Poster: Spinal adenosine A1 and serotonin 5-HT7 receptors mediate analgesia by systemically administered amitriptyline in the mouse formalin test
Abstract: Caffeine is a non-specific adenosine receptor antagonist that is widely used for its stimulant and adjuvant analgesic properties. Rodent studies have shown that caffeine is analgesic at high doses (through adenosine A2 receptor blockade) but prevents analgesia by certain drugs when given at low doses (through adenosine A1 receptors blockade). Adenosine A1 receptor activation is involved in analgesia by amitriptyline (a tricyclic antidepressant used for chronic pain), although the mechanisms and specific sites of action involved are unclear. The present study explored the link between spinal 5-HT7 receptor activation and adenosine A1 receptor-mediated antinociception by systemic amitriptyline in mice. Antinociception by systemic amitriptyline in phase 2 of the formalin test was blocked by oral caffeine given for 8 days. The effects of caffeine were mimicked by intrathecal DPCPX (a selective adenosine A1 receptor antagonist), which prevented antinociception by systemic amitriptyline in normal mice; this was also observed in adenosine A1 receptor +/+ mice, but not in A1 receptor -/- mice. Systemic amitriptyline antinociception was prevented by intrathecal SB269970 (a selective 5-HT7 receptor antagonist) in normal and adenosine A1 receptor +/+ mice, but not in A1 receptor -/- mice. We propose that amitriptyline produces analgesia acutely through the activation of spinal adenosine A1 receptors, secondarily to the activation of spinal 5-HT7 receptors and the release of cyclic AMP and adenosine. In the context of human caffeine consumption, our findings suggest that persistent, low levels of caffeine could reduce the analgesic efficacy of amitriptyline.
This research poster was presented at the 2012 IHRTP (Integrated Health Research Training Partnership) Graduate Student Research Day at Dalhousie University (15 May 2012). These data appear in an article (in press) in the European Journal of Pharmacology: http://dx.doi.org/10.1016/j.ejphar.2012.10.042