Research
Our major research focuses on sex differences in pain and opiate analgesia. Opiate-based analgesics, including morphine, are the primary therapeutic agent prescribed for the alleviation of persistent pain. Recent studies in both human and animals suggest that morphine does not produce the same degree of pain relief in males and females. Indeed, it has been shown in a variety of acute and persistent pain models that females require twice the amount of morphine as a male in order to produce the same degree of pain relief (for research papers on this topic from the lab see Wang et al., 2006 or Ji et al., 2006). To date, the mechanisms underlying sex differences in morphine analgesia are unknown.
The Midbrain Periaqueductal Gray
 Morphine produces an analgesic response by binding to mu opioid receptors (MORs) within a region of the brain called the periaqueductal gray (PAG). Blocking the ability of morphine to bind to mu opioid receptors within the PAG by direct administration of selective antagonists (Bernal et al., 2007) or neurotoxins such as dermorphin-conjugated saporin (Loyd and Murphy, SFN Poster 2007) completely attenuates the pain-relieving effects of systemic morphine.
 Given the importance of the PAG for morphine-induced analgesia, we hypothesized that this brain region may be different anatomically and/or physiologically, and that these differences in the PAG contribute to the sexually dimorphic effects of morphine. Using anterograde and retrograde tract tracers, Dayna Loyd, a graduate student in the lab, demonstrated that there are significant sex differences in the projections from the PAG to the rostral ventromedial medulla (RVM), an essential output of the PAG for morphine-mediated analgesia (Loyd and Murphy, 2006). Dayna’s studies also demonstrated that persistent inflammatory pain differentially activated the PAG-RVM pathway, and that administration of morphine suppressed pain-induced activation of the pathway in males only. These studies were the first to demonstrate a sex difference in the anatomy and physiology of an established pain pathway. Dayna’s research has also implicated this pathway as providing a biological basis for sex differences in the development of morphine tolerance.
Sex differences in Mu Opioid Receptor Expression
 Additional on-going studies in the lab are focusing on both the expression and activation of the mu opioid receptor. Using a variety of techniques, including immunocytochemistry and receptor autoradiography, our data indicate that expression of the mu opioid receptor within discrete regions of the brain is two-fold higher in males in comparison to females. Brain regions showing significant sex differences in MOR expression include the PAG, the parabrachial nucleus – an essential site for visceral pain modulation, and potentially the ventroposterior nuclei of the thalamus. Malcolm Johns, our lab technician, is currently using the GTPgS assay to look at sex differences in G protein coupling within the PAG, RVM and spinal cord. Of particular interest to the lab is the impact of persistent pain on both the expression and activation of MOR in males and females. Remarkably, while it is clear that persistent inflammatory pain results in a left-ward shift in the dose response curve for morphine (Wang et al., 2006), the mechanisms underlying this change in morphine sensitivity are not known.
Impact of Age on Pain and Analgesia
Most recently, our lab is examining the impact of age on the pharmacodynamics of morphine. Surprisingly, there is very little information currently available on how the aging process affects pain and analgesia. These studies are being conducted by Rick Hanberry, a graduate student in the lab.
Impact of Neonatal Injury in Adulthood
 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. Graduate student Jamie LaPrairie has shown that neonatal inflammatory injury results in a significant decrease in pain sensitivity in adulthood, as well as enhanced hyperalgesia following a subsequent injury. These negative consequences are significantly exacerbated in females in comparison to males. Additional studies in our laboratory have shown that one of the mechanisms that may contribute to the neonatal injury-induced hypoalgesia is altered central opioid tone, and that pre-emptive morphine attenuates the behavioral consequences of neonatal injury.
Supraspinal Control of Genital Reflexes
Another line of research in our lab examines the neural mechanisms of sexual behavior. Joe Normandin, a graduate student in our lab, uses tract tracing, pharmacology, and immunocytochemical techniques to examine the anatomy and physiology of the descending inhibition of genital reflexes in male and female rats produced by the nucleus paragigantocellularis (nPGi). He has found that the organization of nPGi afferents of male and female rats is similar in many respects, and is sensitive to gonadal steroids. However, he has observed sex differences in specific subregions of the brain, such as the medial preoptic area and the perifornal nucleus of the hypothalamus, in the number of cells projecting to the nPGi and the number of cells activated during sexual behavior. His is continuing his work with the nPGi to further elucidate it's function and neurochemistry in both sexes. This work has implications not only in our understanding of normal human sexual functioning but also for the treatment of sexual disorders in humans.
|
