κ-Opioid receptors are not necessary for the antidepressant treatment of neuropathic pain.

Abstract

BACKGROUND AND PURPOSE:

Tricyclic antidepressants are used clinically as first-line treatments for neuropathic pain. Opioid receptors participate in this pain-relieving action, and preclinical studies in receptor-deficient mice have highlighted a critical role for δ-, but not μ-opioid receptors. In this study, we investigated whether κ-opioid (KOP) receptors have a role in the antiallodynic action of tricyclic antidepressants.

EXPERIMENTAL APPROACH:

We used a model of neuropathic pain induced by unilateral sciatic nerve cuffing. In this model, the mechanical allodynia was evaluated using von Frey filaments. Experiments were conducted in C57BL/6J mice, and in KOP receptor-deficient mice and their wild-type littermates. The tricyclic antidepressant nortriptyline (5 mg · kg(-1)) was delivered twice a day for over 2 weeks. Agonists and antagonists of opioid receptors were used to test the selectivity of the KOP receptor antagonist norbinaltorphimine (nor-BNI) in mice with neuropathic pain.

KEY RESULTS:

After 12 days of treatment, nortriptyline relieved neuropathic allodynia in both wild-type and KOP receptor-deficient mice. Surprisingly, acute nor-BNI reversed the effect of nortriptyline in both wild-type and KOP receptor-deficient mice. Further experiments showed that nor-BNI action was selective for KOP receptors at a late time-point after its administration (8 h), but not at an early time-point, when it may also interact with δ-opioid (DOP) receptors.

CONCLUSIONS AND IMPLICATIONS:

KOP receptors are not necessary for the effect of a tricyclic antidepressant against neuropathic allodynia. These findings together with previous data indicate that the DOP receptor is the only opioid receptor that is necessary for the antiallodynic action of antidepressants.

• Authors: Salim Megat, Yohann Bohren, Stephane Doridot, Claire Gaveriaux-Ruff, Brigitte L Kieffer, Marie-José Freund-Mercier, Ipek Yalcin, Michel Barrot
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 4 Pg. 1034-44 (Feb 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 25297905 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• Antidepressive Agents, Tricyclic
• Receptors, Opioid, delta
• Receptors, Opioid, kappa
• norbinaltorphimine
• Naltrexone
• Nortriptyline
• naltrindole

Topics

• Animals
• Antidepressive Agents, Tricyclic (pharmacology, therapeutic use)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Naltrexone (analogs & derivatives, pharmacology)
• Neuralgia (drug therapy, metabolism)
• Nortriptyline (pharmacology, therapeutic use)
• Receptors, Opioid, delta (antagonists & inhibitors)
• Receptors, Opioid, kappa (antagonists & inhibitors, genetics, metabolism)
• Sciatic Nerve (injuries)