Associate Director of the Neuroscience Institute
Office: 814 Petit Science Center
Phone: (404) 413-5332
Our major research interest focuses on how endogenous gonadal steroids influence pain sensitivities. It is well established that women exhibit a higher prevalence of temporomandibular disorders, neuropathic pain, fibromyalgia, migraine headaches and some forms of arthritis. Furthermore, variations in hormonal levels associated with the menstrual cycle, menopause, pregnancy and lactation influence pain levels. The midbrain periaqueductal gray (PAG) has long been established as an important neural structure in the endogenous descending analgesia system. Stimulation of this region produces long lasting antinociception that is mediated, in part, via the release of endogenous opioids. In addition to sex-based differences in pain sensitivity, there is also a sex difference in morphine sensitivity, such that the ED50 dose is 8 fold lower for males than for females. These differences are not due to the pharmacokinetics of morphine, but rather, due to inherent differences in the sensitivity of the brain to morphine. Where these differences lie, however, is not known.
Our research utilizes a multidisciplinary approach to examining how pain and opioidergic neural circuits are differentially organized and activated in males and females. Ongoing behavioral studies in the lab have demonstrated that males and females have significantly different sensitivities to morphine in a model of chronic inflammatory pain. Indeed, the ED50 for systemic morphine in males is 4.5 mg/kg in comparison to >14 mg/kg in females. Current molecular studies are examining the potential mechanisms that may contribute to sex based differences in morphine analgesia. Using in situ hybridization along with advanced immunocytochemical techniques, we have recently shown that the distribution of the mu and delta opioid receptor (both protein and mRNA) is sexually dimorphic within the PAG.
Future studies will use adeno-associated viruses to overexpress the mu opioid receptor within the PAG of females in order to make them more ‘male-like’ in their sensitivity to opioids. Additional studies in the laboratory are examining the organization of the descending analgesia circuit in males and females. While this circuit has been well characterized in a variety of species, to date, how this pathway is organized in females remains unknown. Using antero- and retrograde tract tracing techniques, we have recently shown that the descending projections from the PAG are sexually dimorphic both in the anatomical organization, as well as in their activation during either acute or chronic inflammatory pain.
A second line of research in our laboratory is examining the influence of neonatal injury on adult sensory development. All previous studies examining the impact of neonatal injury have been conducted exclusively in males. However, males and females differ significantly in their neuroendocrine profile during the first week of life. In particular, males experience a surge in testosterone that is locally converted into estrogen and ultimately results in the masculinization of the male brain. In females, the ovaries are quiescent and intracerebral estradiol remains low. As estradiol has been previously shown to confer neuroprotection following CNS injury, ongoing experiments in the lab are testing the hypothesis that the effects of neonatal injury on adult sensory thresholds are exacerbated in female rats in comparison to males. These studies also utilize a multidisciplinary approach, including behavioral, neuroanatomical, immunocytochemical and molecular techniques.