Chronic pain afflicts millions of people each year. Opioid-based narcotics are the most prevalent therapeutic treatment for chronic pain management, with morphine being the most commonly prescribed. There are now well-established sex differences in the ability of morphine to alleviate pain; in animals models of acute pain, the effective dose of morphine is approximately 5-lOx greater for females in comparison to males. Similar results have been reported in humans. To date, the underlying mechanisms mediating sex differences in opiate sensitivity are not known. The midbrain periaqueductal gray (PAG) and its descending projections to the nucleus raphe magnus (NRM) are an essential endogenous neural circuit for opioid-based analgesia. Our major hypothesis is that the opiate-sensitive intrinsic and extrinsic circuitry of the FAG is sexually dimorphic and is the major determinant of sex-based differences in opioid analgesia. Previous studies examining the dimorphic effect of opioid administration utilized acute assays of nociception. Studies proposed in Aim 1 will characterize the sexually dimorphic effect of central morphine administration using a model of chronic inflammatory pain. Our preliminary data indicate that the PAG-NRM pathway is sexually dimorphic. Studies proposed in Aim 2 will use neural tract tracing techniques to delineate the anatomical organization of the PAG-NRM-spinal cord circuit in males and females.
Aim 3 will examine the functional organization of this circuit in a model of prolonged inflammatory pain. The PAG is enriched in opioid receptors. Studies proposed in Aim 4 will characterize both the distribution and expression pattern of the opioid receptors. The influence of chronic inflammatory pain and gonadal steroid manipulations will also be examined. In summary, these studies will establish that the intrinsic and extrinsic circuitry of the PAG is sexually dimorphic and provide the neural substrate for sex based differences in opioid analgesia.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Thomas, David A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgia State University
Schools of Arts and Sciences
United States
Zip Code
Doyle, H H; Murphy, A Z (2018) Sex-dependent influences of morphine and its metabolites on pain sensitivity in the rat. Physiol Behav 187:32-41
Doyle, Hillary H; Murphy, Anne Z (2017) Sex differences in innate immunity and its impact on opioid pharmacology. J Neurosci Res 95:487-499
Eidson, Lori N; Inoue, Kiyoshi; Young, Larry J et al. (2017) Toll-like Receptor 4 Mediates Morphine-Induced Neuroinflammation and Tolerance via Soluble Tumor Necrosis Factor Signaling. Neuropsychopharmacology 42:661-670
Doyle, Hillary H; Eidson, Lori N; Sinkiewicz, David M et al. (2017) Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of Morphine. J Neurosci 37:3202-3214
Victoria, Nicole C; Murphy, Anne Z (2016) The long-term impact of early life pain on adult responses to anxiety and stress: Historical perspectives and empirical evidence. Exp Neurol 275 Pt 2:261-73
Victoria, Nicole C; Murphy, Anne Z (2016) Exposure to Early Life Pain: Long Term Consequences and Contributing Mechanisms. Curr Opin Behav Sci 7:61-68
Deak, Terrence; Quinn, Matt; Cidlowski, John A et al. (2015) Neuroimmune mechanisms of stress: sex differences, developmental plasticity, and implications for pharmacotherapy of stress-related disease. Stress 18:367-80
Loyd, Dayna R; Murphy, Anne Z (2014) The neuroanatomy of sexual dimorphism in opioid analgesia. Exp Neurol 259:57-63
Eidson, Lori N; Murphy, Anne Z (2013) Persistent peripheral inflammation attenuates morphine-induced periaqueductal gray glial cell activation and analgesic tolerance in the male rat. J Pain 14:393-404
Victoria, Nicole C; Inoue, Kiyoshi; Young, Larry J et al. (2013) Long-term dysregulation of brain corticotrophin and glucocorticoid receptors and stress reactivity by single early-life pain experience in male and female rats. Psychoneuroendocrinology 38:3015-28

Showing the most recent 10 out of 29 publications