Anne Z. Murphy - US grants

DESCRIPTION: (Adapted From The Applicant's Abstract) The goal of this research is to elucidate the neural mechansims by which specific forebrain, brainstem and spinal cord sites coordinate male reproductive behavior. Our new preliminary studies suggest a potential pathway that mediates forebrain influences on L6/S1 cord. This circuit comprises the MPO-->PGi-->spinal cord. The nucleus paragigantocellularis (PGi) in the ventrolateral medulla receives direct input from the MPO and projects heavily to the L6/S1 cord. Our preliminary data show that descending projections from the PGi selectively terminate within the motoneuronal pools that innervate the pelvic viscera. Aim 1 will test the hypothesis that MPO projections target PGi neruons that project to the lumbosacral spinal cord. A combined approach using both antero and retrograde tracers will be used to delineate the anatomical organization of MPO-->PGi-->spinal cord circuit. Spinal sexual reflexes are under tonic descending inhibition, presumably via input from the PGi. Recent studies suggest that MPO neuronal activity must increase for normal male reproductive behavior to occur. We postulate therefore that increased MPO activity before and during copulation functions, in part, to reduce the tonic inhibition ("disinhibition hypothesis") on spinal motor reflexes. Aim 2 employs coordinate neuroanatomical, immunocytochemical and electrophysiological techniques to test this disinhibition hypothesis: MPO activation inhibits PGi-->spinal cord neurons allowing for spinally mediated sexual reflexes to occur. The MPO and its output to the PGi are central for the initiation and maintenance of male sex behavior. Aim 3 tests the hypothesis that the MPO-->PGi circuit is selectively engaged during male sex behavior; activation of this circuit during copulation inhibits PGi pudendal premotor neurons via the release of GABA. As copulation is a steroid dependent behavior, we predict that the critical neural substrates along this MPO-->PGi-->spinal cord circuit will contain receptors for gonadal steroids. These studies will provide the first functional characterization of the MPO-->PGi-->spinal cord pathway. Together, these studies will provide detailed anatomical and physiological data on a neural circuit regulating male sex behavior.

DESCRIPTION (provided by applicant): 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.

ABSTRACT The goal of these studies is to understand the impact of advanced age on opiate modulation of persistent pain. In 2013, people aged 65 and older represented 14.1% of the US population. These numbers are expected to rise dramatically, with person?s aged 65 years or older accounting for 20- 30% of the total population by 2030. Unfortunately, one of the consequences of increased longevity is pain, with 45-85% of the population aged 65 or older experiencing pain on a daily basis. Unfortunately, chronic pain is under-treated for the majority of elderly persons. A primary factor contributing to the under management of pain is the dearth of knowledge on the impact of age on pain and opiate sensitivity. Indeed, a recent consensus statement issued by a multidisciplinary group of pain experts states: ?The paucity of guidelines for opioid use in the elderly reflects the lack of studies of these drugs on the old.? A clear understanding of age-associated changes in opioidergic circuits of males and females is critical for evidence-based pain management in this population. Our behavioral data indicate that the antihyperalgesic effect of morphine is significantly attenuated in aged (18-24 mos) versus adult (2-3 mos) rats. Indeed, the ED50 dose for aged animals is 7.0 mg/kg in comparison to 3.5 mg/kg for adults. Our overarching hypothesis is that age- induced changes in mu opioid receptor expression and signaling within the midbrain periaqueductal gray (PAG) provide the biological bases for the decreased sensitivity to opiates observed in the elderly. Three specific aims are proposed to determine the influence of advanced age on mu opioid receptor expression and receptor pharmacodynamics (SA1) and G protein receptor coupling and regulation (SA2). Aim 3 will use molecular and pharmacological techniques to boost central MOR signaling, thereby reducing morphine dosing requirements. Together, these studies will provide novel and critical data on the impact of age on opiate effectiveness, and will stimulate evidence-based therapies for the management of pain in the elderly.