Abstract
Rationale
Sex differences in the potency of the antinociceptive effects of κ opioids have been reported in various acute pain models with evidence suggesting that these sex differences are mediated by activity in the N-methyl-d-aspartate (NMDA) system.
Objectives
The purpose of the present study was to evaluate sex differences in the antihyperalgesic actions of selected κ and mixed-action opioids in a persistent pain model and determine if the NMDA system modulates these effects in a sexually dimorphic manner.
Methods
Using gonadally intact male and female F344 rats, hyperalgesia was induced by local administration of capsaicin in the tail, after which the tail was immersed in a mildly noxious thermal stimulus (45°C water), and tail-withdrawal latency measured. Opioids were then administered systemically (s.c.) and locally (in the tail) alone, and in selected combinations with the noncompetitive NMDA antagonist dextromethorphan.
Results
When administered systemically and locally, the κ opioids spiradoline, U69,593 and U50,488, and the mixed-action opioids butorphanol and nalbuphine, produced dose-dependent antihyperalgesic effects. Whereas the κ opioids were generally more potent in males, sex differences were not observed with the mixed-action opioids. Peripheral receptor activity was confirmed for local administration of κ opioids by the antagonism observed after local, but not intracerebroventricular (i.c.v.), administration of the κ antagonist nor-binaltorphamine (nor-BNI). Dextromethorphan was equally potent in attenuating the antihyperalgesia induced by κ opioids in both males and females.
Conclusions
These findings demonstrate sex differences in κ opioid activity in a persistent pain model. Although an NMDA antagonist blocked the effects of κ opioids in this model, these effects were not sexually dimorphic as reported in most acute pain models.
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Acknowledgements
Animals used in this study were cared for in accordance with the guidelines of the Institutional Animal Care and Use Committee of the University of North Carolina at Chapel Hill and the “Guide for the Care of and Use of Laboratory Animals” (Institute of Laboratory Animal Resources, National Academy Press, 1996). This work was supported by the National Institute on Drug Abuse (NIDA) Grant DA10277 awarded to M.J.P and NIDA grant DA15709 awarded to D.T.L. L.M.L was supported by NIDA training Grant DA07244. A.C.B. was supported by NIDA predoctoral fellowship DA15273 and is currently at Cephalon, Frazer PA. J.M.T. was supported by NIDA predoctoral fellowship DA17404 and is currently a postdoctoral fellow in the Department of Psychiatry at the University of Chicago.
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Lomas, L.M., Barrett, A.C., Terner, J.M. et al. Sex differences in the potency of κ opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats. Psychopharmacology 191, 273–285 (2007). https://doi.org/10.1007/s00213-006-0663-1
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DOI: https://doi.org/10.1007/s00213-006-0663-1