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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 volume 191, pages 273–285 (2007)Cite this article

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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References

  • Antonijevic I, Mousa AS, Schafer M, Stein C (1995) Perineurial defect and peripheral opioid analgesia in inflammation. J Neurosci 15:165–172

    PubMed  CAS  Google Scholar 

  • Barrett AC (2006) Low efficacy opioids: implications for sex differences in opioid antinociception. Exp Clin Psychopharmacol 14:1–11

    PubMed  Article  CAS  Google Scholar 

  • Barrett AC, Smith ES, Picker MJ (2002) Sex-related differences in mechanical nociception and antinociception produced by μ- and κ-opioid receptor agonists in rats. Eur J Pharmacol 452:163–173

    PubMed  Article  CAS  Google Scholar 

  • Barrett AC, Smith ES, Picker MJ (2003) Capsaicin-induced hyperalgesia and mu opioid-induced antihyperalgesia in male and female rats. J Pharmacol Exp Ther 307:237–245

    PubMed  Article  CAS  Google Scholar 

  • Binder W, Carmody J, Walker J (2000) Effect of gender on anti-inflammatory and analgesic actions of two κ-opioids. J Pharmacol Exp Ther 292:303–309

    PubMed  CAS  Google Scholar 

  • Butelman ER, Ko M-C, Sobczyk-Kojiro K, Mosberg HI, van Bemmel B, Zernig G, Woods JH (1998) Kappa-opioid receptor binding populations in rhesus monkey brain: relationship to an assay of thermal antinociception. J Pharmacol Exp Ther 285:595–601

    PubMed  CAS  Google Scholar 

  • Clemente JT, Parada CA, Veiga MC, Gear RW, Tambeli CH (2004) Sexual dimorphism in the antinociception mediated by kappa opioid receptors in the rat temporomandibular joint. Neurosci Lett 372:250–255

    PubMed  Article  CAS  Google Scholar 

  • Cook CD, Nickerson MD (2005) Nociceptive sensitivity and opioid antinociception and antihyperalgesia in Freund’s adjuvant-induced arthritic male and females rats. J Pharmacol Exp Ther 313:449–459

    PubMed  Article  CAS  Google Scholar 

  • Cook CD, Barrett AC, Roach EL, Bowman JR, Picker MJ (2000) Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity and efficacy at the μ opioid receptor. Psychopharmacology 150:430–442

    PubMed  Article  CAS  Google Scholar 

  • Craft RM (2003) Sex differences in opioid analgesia: “from mouse to man”. Clin J Pain 19:175–186

    PubMed  Article  Google Scholar 

  • Craft RM, Bernal SA (2001) Sex differences in opioid antinociception: kappa and ‘mixed action’ agonists. Drug Alcohol Depend 63:215–228

    PubMed  Article  CAS  Google Scholar 

  • Craft R, Lee D (2005) NMDA antagonist modulation of morphine antinociception in female vs. male rats. Pharmacol Biochem Behav 80:639–649

    PubMed  Article  CAS  Google Scholar 

  • Danysz W, Essmann U, Bresink R (1994) Glutamate antagonists have different effects on spontaneous locomotor activity in rats. Pharmacol Biochem Behav 48:111–118

    PubMed  Article  CAS  Google Scholar 

  • Dykstra LA (1990) Butorphanol, levallorphan, nalbuphine and nalorphine as antagonists in the squirrel monkey. J Pharmacol Exp Ther 214:245–252

    Google Scholar 

  • Eisenberg E, Vos BP, Strassman AM (1993) The NMDA antagonist memantine blocks pain behavior in a rat model of formalin induced facial pain. Pain 54:301–307

    PubMed  Article  CAS  Google Scholar 

  • Falcon M, Guendellman D, Stolberg A, Frenk H, Urca G (1996) Development of thermal nociception in rats. Pain 67:203–208

    PubMed  Article  CAS  Google Scholar 

  • Holtman JR Jr, Wala EP (2006) Characterization of the antinociceptive effect of oxycodone in male and female rats. Pharmacol Biochem Behav 83:100–108

    PubMed  Article  CAS  Google Scholar 

  • Holtman JR Jr, Jing X, Wala EP (2003) Sex related differences in the enhancement of morphine antinociception by NMDA receptor antagonists in rats. Pharmacol Biochem Behav 76:285–293

    PubMed  Article  CAS  Google Scholar 

  • Holzer P (1991) Capsaicin: cellular targets, mechanisms of action and selectivity for thin sensory neurons. Pharmacol Rev 43:143–201

    PubMed  CAS  Google Scholar 

  • Ji RR, Zhang Q, Law PY, Low HH, Elde R, Hokfelt T (1995) Expression of mu, delta and kappa opioid receptor like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation. J Neurosci 15:8156–8166

    PubMed  CAS  Google Scholar 

  • Joshi SK, Gebhart GF (2003) Nonopioid actions of U50,488 enantiomers contribute to their peripheral cutaneous antinociceptive effects. J Pharmacol Exp Ther 305:919–924

    PubMed  Article  CAS  Google Scholar 

  • Kavaliers M, Choleris E (1997) Sex differences in N-methyl-D-aspartate involvement in κ opioid and non-opioid predator-induced analgesia in mice. Brain Res 768:30–36

