J. Sawynok et al., Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine, PAIN, 80(1-2), 1999, pp. 45-55
The present study determined (1) whether amitriptyline could produce a loca
l antinociceptive action in the formalin test, (2) whether endogenous adeno
sine was involved in this action, and (3) which other systems might contrib
ute 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 ph
ase 2 (16-60 min) flinching behaviours, as well as in phase 2 biting/lickin
g 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 acti
on of amitriptyline against both behaviours at 2.5% formalin. At 1.5% forma
lin, caffeine still produced only a partial reversal of effect; this appear
ed to be due to a block of adenosine A(l) receptors, as it was also seen wi
th the selective adenosine A(l) receptor antagonist, 8-cyclopentyl-1,3-dime
thylxanthine. 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 lo
cal peripheral antinociceptive action which is mediated, in part, by an int
eraction with endogenous adenosine, most likely an inhibition of the cellul
ar uptake of adenosine with a consequent activation of adenosine Al recepto
rs on sensory nerve terminals. Local application of amitriptyline by cream
or gel might prove to be a useful method of drug delivery in inflammatory p
ain states. (C) 1999 International Association for the Study of Pain. Publi
shed by Elsevier Science B.V.