the percentages of spontaneously-active PAN’s, in the TG or cervical DRG, innervating the corneas or ears, respectively. UVR may influence, via PAN’s, the thermoregulatory and neuroendocrine aspects of circadian rhythms and influence other processes in the CNS, such as the immune responses of microglia and dendritic cells, by altering the release of CGRP, SP, and glutamate at different sites in the brain.

UVR can induce spontaneous AP’s in C-fibers (3,21,56) and A-fibers (3) innervating the exposed skin (3,21,56). These sensory fibers (SF’s) develop graded receptor potentials, which are analogous to excitatory postsynaptic potentials (EPSP’s), and AP’s in response to their rapid depolarization by cytokines and NGF and other mediators (48), and the increases in the release of many of these mediators from keratinocytes (KC’s) and mast cells (54), in UV-exposed skin, are likely to produce the AP’s in SF’s (48). The UVR-induced AP’s in PAN’s can begin as soon as 30 minutes after exposure (56) and persist for up to five days (3,21), and the dermal concentrations of bradykinin, a neuropeptide that induces AP’s and not just sensitization in C-fibers (56), in human skin within 21 minutes of exposure (19). Spontaneous AP’s in SF’s are likely to be largely asynchronous (32), and UVR-induced AP’s in SF’s have occurred at frequencies of 0.8-1.25 Hz (21) or 6.64 AP’s per minute (an arithmetic mean of 0.1 Hz) (56) or 6-108 AP’s per minute (~0.1-1.8 Hz) (3). Thus, the visual-evoked potentials measured in UVA-exposed humans (11) and rapid emergence of changes in the pineal gland (12) and SCN (2) may, particularly given the use of high intensity UVA (11), have been partially a result of early, UVA-induced AP’s in TG neurons.

The UVR-induced release of neuropeptides into the skin is likely to occur through axon reflexes (AXR) (4,18,37) or dorsal root reflexes (DRR’s). In an AXR, it is thought that an afferent, or orthodromic, AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent, or antidromic, direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber (64). In a DRR, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber (64).

The UVR-induced afferent AP’s in SF’s are likely to first deplete and subsequently increase the levels of CGRP and SP in both the skin and DH. UVR is thought to induce the release and depletion of CGRP and SP from cutaneous SF’s, during the first several hours after exposure in rats (25), and to then induce adaptive increases in the anterograde transport of those neuropeptides, from the cell bodies to the peripheral terminals of PAN’s, and in the formation of new CGRP and SP in PAN’s (39). The increases in CGRP and SP in the DH have also been attributed to adaptive increases in the formation and storage of CGRP and SP in the central terminals of DRG neurons, in response to the UVR-induced release of CGRP and SP from those terminals (26,46). Those increases in CGRP and SP may also result from adaptive decreases, over the long term (39) or short term (26), in the rates of release of CGRP and SP from the peripheral or central terminals, respectively, of PAN’s (26,39). For example, the UVR-induced increases in the firing rates of DH projection neurons could activate neurons in supraspinal sites that produce descending inhibition of nociceptive transmission in the DH.

The apparent polysynaptic pathways by which UVR can produce changes in the CNS have not been precisely delineated, but TG and DRG neurons are likely to serve as the primary inputs for those changes. UVR can also cause neurons in the DH to fire spontaneously (15,61), to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission (10,15,60,61), and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS (1,2,9,17,29,31,46,50,65) in animals or humans. The apparent effects of UVB or UVA on the brain, as indicated by increases in plasma ACTH or -MSH (29,31) or on IEG expression (1,2) or NAT activity (65) in parts of the brain, have sometimes been blocked by ciliary ganglionectomy (31), ON transection (30) or denervation (33), hypophysectomy (31,33), or orbital enucleation (1,2). Despite the evidence suggesting that UVR induces AP’s in ON fibers (1,2,30,33), ocular UVB is known to reliably induce HSV reactivation in the TG (52) and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. (31) suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears were likely to have been mediated by the activation of TG neurons, in V1, and also by neurons in the ciliary ganglion/ganglia (CG) (31). The apparent effects of UVR on the CNS were more pronounced after exposure to the eyes alone than after exposure to the ears alone (29,31), and this could be explained by the exceptionally-dense trigeminal innervation of the corneas {{771}}. Additionally, corneal inflammation can increase plasma ACTH by inducing the SP-mediated activation of neurons in the Vc (6), and the UVR-induced increases in plasma ACTH (29) or -MSH (31) in mice could be explained in terms of UVR-induced changes in the firing rates or firing patterns of neurons in the Vc. Some Vc neurons project to the hypothalamus (42) and receive monosynaptic inputs from TG neurons innervating the facial skin (42). Ocular UVB exposure, in mice that had not been infected with HSV-1, also increased the concentrations of cytokines in satellite cells in the TG and in cells in the dorsal root entry zone of the Vc (52).

In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised (11,12), it is also relevant that, in the intact eye, only ~ 2 percent of UVB reaches the lens and that the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor (53). Sliney et al. (53) noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum (62), can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by the excised ocular tissues of nonprimate, mammalian species (11,12). The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses (11), but neither UVA nor UVB is likely to act directly on cells in the retina. It should be noted that most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules (53), and any prolonged exposure of the eyes to direct UVR could damage corneal SF’s and impact neurotransmission in the brain by atypical mechanisms.

The axons of many neurons in the TG or CG or accessory CG, in rats (38) and some mice (45) and also humans (44), extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON (45), and it is possible that the ON denervation or transection procedures (1,2,33) severed some axons of neurons whose cell bodies are in the CG, accessory CG, or TG. Most of the sensory neurons in the TG that innervate parts of the eye are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, and the nasociliary nerve is a subdivision of V1 (38). Many of the TG neurons that project to the corneas, within the ciliary nerves, pass through the CG without forming synapses (38). Despite the anatomical differences among mice, rats, and humans (38,44,45), the short or long ciliary nerves that contain corneal afferents from the TG also extend along sections of the ON, just posterior to the globe, in rats (38), mice (45), and also humans (44) and could have been damaged or severed during the ciliary ganglionectomy (31,33), ON transection (1,2,30) or denervation (31,33), or orbital enucleation (1,2) procedures.

UVR exposure could influence circadian neuroendocrine rhythms and other processes in the brain, including immune privilege, by inducing low-frequency AP’s in TG and DRG neurons and thereby inducing changes in the firing patterns of neurons in the Vc or DH, and these mechanisms could be relevant to the interpretation of research suggesting that changes in sun exposure may influence the risk of developing multiple sclerosis or various cancers. Researchers could expand upon the fMRI research in UVR-exposed humans (50) or examine the changes in the CNS, in rodents, in more detail and over longer periods of time.

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