Sex Differences in Opioid Analgesia and Addiction: Interactions Among Opioid Receptors and Estrogen Receptors

Overview

Journal Mol Pain

Date 2013 Sep 10

PMID 24010861

Citations 50

Authors

Cynthia Wei-Sheng Lee

Ing-Kang Ho

Affiliations

Soon will be listed here.

Abstract

Opioids are widely used as the pain reliever and also notorious for being addictive drugs. Sex differences in the opioid analgesia and addiction have been reported and investigated in human subjects and animal models. Yet, the molecular mechanism underlying the differences between males and females is still unclear. Here, we reviewed the literature describing the sex differences in analgesic responses and addiction liabilities to clinically relevant opioids. The reported interactions among opioids, estrogens, opioid receptors, and estrogen receptors are also evaluated. We postulate that the sex differences partly originated from the crosstalk among the estrogen and opioid receptors when stimulated by the exogenous opioids, possibly through common secondary messengers and the downstream gene transcriptional regulators.

Citing Articles

Brain-wide mapping reveals temporal and sexually dimorphic opioid actions.

Vasylieva I, Smith M, Aravind E, He K, Ling T, Kozel J bioRxiv. 2025; .

PMID: 40060548 PMC: 11888231. DOI: 10.1101/2025.02.19.638902.

Superior efficacy of intramuscular diclofenac compared to intravenous tramadol for acute renal colic in northern Thai patients: A randomised double-blind, sham-controlled trial.

Yaowalaorng J, Kunthasook W, Lokeskrawee T, Patumanond J, Wongyikul P, Lawanaskol S Emerg Med Australas. 2025; 37(1):e14550.

PMID: 39763427 PMC: 11704847. DOI: 10.1111/1742-6723.14550.

Validation studies and multi-omics analysis of Zhx2 as a candidate quantitative trait gene underlying brain oxycodone metabolite (oxymorphone) levels and behavior.

Lynch W, Miracle S, Goldstein S, Beierle J, Bhandari R, Gerhardt E bioRxiv. 2024; .

PMID: 39257803 PMC: 11383981. DOI: 10.1101/2024.08.30.610534.

Epigenetic and sex differences in opioid use disorder in chronic pain: A real-world study linked with OPRM1 DNA methylation.

Agullo L, Escorial M, Orutno S, Muriel J, Sandoval J, Margarit C Addict Biol. 2024; 29(7):e13422.

PMID: 38949208 PMC: 11215788. DOI: 10.1111/adb.13422.

County-Level Atrazine Use and Gastroschisis.

Krishnapura S, McNeer E, Dupont W, Patrick S JAMA Netw Open. 2024; 7(5):e2410056.

PMID: 38709530 PMC: 11074809. DOI: 10.1001/jamanetworkopen.2024.10056.

References

Sibille K, Kindler L, Glover T, Gonzalez R, Staud R, Riley 3rd J . Individual differences in morphine and butorphanol analgesia: a laboratory pain study. Pain Med. 2011; 12(7):1076-85. PMC: 3155877. DOI: 10.1111/j.1526-4637.2011.01157.x. View

Lu C, Hsieh J, Dun N, Oprea T, Wang P, Luo J . Estrogen rapidly modulates 5-hydroxytrytophan-induced visceral hypersensitivity via GPR30 in rats. Gastroenterology. 2009; 137(3):1040-50. DOI: 10.1053/j.gastro.2009.03.047. View

Gear R, Miaskowski C, Gordon N, Paul S, Heller P, Levine J . Kappa-opioids produce significantly greater analgesia in women than in men. Nat Med. 1996; 2(11):1248-50. DOI: 10.1038/nm1196-1248. View

Fillingim R, King C, Ribeiro-Dasilva M, Rahim-Williams B, Riley 3rd J . Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009; 10(5):447-85. PMC: 2677686. DOI: 10.1016/j.jpain.2008.12.001. View

Krzanowska E, Bodnar R . Morphine antinociception elicited from the ventrolateral periaqueductal gray is sensitive to sex and gonadectomy differences in rats. Brain Res. 1999; 821(1):224-30. DOI: 10.1016/s0006-8993(98)01364-x. View

