Dynorphin prolongs the action potential of mouse sensory ganglion neurons by decreasing a potassium conductance whereas another specific kappa opioid does so by increasing a calcium conductance

Previous studies have reported that large (μM) concentrations of kappa opioids, e.g. dynorphin and 3,4 dichloro- N-methyl- N-(-2[1-pyrrolidinyl]-cyclohexyl)benzene-acetamide (U-50.488H), shorten the duration of the calcium component of the action potential of dorsal root ganglion neurons by decreasing a voltage-sensitive Cs 2+ conductance. The present study showed that, in addition to these inhibitory modulatory effects, small (nM) concentrations of dynorphin, as well as U-50.488H, prolonged the action potential in about 75% of the neurons of dorsal root ganglia in ganglion spinal cord explants of mouse (tested in 5 mM Ba 2+). Both the excitatory and inhibitory effects of these kappa opioids were prevented by perfusion together with the opioid antagonist, diprenorphine (10nM). However, when responsivity tests with opioids were carried out in the presence of multiple K + channel Mockers [Ba 2+, Cs + and tetraethylammonium (TEA)], 1 nM dynorphin prolonged the action potential in only 7% of the neurons ( n = 28), whereas 1 nM U-50,488H still elicited the prolongation of the action potential in 60% of the cells ( n = 39). These data suggest that dynorphin prolongs the action potential of neurons of dorsal root ganglion by activating a kappa subtype of receptor that decreases a voltage-sensitive K + conductance, whereas U-50,488H produces similar excitatory modulation of the action potential by activating another kappa subtype of receptor that increases a voltage-sensitive Ca 2+ conductance. Thus, U-50,488H-induced prolongation of the action potential appears to be mediated by a kappa subtype of receptor that produces the opposite effect on Ca 2+ channels to that which occurs during kappa opioid-induced shortening of the action potential. On the other hand, dynorphin-induced prolongation of the action potential is mediated by a kappa opioid-receptor that decreases a voltage-sensitive K + conductance. After chronic exposure to d-ala 2- d-leu 5 enkephalin (DADLE), neurons of dorsal root ganglia became tolerant to dynorphin-induced excitatory, but not inhibitory, modulatory effects on the action potential. Electrophysiological studies of multiple modes of kappa opioid modulation of the action potential of dorsal root ganglion neurons in vitro may provide clues to the functional roles of high- and low-affinity kappa receptors, that have been reported in opioid binding assays of spinal cord and brain tissues, and may help to analyze the second messengers that couple