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The Journal of Neuroscience, August 6, 2003, 23(18):7227-7236
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KCNQ/M Currents in Sensory Neurons: Significance for Pain Therapy
Gayle M. Passmore,1 Alexander A. Selyanko,1 Mohini Mistry,1 Mona Al-Qatari,1 Stephen J. Marsh,1 Elizabeth A. Matthews,1 Anthony H. Dickenson,1 Terry A. Brown,2 Stephen A. Burbidge,2 Martin Main,3 andDavid A. Brown1 1Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, 2Neurological and Gastrointestinal Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow CM19 5AW, United Kingdom, and 3Systems Research, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, United Kingdom
Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M currents [IK(M)] play a key role in regulating neuronal excitability, and mutations in neuronal KCNQ2/3 subunits, the molecular correlates of IK(M), have previously been linked to benign familial neonatal epilepsy. Here, we demonstrate that KCNQ/M channels are also present in nociceptive sensory systems. IK(M) was identified, on the basis of biophysical and pharmacological properties, in cultured neurons isolated from dorsal root ganglia (DRGs) from 17-d-old rats. Currents were inhibited by the M-channel blockers linopirdine (IC50, 2.1 µM) and XE991 (IC50, 0.26 µM) and enhanced by retigabine (10 µM). The expression of neuronal KCNQ subunits in DRG neurons was confirmed using reverse transcription-PCR and single-cell PCR analysis and by immunofluorescence. Retigabine, applied to the dorsal spinal cord, inhibited C and A
fiber-mediated responses of dorsal horn neurons evoked by natural or electrical afferent stimulation and the progressive "windup" discharge with repetitive stimulation in normal rats and in rats subjected to spinal nerve ligation. Retigabine also inhibited responses to intrapaw application of carrageenan in a rat model of chronic pain; this was reversed by XE991. It is suggested that IK(M) plays a key role in controlling the excitability of nociceptors and may represent a novel analgesic target.
Key words: M-current; dorsal root ganglion; neuropathic pain; retigabine; KCNQ; nociceptors
Received Feb. 24, 2003; revised Jun. 2, 2003; accepted Jun. 6, 2003.
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