Cicero T, Aylward S, Meyer E . Gender differences in the intravenous self-administration of mu opiate agonists. Pharmacol Biochem Behav. 2003; 74(3):541-9. DOI: 10.1016/s0091-3057(02)01039-0. View

Hall J, Couse J, Korach K . The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem. 2001; 276(40):36869-72. DOI: 10.1074/jbc.R100029200. View

Sidebotham D, Dijkhuizen M, Schug S . The safety and utilization of patient-controlled analgesia. J Pain Symptom Manage. 1997; 14(4):202-9. DOI: 10.1016/s0885-3924(97)00182-6. View

Landheim A, Bakken K, Vaglum P . Gender differences in the prevalence of symptom disorders and personality disorders among poly-substance abusers and pure alcoholics. Substance abusers treated in two counties in Norway. Eur Addict Res. 2003; 9(1):8-17. DOI: 10.1159/000067732. View

10.

Hughes Z, Liu F, Marquis K, Muniz L, Pangalos M, Ring R . Estrogen receptor neurobiology and its potential for translation into broad spectrum therapeutics for CNS disorders. Curr Mol Pharmacol. 2009; 2(3):215-36. DOI: 10.2174/1874467210902030215. View

11.

Tsang A, Von Korff M, Lee S, Alonso J, Karam E, Angermeyer M . Common chronic pain conditions in developed and developing countries: gender and age differences and comorbidity with depression-anxiety disorders. J Pain. 2008; 9(10):883-91. DOI: 10.1016/j.jpain.2008.05.005. View

12.

Lynch W, Carroll M . Sex differences in the acquisition of intravenously self-administered cocaine and heroin in rats. Psychopharmacology (Berl). 1999; 144(1):77-82. DOI: 10.1007/s002130050979. View

13.

Dun S, Brailoiu G, Gao X, Brailoiu E, Arterburn J, Prossnitz E . Expression of estrogen receptor GPR30 in the rat spinal cord and in autonomic and sensory ganglia. J Neurosci Res. 2009; 87(7):1610-9. PMC: 2692324. DOI: 10.1002/jnr.21980. View

14.

Kecskes I, Rihmer Z, Kiss K, Sarai T, Szabo A, Kiss G . Gender differences in panic disorder symptoms and illicit drug use among young people in Hungary. Eur Psychiatry. 2002; 17(1):29-32. DOI: 10.1016/s0924-9338(02)00626-0. View

15.

Cepeda M, Carr D . Women experience more pain and require more morphine than men to achieve a similar degree of analgesia. Anesth Analg. 2003; 97(5):1464-1468. DOI: 10.1213/01.ANE.0000080153.36643.83. View

16.

Cardona-Gomez G, Mendez P, Garcia-Segura L . Synergistic interaction of estradiol and insulin-like growth factor-I in the activation of PI3K/Akt signaling in the adult rat hypothalamus. Brain Res Mol Brain Res. 2002; 107(1):80-8. DOI: 10.1016/s0169-328x(02)00449-7. View

17.

McQuay H, Bullingham R, Paterson G, Moore R . Clinical effects of buprenorphine during and after operation. Br J Anaesth. 1980; 52(10):1013-9. DOI: 10.1093/bja/52.10.1013. View

18.

Craft R, Stratmann J, Bartok R, Walpole T, King S . Sex differences in development of morphine tolerance and dependence in the rat. Psychopharmacology (Berl). 1999; 143(1):1-7. DOI: 10.1007/s002130050911. View

19.

Tamsen A, Hartvig P, Fagerlund C, Dahlstrom B . Patient-controlled analgesic therapy. Part I: Pharmacokinetics of pethidine in the per- and postoperative periods. Clin Pharmacokinet. 1982; 7(2):149-63. DOI: 10.2165/00003088-198207020-00004. View

20.

Gravanis A, Makrigiannakis A, Stournaras C, Margioris A . Interaction between steroid hormones and endometrial opioids. Ann N Y Acad Sci. 1994; 734:245-56. DOI: 10.1111/j.1749-6632.1994.tb21754.x. View