Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine

The present study determined (1) whether amitriptyline could produce a local antinociceptive action in the formalin test, (2) whether endogenous adenosine was involved in this action, and (3) which other systems might contribute to such an action. Coadministration of amitriptyline 10-100 nmol with 2.5% formalin produced a dose-related reduction in phase 1 (0-12 min) and phase 2 (16-60 min) flinching behaviours, as well as in phase 2 biting/licking time (no phase 1 expression). This action was not seen or only partially expressed at low concentrations of formalin (0.5%, 0.75%). Coadministration of caffeine with amitriptyline partially reversed the antinociceptive action of amitriptyline against both behaviours at 2.5% formalin. At 1.5% formalin, caffeine still produced only a partial reversal of effect; this appeared to be due to a block of adenosine A1 receptors, as it was also seen with the selective adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine. Using antagonists for a number of other systems, no evidence for an involvement of alpha-adrenergic, histamine, excitatory amino acid or opioid receptors in the action of amitriptyline was observed or inferred. A local anaesthetic action for amitriptyline remains a possibility for the residual action. These results indicate that amitriptyline can produce a local peripheral antinociceptive action which is mediated, in part, by an interaction with endogenous adenosine, most likely an inhibition of the cellular uptake of adenosine with a consequent activation of adenosine A1 receptors on sensory nerve terminals. Local application of amitriptyline by cream or gel might prove to be a useful method of drug delivery in inflammatory pain states.