Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve‐injured mice

<jats:sec><jats:title>Background and Purpose</jats:title><jats:p>Mu and delta opioid receptors (MOP, DOP) contribution to the manifestations of pathological pain is not understood. We used genetic approaches to investigate the opioid mechanisms modulating neuropathic pain and its comorbid manifestations.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>We generated conditional knockout mice with MOP or DOP deletion in sensory Nav1.8‐positive neurons (Nav1.8), in GABAergic forebrain neurons (DLX5/6) or constitutively (CMV). Mutant mice and wild‐type littermates were subjected to partial sciatic nerve ligation (PSNL) or sham surgery and their nociception was compared. Anxiety‐, depressive like behaviour and cognitive performance were also measured. Opioid receptor mRNA expression, microgliosis and astrocytosis were assessed in the dorsal root ganglia (DRG) and/or the spinal cord (SC).</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>Constitutive CMV‐MOP knockouts after PSNL displayed reduced mechanical allodynia and enhanced heat hyperalgesia. This phenotype was accompanied by increased DOP expression in DRG and SC, and reduced microgliosis and astrocytosis in deep dorsal horn laminae. Conditional MOP knockouts and control mice developed similar hypersensitivity after PSNL, except for anenhanced heat hyperalgesia by DLX5/6‐MOP male mice. Neuropathic pain‐induced anxiety was aggravated in CMV‐MOP and DLX5/6‐MOP knockouts. Nerve‐injured CMV‐DOP mice showed increased mechanical allodynia, whereas Nav1.8‐DOP and DLX5/8‐DOP mice had partial nociceptive enhancement. CMV‐DOP and DLX5/6‐DOP mutants showed increased depressive‐like behaviour after PSNL.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Implications</jats:title><jats:p>MOP activity after nerve injury increased anxiety‐like responses involving forebrain GABAergic neurons and enhanced mechanical pain sensitivity along with repression of DOP expression and spinal cord gliosis. In contrast, DOP shows a protective function limiting nociceptive and affective manifestations of neuropathic pain.</jats:p></jats:sec>