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Jon D. Levine, M.D.
Medicine Major Research Interest:
Signal transduction and second messenger signaling in pain sensory neurons
PNS and CNS pain control mechanisms. Neural-endocrine control of inflammation; effects of stress on inflammation.
Alterations in nociceptive mechanisms in clinically relevant experimental neuropathic models: diabetes, chemotherapy, alcohol and sympathetically-maintained pain Phone: 415-476-5108/4902
Email:
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Date Available: Ongoing Project Type | | Funding | | | Rotation | Yes | NIH | Yes | | Summer | Yes | Private Foundation | Yes | | Thesis | Yes | Other | Yes | Abstract: My laboratory employs a multidisciplinary approach: molecular, biochemical, in vitro and in vivo electrophysiological and behavioral techniques are employed to evaluate mechanisms underlying pain, analgesia and inflammatory states. I am investigating signal transduction mechanisms for mechanical, thermal and chemical stimulus-induced activation of sensory neurons and mechanisms underlying sensitization of responses to these stimuli. We have described novel transducer mechanisms for thermal stimuli. We have also described a second messenger pathway mediating sensitization. We have demonstrated recently, using knockout mice, a novel role for the epsilon isoform of PKC in mediating nociception. We have also recently developed the first in vitro model for study of mechanical transduction in somatosensory neurons. We are in the process of developing a model for the development of a propensity for a chronic inflammatory pain state after a period of resolved acute inflammation. I also investigate circuits that mediate analgesia and have described a novel analgesia circuit involving limbic pathways. Recently we demonstrated that a sufficiently intense painful stimulus could result in a prolonged period of heterosegmental antinociception that depends on mechanisms of the mesolimbic dopaminergic reward pathway. The modulation of transduction in the periphery, by opioids, is also being investigated, including the mechanisms underlying opioid tolerance and dependence for peripheral antinociception. I am investigating neural and endocrine contributions to inflammation and to the immune response. We have elucidated a physiological mechanism consisting of a negative feedback inhibition of the inflammatory response, involving neural and endocrine circuits. Shedding of the neutrophil adhesion molecule L-selectin plays a critical role in this feedback inhibition as well as action locally of annexin. We have also recently investigated effects of nicotine on inflammation, at very low dose, relevant to both smokers and individuals exposed to secondhand smoke. In a recent study we demonstrated that stress, when introduced chronically, intermittently, can be a potent modulator of inflammatory response. The roles of the individual stress axes (HPA, sympathoadrenal and sympathetic) are investigated. Our laboratory has an emerging interest in developing and understanding mechanistically, animal models relevant to the major neuropathies experienced in clinical medicine. We have demonstrated alterations in electrophysiological and cellular second messenger response in models of diabetes and chemotherapy-induced neuropathy. We are presently embarking on the establishment of a model for painful alcoholic neuropathy. We also have had a longstanding interest in the roles of the different adrenergic receptors in sympathetically-maintained pain models. Finally, we have, in both experimental and clinical studies, demonstrated a profound role of gender and often sex hormones in nociception and anti-nociception, including that mediated by opioids of different receptor class. We also have demonstrated marked effects of gender for the influence of vagal afferent activity on processing of nociceptive stimuli, both acutely and tonically.
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