(235) Homeostatic Regulation of Intrinsic Plasticity in Peripheral Nociceptors

Abstract

Stabilization of neuronal activity is crucial for normal nervous system regulation. When changes in the environment chronically alter neuronal activity, homeostatic plasticity creates compensatory shifts (i.e., regulation of intrinsic excitability) to return the system to a physiological level. This plasticity helps prevent circuits from becoming either hyper- or hypoexcitable. Despite this protective mechanism, evidence suggests that the development and maintenance of many chronic pain conditions depend on chronically altered sensory afferent activity. This led us to consider the possibility that malfunction of homeostatic mechanisms may contribute to chronic pain. Since homeostatic plasticity has been primarily studied in the central nervous system, we first tested whether this plasticity also occurs in peripheral nociceptors [i.e., small diameter dorsal root ganglia (DRG) sensory afferent neurons]. We hypothesized that mouse and human primary sensory afferents undergo homeostatic regulation of intrinsic plasticity, evidenced by compensatory changes in neuronal excitability in response to chronic stimuli. Using a combination of pharmacologic and optogenetic approaches with whole-cell electrophysiology, we previously presented that sustained, 24-hour KCl depolarization of dissociated mouse and human DRG neurons led to a compensatory decrease in excitability of small diameter cells. This suggested that putative nociceptors undergo homeostatic regulation of intrinsic excitability. In an effort to demonstrate bidirectionality of this homeostatic plasticity, in this study we used a 24-hour incubation with lidocaine and TTX. We found no change in excitability, likely due to the already quiescent nature of DRG neurons in vitro. Ongoing experiments are being performed to determine whether mechanisms of this plasticity are altered in vivo and during chronic pain. This work was supported by grants R01 NS042595 (RG) and T32DA007261 (LM).