Kappa-opioid receptors are not necessary for the antidepressant treatment of neuropathic pain

Authors
Salim Megat, Yohann Bohren, Stephane Doridot, Claire Gaveriaux?Ruff, Brigitte L. Kieffer, Marie?José Freund?Mercier, Ipek Yalcin, Michel Barrot

Lab
French National Centre for Scientific Research, Lutetia Parisorum, Île-de-France, France

Journal
British Journal of Pharmacology

Abstract
BACKGROUND AND PURPOSE
Tricyclic antidepressants are clinically first line treatments of neuropathic pain. Opioid receptors participate in this pain-relieving action, and preclinical studies in receptor-deficient mice have highlighted a critical role of the delta, but not mu opioid receptors. In this work, we address the question of the role of kappa opioid receptors (KOP) 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-deficient mice and their wild-type littermates. The tricyclic antidepressant nortriptyline (5 mg.kg-1) was delivered twice a day over two weeks. Agonists and antagonists of opioid receptors allowed testing the selectivity of the KOP 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-deficient mice. Surprisingly, acute nor-BNI reversed nortriptyline action in both wild-type and KOP-deficient mice. Further experiments exploring the time-dependent selectivity of nor-BNI showed that nor-BNI action is KOP-selective at a late time-point after administration (8 h), but not selective at an early time-point, when it may also interact with delta opioid receptors (DOP).

CONCLUSIONS AND IMPLICATIONS
KOP are not necessary to the action of a tricyclic antidepressant against neuropathic allodynia. Present findings together with previous data designate DOP as the only opioid receptor that is necessary for the antiallodynic action of antidepressants.

BIOSEB Instruments Used:
Von Frey Filaments (Bio-VF-M)