1. Academic Validation
  2. Sex differences in kappa opioid receptor inhibition of latent postoperative pain sensitization in dorsal horn

Sex differences in kappa opioid receptor inhibition of latent postoperative pain sensitization in dorsal horn

  • Neuropharmacology. 2020 Feb;163:107726. doi: 10.1016/j.neuropharm.2019.107726.
Lilian Custodio-Patsey 1 Renée R Donahue 1 Weisi Fu 1 Joshua Lambert 2 Bret N Smith 3 Bradley K Taylor 4
Affiliations

Affiliations

  • 1 Department of Physiology, College of Medicine, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY, 40536-0298, USA.
  • 2 Department of Statistics, College of Arts and Sciences, University of Kentucky, 302 Multidisciplinary Science Building, Lexington, KY, 40536-0082, USA.
  • 3 Department of Physiology, College of Medicine, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY, 40536-0298, USA; Department of Neuroscience, College of Medicine, University of Kentucky Medical Center, 800 Rose Street, Lexington, KY, 40536-0298, USA.
  • 4 Department of Anesthesiology, Pittsburgh Center for Pain Research, and the Pittsburgh Project to End Opioid Misuse, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: bkt@pitt.edu.
Abstract

Tissue injury produces a delicate balance between latent pain sensitization (LS) and compensatory endogenous Opioid Receptor analgesia that continues for months, even after re-establishment of normal pain thresholds. To evaluate the contribution of mu (MOR), delta (DOR), and/or kappa (KOR) opioid receptors to the silencing of chronic postoperative pain, we performed plantar incision at the hindpaw, waited 21 days for the resolution of hyperalgesia, and then intrathecally injected subtype-selective ligands. We found that the MOR-selective inhibitor CTOP (1-1000 ng) dose-dependently reinstated mechanical hyperalgesia. Two DOR-selective inhibitors naltrindole (1-10 μg) and TIPP[Ψ] (1-20 μg) reinstated mechanical hyperalgesia, but only at the highest dose that also produced itching, licking, and tail biting. Both the prototypical KOR-selective inhibitors nor-BNI (0.1-10 μg) and the newer KOR inhibitor with more canonical pharmocodynamic effects, LY2456302 (0.1-10 μg), reinstated mechanical hyperalgesia. Furthermore, LY2456302 (10 μg) increased the expression of phosphorylated signal-regulated kinase (PERK), a marker of central sensitization, in dorsal horn neurons but not glia. Sex studies revealed that LY2456302 (0.3 μg) reinstated hyperalgesia and PERK expression to a greater degree in female as compared to male mice. Our results suggest that spinal MOR and KOR, but not DOR, maintain LS within a state of remission to reduce the intensity and duration of postoperative pain, and that endogenous KOR but not MOR analgesia is greater in female mice.

Keywords

Dorsal horn; Hyperalgesia; Kappa opioid receptor; Mu opioid receptor; Pain; Postoperative; Sex; Spinal cord.

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