Tissue injury induces a long-lasting latent sensitization (LS) of spinal nociceptive signaling that is kept in remission by an opposing µ-
opioid receptor (MOR) constitutive activity. To test the hypothesis that supraspinal sites become engaged, we induced hindpaw
inflammation, waited 3 weeks for mechanical
hypersensitivity to resolve, and then injected the
opioid receptor inhibitors
naltrexone,
CTOP or β-funaltrexamine subcutaneously, and/or into the cerebral ventricles. Intracerebroventricular injection of each inhibitor reinstated
hypersensitivity and produced somatic signs of withdrawal, indicative of LS and endogenous
opioid dependence, respectively. In naïve or
sham controls, systemic
naloxone (3 mg/kg) produced conditioned place aversion, and systemic
naltrexone (3 mg/kg) increased Fos expression in the central nucleus of the amygdala (CeA). In LS animals tested 3 weeks after plantar incision, systemic
naltrexone reinstated mechanical
hypersensitivity and produced an even greater increase in Fos than in
sham controls, particularly in the capsular subdivision of the right CeA. One third of Fos+ profiles co-expressed
protein kinase C delta (PKCδ), and 35% of PKCδ neurons co-expressed tdTomato+ in Oprm1Cre ::
tdTomato transgenic mice. CeA microinjection of
naltrexone (1 µg) reinstated mechanical
hypersensitivity only in male mice and did not produce signs of somatic withdrawal. Intra-CeA injection of the MOR-selective inhibitor CTAP (300 ng) reinstated
hypersensitivity in both male and female mice. We conclude that MORs in the capsular subdivision of the right CeA prevent the transition from acute to
chronic postoperative pain.