Evidence for a differential opioidergic involvement in the analgesic effect of antidepressants: prediction for efficacy in animal models of neuropathic pain?

Abstract

Antidepressants are one of the recommended treatments for neuropathic pain. However, their analgesic action remains unpredictable, and there are no selection criteria for clinical use. Better knowledge of their mechanism of action could help highlight differences underlying their unequal efficacy. We compared the activity of a tricyclic antidepressant (clomipramine) with selective 5-HT and noradrenaline reuptake inhibitors (milnacipran and duloxetine) in streptozocin-induced diabetic and chronic constriction nerve injury-induced neuropathic rats, after repeated injections. We looked for an opioidergic mechanism in their action. Abolition of mechanical hyperalgesia was observed in mononeuropathic rats after five injections of clomipramine (5 mg·kg(-1) , s.c.) and milnacipran (10 or 20 mg·kg(-1) , i.p.) and in diabetic rats after clomipramine. An additional antinociceptive effect was obtained with five injections of duloxetine (3 mg·kg(-1) , i.p.) in both models and milnacipran (10 mg·kg(-1) , i.p.) in diabetic rats. These effects were observed with plasma antidepressant concentrations similar to those found in patients treated for neuropathic pain. Naloxone (1 mg·kg(-1) , i.v.) only suppressed the anti-hyperalgesic effects of clomipramine in both models of pain and of milnacipran in the traumatic model. The opioid system appears to be involved in the mechanism of action of antidepressants that only have an anti-hyperalgesic effect but not in those that have a stronger (i.e. antinociceptive) effect. These differences between the antidepressants occurred whatever the aetiology of the neuropathy and, if confirmed in clinical trials, could be used to decide which antidepressant is administered to a patient with neuropathic pain.