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Evidence for an Involvement of Supraspinal δ- and Spinal μ-Opioid Receptors in the Antihyperalgesic Effect of Chronically Administered Clomipramine in Mononeuropathic Rats

The mechanisms of involvement of the opioidergic system in the antinociceptive effect of antidepressants remain to be elucidated. The present study was designed to determine what type of opioid receptors may be involved at the spinal and supraspinal levels in the antihyperalgesic effect of clomipramine, a tricyclic antidepressant commonly prescribed in the treatment of neuropathic pain. Its antihyperalgesic effect on mechanical hyperalgesia (paw pressure test) in rats induced by chronic constriction injury of the sciatic nerve was assessed after repeated administrations (five injections every half-life, a regimen close to clinical use). Naloxone administered at a dose of 1 mg/kg i.v., which blocks all opioid receptors, or at a low dose of 1 μg/kg i.v., which selectively blocks the μ-opioid receptor, inhibited the anti-hyperalgesic effect of clomipramine and hence indicated that μ-opioid receptor is involved. Depending on whether they are administered by the intracerebroventricular or intrathecal route, specific antagonists of the various opioid receptor subtypes [d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-ThrNH2 (CTOP), μ; naltrindole (NTI), δ; and nor-binaltorphimine (nor-BNI), κ] differently modify the antihyperalgesic effect of chronically injected clomipramine. The effect was inhibited by intrathecal administration of CTOP and intracerebroventricular administration of naltrindole, whereas nor-BNI was ineffective whatever the route of injection. These results demonstrate a differential involvement of opioid receptors according to the level of the central nervous system: δ-receptors at the supraspinal level and μ-receptors at the spinal level. Clomipramine could act via a neuronal pathway in which these two receptors are needed.