Endogenous μ-opioid receptor activity in the lateral and capsular subdivisions of the right central nucleus of the amygdala prevents chronic postoperative pain

Tissue injury induces a long-lasting latent sensitization (LS) of spinal nociceptive signaling that is kept in remission by an opposing mu-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 beta-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 naive 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 (PKC delta), and 35% of PKC delta neurons co-expressed tdTomato+ in Oprm1(Cre)::tdTomato transgenic mice. CeA microinjection of naltrexone (1 mu g) 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.

Automated summary

The experiment demonstrated that by intracerebroventricular injection of opioid receptor inhibitors, mechanical hypersensitivity can be reinstated, suggesting that MORs in the capsular subdivision of the right CeA prevent the transition from acute to chronic postoperative pain. Furthermore, it was found that systemic administration of naloxone and naltrexone in LS animals produced different effects compared to naive or sham controls.