Peripheral mechanisms of adenosine and 5-hydroxytryptamine contributing to nociception and inflammation in the rat formalin model.
Date
1997
Authors
Doak, Gregory James.
Journal Title
Journal ISSN
Volume Title
Publisher
Dalhousie University
Abstract
Description
When applied peripherally, adenosine and 5-HT have been shown to be pronociceptive in a number of animal and human models. There are no data on possible interactions between adenosine and 5-HT in the context of inflammatory pain. It was hypothesized that nociceptor activation occurred through stimulation of adenosine and 5-HT receptors. The role of adenosine, 5-HT, and possible interactions between these substances was investigated using the rat formalin model. Injection of dilute formalin in the rat hindpaw produces an inflammatory, nociceptive response which is quantifiable and characterized by flinching and swelling of the affected hindpaw. Injection of 2.5% formalin produces a maximal inflammatory and nociceptive response, the mediators of which can be identified by using selective blockers. Injection of 0.5% formalin produces a low level inflammatory response but provides a background of the necessary co-mediators to which may be added putative pronociceptive substances. The role of endogenously released adenosine and 5-HT was assessed using subtype selective antagonist analogues of the respective mediators co-injected with 2.5% formalin, and observing for any block of the nociceptive response or paw swelling. The receptor subtypes involved were further defined by attempting to augment the response to 0.5% formalin by the exogenous co-injection of adenosine, 5-HT or their respective subtype selective agonist analogues. Interactions between adenosine and 5-HT were studied using co-injection of adenosine and 5-HT and combinations of antagonist analogues with 0.5% formalin. Stimulation of peripheral adenosine A$\sb2$ receptors produces hyperalgesia while peripheral A$\sb1$ receptor stimulation has an analgesic effect. These receptors appear to have no significant effect on edema formation. Multiple 5-HT receptors, including 5-HT$\sb1$, 5-HT$\sb3$, and 5-HT$\sb4$ receptors, are involved in generating the nociceptive response to formalin injection. 5-HT$\sb1$, 5-HT$\sb2$, and 5-HT$\sb4$ but not 5-HT$\sb3$ receptors contribute to edema formation but no single subtype selective 5-HT antagonist is effective at diminishing edema. Combining adenosine and 5-HT with 0.5% formalin revealed a greater than additive response and it appears that 5-HT may sensitize the nociceptor to the effects of adenosine. The data do not support the hypothesis of a peripheral nociceptive effect of 5-HT being mediated through adenosine release.
Thesis (Ph.D.)--Dalhousie University (Canada), 1997.
Thesis (Ph.D.)--Dalhousie University (Canada), 1997.
Keywords
Health Sciences, Pharmacology.