Neuronal nicotinic acetylcholine receptors (nAChRs) are expressed throughout the central nervous system, and are active in a wide array of physiological phenomena including addiction, cognition, locomotion, autonomic function, and sensation. While a role for nAChRs in these activities is clear from the pharmacological action of cholinergic agonists, the physiological role of specific nAChR subtypes in these processes is often unresolved. Neuronal nAChRs are pentameric ion channels composed of a variety of alpha and beta subunits, and the specific subunit combination can have a dramatic impact on channel properties including agonist and antagonist selectivity profiles, as well as the kinetics of activation, inactivation, and desensitization. The proposed research plan describes a set of experiments designed to study nAChR subunit expression in dorsal root ganglia (DRG) and the spinal cord dorsal horn (SC). The experiments will also examine the physiological role of specific receptor subtypes in the modulation of nociceptive processing. Whole-cell patch clamp recordings of neurons will be used to characterize the functional nAChRs expressed in these cells. Corroborative evidence will come from single-cell RT-PCR analysis of mRNA expression in recorded neurons, as well as immunohistochemistry of neurons in culture and tissue slices. Finally, spinal cord slices and neuronal co-cultures will be used to directly assay the modulation of synaptic transmission between DRG and SC neurons.
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