Opening of KCNQ/Kv7 channels blocks both spontaneous activity in small DRG neurons and signs of chronic pain after spinal cord injury

Abstract

Spinal cord injury (SCI) often causes chronic, intractable pain. Increased spontaneous activity (SA) has been found months after contusive SCI in a large fraction of nociceptors. SA recorded in small dissociated DRG neurons is significantly correlated with hypersensitivity of withdrawal reflexes tested prior to dissociation. The association of nociceptor SA with depolarization and increased membrane resistance suggests that SA involves a decrease in open K+ channels. Conversely, opening background K+ channels that remain after SCI might be a useful strategy to reduce nociceptor SA and ameliorate chronic pain. KCNQ/Kv7 channels are expressed in presumptive nociceptors, and are important for controlling resting membrane potential and excitability. Whole-cell patch clamp recording and dorsal root filament recording were performed in this study. KCNQ/Kv7 currents were unchanged after SCI compared to controls, suggesting that alterations of other K+ channels are responsible for the chronic depolarization and increased membrane resistance observed after SCI. A specific KCNQ channel blocker (XE991,10 μM) caused similar depolarization and repetitive firing in previously silent neurons dissociated from naïve, sham and SCI rats. Importantly, retigabine (10 μM), an FDA-approved opener of KCNQ channels, hyperpolarized DRG neurons and reversibly reduced SA and repetitive firing in vitro and in vivo. Furthermore, hypersensitivity of hindlimb and forelimb withdrawal reflexes to mechanical and thermal stimuli 1 month after SCI was reversed by retigabine (10 mg/kg i.p.). Preliminary results indicate that retigabine also reduces an operant measure of pain. Thus, KCNQ channel openers that potently reduce nociceptor activity may be a useful treatment for chronic pain after SCI. (Bedi, J Neurosci, 2010; Carlton, Pain, 2009; Passmore J Neurosci, 2003.) Supported by the Paralyzed Veterans of America and Craig H. Neilsen Foundations.