Retigabine-induced population primary afferent hyperpolarisation in vitro.
Retigabine is a compound of potential interest in analgesia which acts as an M-channel opener to depress neuronal excitability. Here we study the effects of retigabine and its antagonist XE-991 on populations of primary afferents. Experiments were performed using a hemisected spinal cord preparation from rat pups maintained under in vitro conditions. Recording from dorsal roots were performed using tight fitting suction electrodes coupled to AC and DC amplifiers. The adjacent dorsal root was electrically stimulated at regular intervals. The effects of the modulators on basal potential, spontaneous potentials and dorsal root-dorsal root responses were studied. Superfusion of retigabine (10 microM) produced long lasting and robust hyperpolarisation of primary afferents which persisted during superfusion of picrotoxin (20 microM) and tetrodotoxin (0.5 microM). Other effects of retigabine were (1) increase in stimulation threshold; (2) increase in size of responses to suprathreshold stimuli; and (3) increase in amplitude and decrease in frequency of spontaneous dorsal root potentials. Superfusion of XE-991 had little effect on its own but blocked all the effects of retigabine. These results indicate the presence of functional M-currents in central terminals of primary afferents and in the interneurones that mediate dorsal root potentials. The depressant effects of retigabine on the excitability of these structures may contribute to its analgesic effects after pain-inducing treatments.
Rivera-Arconada
I
I
Department of Physiology, Edificio de Medicina, Campus Universitario, University of Alcala, Alcala de Henares, 28871 Madrid, Spain.
Lopez-Garcia
J A
JA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D000344:Afferent Pathways / Q000187:drug effects*; D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology*; D002219:Carbamates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005971:Glutamates / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010655:Phenylenediamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects
D000873:Anthracenes; D000927:Anticonvulsants; D002219:Carbamates; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D005971:Glutamates; D010655:Phenylenediamines; D010852:Picrotoxin; C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; C101866:ezogabine; C046105:4-methylglutamic acid