κ‐ opioid receptors are not necessary for the antidepressant treatment of neuropathic pain

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.