Dual opioid modulation of the action potential duration of mouse dorsal root ganglion neurons in culture

Multiple modulatory effects of opioids on the duration of the calcium component of the action potential (APD) of dorsal-root ganglion (DRG) neurons of mouse spinal cord-ganglion explants were studied. The APD of DRG neuron perikarya has been previously shown to be shortened by exposure to high concentrations of opioids (ca. 0.1–1 μM) in about1/2 of the cells tested. The present study demonstrates that in addition to these inhibitory modulatory effects of opioids, lower concentrations (1–10 nM) of δ, μ, and κ-opioid agonists elicit excitatory modulatory effects, i.e. prolongation of the APD, in about2/3 of the sensory neurons tested. APD prolongation as well as shortening elicited by δ, μ, and κ agonists were prevented by coperfusion with the opioid antagonists, naloxone or diprenorphine (10 nM). APD prolongation induced by the δ-agonist [ d-Ala 2- d-Leu 5enkephalin (DADLE) was prevented in the presence of multiple K + channel blockers, whereas excitatory modulation by the specific κ-agonist, U-50,488H was not attenuated under these conditions. After treatment of DRG neurons with pertussis toxin (1 μg/ml for several days) or forskolin (50 μM for >15 min), a much smaller fraction of cells showed opioid-induced APD shortening; moreover, a much larger fraction of cells showed opioid-induced APD prolongation, even when tested with high concentrations of DADLE (1–10 μM). These data indicate that opioid-induced APD prolongation is not mediated by pertussis toxin-sensitive G proteins (which have been shown to regulate opioid inhibitory effects) and suggest that elevation of cyclic AMP levels may enhance opioid excitatory responsiveness. Furthermore, our analyses indicate that μ, δ- and κ-subtypes of excitatory as well as inhibitory opioid receptors may be expressed on the same DRG neuron perikaryon under in vitro conditions. If dual opioid modulation of the APD of DRG perikarya also occurs in central DRG terminals this may play a significant role both in nociceptive signal transmission as well as tolerance to opioid analgesia.