Role of Adenosine Transport Inhibition in the Antinociceptive and Antidepressant Effects of Tricyclic Antidepressants

These are some articles suggesting that tricyclics may produce some of their antinociceptive or antidepressant effects by inhibiting adenosine transport, an effect that would tend to increase extracellular adenosine and producing increases in plasma-membrane adenosine receptor activation. These articles can get kind of crazy, and they don't show that the antidepressants are acting only by adenosinergic mechanisms or anything. One could conceivably show that the effects of many drugs could be partially blocked by one or another adenosine receptor antagonist, because adenosine receptors affect most other neurotransmitter systems and countless other processes. For example, a tricyclic could bind to some "non-adenosine-binding" receptor or block some transporter that doesn't transport purines, and that action could indirectly interfere with adenosine-receptor activation or adenosine-receptor-mediated signal transduction events. Also, the acute effect on adenosine receptor subtypes (predominance of A1 adenosine receptor activation, for example) might not be the same as the effect in the long term (the A1 adenosine receptor density or sensitivity, for example, might decrease).

The tricyclics have many mechanisms other than serotonin and noradrenaline reuptake inhibition and other than adenosine transport inhibition that are thought to contribute to their antidepressant or antinociceptive (neuropathic pain-relieving) effects. For example, the anticholinergic effects create problems but nonetheless may contribute to their antidepressant effects. And the tricyclics are thought to relieve neuropathic pain, in part, by blocking sodium channels on neurons (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=tricyclic+sodium+channel), and they are like local anesthetics (lidocaine, procaine, etc., exert anesthetic effects by blocking sodium channels) in that regard. They also may relieve neuropathic pain partly by inhibiting noradrenaline and serotonin reuptake and thereby increasing the descending inhibitory influence that neurons in the locus ceruleus and locus subceruleus and raphe nuclei exert on ascending nociceptive transmission in the dorsal horn of the spinal cord. But those mechanisms are looking to be less important than the sodium-channel-blocking effects. There can also be an indirect sodium channel blocking effect of tricyclics on some cell types that's secondary to their anticholinergic effects (muscarinic acetylcholine receptor antagonism). And some of those pain articles discuss the complex interactions of the tricyclics' adenosinergic and catecholaminergic effects in animal models of hyperalgesia. But these articles showing adenosinergic effects of tricyclics are nonetheless interesting.

The apparent inhibitory effect of some tricyclics on adenosine transport seems to be one of their mechanisms of action that could plausibly occur in vivo [Phillis, 1984: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1987110&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/6487906); Sawynok et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/16156010)] Phillis (1984) discusses some of the lines of pharmacological evidence suggesting that the concentrations of the tricyclics in the interstitial fluid in the CNS might be high enough, in response to commonly-used dosages, to produce meaningful inhibition of adenosine transport (adenosine "reuptake"). Phillis (1984), for example, found that some tricyclic antidepressants inhibited adenosine transport and potentiated the adenosine-induced decreases in the firing rates of neurons from the cerebral cortices of rats.

There are lots of other articles showing these types of effects of tricyclics (a lot of these articles test amitriptyline) in animal models of depression or hyperalgesia [Esser and Sawynok, 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10884512); Sawynok et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18562097); Esser et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11711033); Sawynok et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10204717); Skrabanja et al., 2005: (http://bja.oxfordjournals.org/cgi/content/full/94/5/556)(http://www.ncbi.nlm.nih.gov/pubmed/15722385?dopt=Abstract); Waldron et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15381049); Golembiowska and Dziubina, 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11414661); Enriquez-Castillo et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18436269)].