KCNQ/M currents in sensory neurons: significance for pain therapy.
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 microm) and XE991 (IC50, 0.26 microm) and enhanced by retigabine (10 microm). 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 Adelta 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.
Passmore
Gayle M
GM
Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom.
Selyanko
Alexander A
AA
Mistry
Mohini
M
Al-Qatari
Mona
M
Marsh
Stephen J
SJ
Matthews
Elizabeth A
EA
Dickenson
Anthony H
AH
Brown
Terry A
TA
Burbidge
Stephen A
SA
Main
Martin
M
Brown
David A
DA
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001001:Anura; D016466:CHO Cells; D002219:Carbamates / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D010146:Pain / Q000378:metabolism*; D059408:Pain Management; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D010655:Phenylenediamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D002219:Carbamates; D007211:Indoles; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011725:Pyridines; C101866:ezogabine; C061017:linopirdine