Antinociceptive effects of acute and ‘chronic’ injections of tricyclic antidepressant drugs in a new model of mononeuropathy in rats

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Abstract
The tricyclic antidepressant drugs (TCAs) are commonly used in the treatment of chronic, especially neuropathic, pain. We evaluated their possible effect on a new model of neuropathic pain-related behaviour induced by ligatures tied loosely around the common sciatic nerve. The effects of 3 TCAs with different monoaminergic spectra (clomipramine, amitriptyline and desipramine) were assessed 2 weeks after surgery, the time of the maximum hyperalgesia, on a 'phasic' test (vocalization threshold to paw pressure) and on a 'tonic' test (score of the spontaneous pain-related behaviour). TCAs were acutely (0.5 and 2 mg/kg, i.v.) and 'chronically' injected (7 injections, once every half-life of the drug: 0.75 and 1.5 mg/kg, s.c., for clomipramine and 1.5 and 3 mg/kg, s.c., for amitriptyline and desipramine). Acutely injected clomipramine and amitriptyline (0.5 mg/kg, i.v.) and desipramine (2 mg/kg, i.v.) showed an antinociceptive naloxone-reversible effect, assessed by an increase in the vocalization threshold to the paw pressure test and, for amitriptyline, by a decrease in tonic pain scores. Chronically injected TCAs induced a significant and progressive increase in the vocalization threshold with a time course parallel to that of their suspected plasma or nerve tissue levels: (i) a regular increase of scores for the first 3-4 injections, (ii) then a plateau until the last injection, and (iii) a progressive decrease with a dose-dependent duration of the effect, longer than that obtained with a corresponding acute dose. This study showed that in this new model of mononeuropathy, acutely and chronically injected TCAs induce an antinociceptive effect and suggested that their analgesic action could be related to the monoaminergic spectrum of the drug in relation to the opiate systems.