416 Brain Research, 214 (1981) 416~23 © Elsevier/North-Holland Biomedical Press Substance P decreases a potassium conductance of spinal cord neurons in cell culture LINDA M. NOWAK and ROBERT L. MACDONALD* Neurosciences Program, University of Michigan and ( R.L.M.) Department of Neurology, University of Michigan Medical Center, 1103 East Huron, Mich. Ann Arbor, Mich. 48109 (U.S.A.) Accepted February 5th, 1981) Key words: substance P - - potassium conductance - - neuron - - cell culture Substance P (SP) produced membrane depolarization and decreased membrane conductance of mouse spinal cord neurons in primary dissociated cell culture. SP-responses were abolished by intracellular tetraethylammonium suggesting that SP decreased potassium conductance. Reversal of SP-responses was not observed with membrane hyperpolarization suggesting that SP reduced a voltage-dependent potassium conductance that was activated by membrane depolarization. The undecapeptide substance P (SP) has a widespread, but specific, regional distribution in the central nervous system (CNS)6,2s, 32, peripheral nervous system (PNS) 15-t7, and gut31,sL The peptide has been investigated most extensively in the spinal cord where it is a neurotransmitter candidate for small diameter dorsal root primary afferent fibers15-17, 27,36,42. SP-like immunoreactivity has been localized to a subpopulation of small diameter dorsal root ganglion (DRG) neuronsTA 5-17 and to nerve fibers, synaptic terminals and synaptic vesicles in laminae I-III of the dorsal horn of the spinal c0rd3,7-9,18,37, 3s. Dorsal root and dorsal horn concentrations of SP were greater than ventral root and ventral horn concentrationsS,7,16,17, 42, and transection or ligation of dorsal roots reduced the SP content of spinal cord 3,7,16,17, 23,4L Furthermore, calcium-dependent release of SP from small diameter, but not large diameter, primary afferents has been demonstrated in vivo 19. A role for SP in transmitting noxious stimuli is particularly likely since SP stimulated dorsal horn neurons receiving nociceptive input but not those receiving mechanoreceptive input 13,z9,41, and depletion of SP from primary afferent terminals by capsaicin treatment increased pain threshold in rats 44. Electrophysiological studies in both CNS12,13, z3- 26,33,39,41,45 and PNS10,11,21, ~2 have shown that SP was excitatory, and when applied to spinal cord neurons, SP depolarized membrane potential and increased firing rate24,a°,41, 4a,45. Thus, there is considerable evidence to support the hypothesis that SP is an excitatory neurotransmitter released from small diameter primary afferent fibers mediating noxious stimuli. * To whom correspondence should be addressed.