    PubMed  Article  CAS  Google Scholar 

  • Kavaliers M, Galea L (1995) Sex differences in the expression and antagonism of swim stress-induced analgesia in deer mice vary with the breeding season. Pain 63:327–334

    PubMed  Article  CAS  Google Scholar 

  • Ko MCH, Johnson MD, Butelman ER, Willmont KJ, Mosberg HI, Woods JH (1999) Intracisternal nor-binaltorphimine distinguishes central and peripheral kappa-opioid antinociception in rhesus monkeys. J Pharmacol Exp Ther 291:1113–1120

    PubMed  CAS  Google Scholar 

  • Ko MCH, Tuchman JE, Johnson MD, Wiesanuer K, Woods JH (2000) Local administration of mu or kappa opioid agonists attenuates capsaicin-induced thermal hyperalgesia via peripheral opioid receptors in rats. Psychopharmacology 148:180–185

    PubMed  Article  CAS  Google Scholar 

  • Kumor KM, Haertzen CA, Johnson RE, Kocher T, Jasinski D (1986) Human psychopharmacology of ketocyclazocine as compared with cyclazocine, morphine and placebo. J Pharmacol Exp Ther 238:960–968

    PubMed  CAS  Google Scholar 

  • Le Bars D, Gozariu M, Cadden SW (2001) Animal models of nociception. Pharmacol Rev 53:597–652

    PubMed  Google Scholar 

  • McCall WD, Tanner KD, Levine JD (1996) Formalin induces biphasic activity in C-fibers in the rat. Neurosci Lett 208:45–48

    PubMed  Article  CAS  Google Scholar 

  • Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KVS, Lariviere WR, Groce MK, Wallace MR, Kaplan L, Staud R, Ness TJ, Glover TL, Stankova M, Mayorov A, Hruby VJ, Grisel JE, Fillingim RB (2003) The melanocortin-1 receptor gene mediates female specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci USA 100:4867–4872

    PubMed  Article  CAS  Google Scholar 

  • Nishimura W, Tadatoshi M, Tatsumi S, Sakimura K, Mishina M, Minami T, Ito S (2004) Characterization of N methyl-D-aspartate receptor subunits responsible for post operative pain. Eur J Pharmacol 503:71–75

    PubMed  Article  CAS  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, San Diego

    Google Scholar 

  • Plesan A, Hedman U, Xu X-J, Wiesenfeld-Hallin Z (1998) Comparison of ketamine and dextromethorphan in potentiating the antinociceptive effect of morphine in rats. Anesth Analg 86:825–829

    PubMed  Article  CAS  Google Scholar 

  • Przewlocki R, Przewlocka B (2001) Opioids in chronic pain. Eur J Pharmacol 429:79–91

    PubMed  Article  CAS  Google Scholar 

  • Redwine KE, Trujillo KA (2003) Effects of NMDA receptor antagonists on acute opioid analgesia in the rat Pharmacol Biochem Behav 76:361–372

    PubMed  Article  CAS  Google Scholar 

  • Richardson JD, Vasko MR (2002) Cellular mechanisms of neurogenic inflammation J Pharmacol Exp Ther 302:839–845

    PubMed  Article  CAS  Google Scholar 

  • Rimoy GH, Bhaskar NK, Wright DM, Rubin PC (1991) Mechanism of diuretic action of spiradoline (U-62066E)–a kappa opioid receptor agonist in the human. Br J Clin Pharmacol 32:611–615

    PubMed  CAS  Google Scholar 

  • Sakurada R, Wako K, Sguiyama A, Sakurada C, Tan-Ho K, Kisara K (1998) Involvement of spinal NMDA receptors in capsaicin-induced nociception. Pharmacol Biochem Behav 59:339–345

    PubMed  Article  CAS  Google Scholar 

  • Sternberg WF, Chesler EJ, Wilson SG, Mogil JS (2004) Acute progesterone can recruit sex-specific neurochemical mechanisms mediating swim stress-induced and kappa-opioid analgesia in mice. Horm Behav 46:467–473

    PubMed  Article  CAS  Google Scholar 

  • Tallarida RJ, Murray RB (1987) Manual of pharmacologic calculations with computer programs. Springer, Berlin Heidelberg New York

    Google Scholar 

  • Yaksh TL (1997) Pharmacology and mechanisms of opioid analgesic activity. Acta Anaesthesiol Scand 41:94–111

    PubMed  CAS  Article  Google Scholar 

  • Zollner C, Shaqura MA, Bopaiah CP, Mousa S, Stein C, Schafer M (2003) Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons. Mol Pharmacol 64:202–210

    PubMed  Article  CAS  Google Scholar 

Download references

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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  1. Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-3270, USA

    Lisa M. Lomas, Andrew C. Barrett, Jolan M. Terner, Donald T. Lysle & Mitchell J. Picker

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  1. Lisa M. Lomas
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  2. Andrew C. Barrett
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  3. Jolan M. Terner
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  4. Donald T. Lysle
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  5. Mitchell J. Picker
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Correspondence to Mitchell J. Picker.

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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

Keywords

  • Sex differences
  • Capsaicin
  • Kappa opioid
  • NMDA
  • Peripheral opioid receptor
  • Mixed-action opioid