Andrea G. Nackley

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My research experience began as a graduate student in the laboratory of Dr. Karl Pribram at Radford University, where I studied the representation of somatosensory information at the level of the central nervous system. My thesis work employed multi-electrode electrophysiology to evaluate the representation of rat’s vibrissal cues in the barrel cortex, an anatomically distinct brain area corresponding to the facial whiskers. I found that spectral and spatiotemporal approaches best account for texture discrimination and receptive field properties, such as directional selectivity. This work laid the foundation for my longstanding interest in sensory processes.

My graduate efforts in the laboratory of Dr. Andrea Hohmann at the University of Georgia focused on characterizing the role of the cannabinoid CB2 receptor in the modulation of inflammatory pain. The cannabinoid system, composed of CB1 and CB2 receptor subtypes, is an endogenous system involved in pain suppression. My early work in Dr. Hohmann’s laboratory involved characterizing the role of CB2 in modulating inflammatory pain. My research provided the first evidence that selective activation of CB2 receptors in the periphery suppresses the transmission of inflammation-evoked neuronal activity. In neuroanatomical studies, I demonstrated that activation of CB2 receptors in the periphery selectively suppressed the development of Fos protein expression, a marker of neuronal activity, in populations of spinal dorsal horn neurons that contribute to nociception.

My dissertation work employed electrophysiological methods to directly examine the effects of local CB2 activation on spinal processing under inflammatory conditions. Carrageenan-induced inflammation produces a variety of changes in spinal neuronal excitability, such as increased spontaneous activity and neuronal sensitization. Application of a CB2-specific agonist decreased the excitability of nociceptive neurons in the spinal dorsal horn under inflammatory conditions. Furthermore, I found that CB2 activation in the periphery attenuates the development of inflammation-evoked behavioral sensitization to thermal and mechanical stimulation. Collectively, these data demonstrated that actions at peripheral CB2 receptors are sufficient to suppress inflammation-evoked neuronal activity in the spinal dorsal horn, consistent with the ability of CB2 agonists to suppress inflammation-evoked pain behavior.

My interest in pain modulatory mechanisms led me to pursue a postdoctoral position with Drs. Diatchenko and Maixner at the University of North Carolina, where I investigated human genetic risk factors that contribute to temporomandibular joint disorder (TMJD), a common chronic musculoskeletal pain condition, and related chronic pain conditions. In a prospective cohort study, we identified three common variants of the gene encoding catechol-O-methyltransferase (COMT; an enzyme that metabolizes epinephrine, norepinephrine, and dopamine) that are associated with pain sensitivity and the likelihood to develop TMJD. My recent work extended these findings by directly assessing the relationship between single nucleotide polymorphisms in the COMT gene, COMT enzymatic activity, and pain sensitivity. I found that cells expressing the variant associated with high pain sensitivity exhibited low levels of COMT activity. In subsequent studies, I found that elevated levels of epinephrine/norepinephrine in the rat, resulting from low COMT activity, lead to increased pain sensitivity and proinflammatory cytokine production by stimulating beta2-and beta3-adrenergic receptors. These findings are of considerable clinical importance, suggesting that persistent pain conditions resulting from low COMT can be treated with pharmacological agents that block beta2-and beta3-adrenergic receptors.

Upon completion of my postdoctoral fellowship in July 2006, I began working as a Research Assistant Professor in the School of Dentistry’s Center for Neurosensory Disorders with K12 funding. Through the support of the roadmap K12, I have acquired additional molecular genetic and clinical pain assessment training. This training has facilitated my current research efforts aimed at identifying genetic polymorphisms and markers of COMT and beta2/3-adrenergic receptor biological activity that are predictive for pain sensitivity and TMJD onset.

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