Mu- and kappa-opioid receptors selectively reduce the same transient components of high-threshold calcium current in rat dorsal root ganglion sensory neurons.
Whole-cell patch-clamp recordings were used to examine the regulation of voltage-dependent calcium channels by mu- and kappa-opioid receptors in acutely isolated rat dorsal root ganglion (DRG) sensory neurons. Agonists selective for either mu- (Tyr-Pro-NMePhe-D-Pro-NH2, PLO17) or kappa-opioid receptors (dynorphin A, U69,593) inhibited high-threshold calcium currents in a reversible and naloxone-sensitive manner, whereas administration of D-Pen2,5-enkephalin, a delta-selective agonist, was without effect. However, none of the opioids reduced low-threshold T-type currents. The inhibitory effects of PLO17 were blocked by the irreversible mu-opioid antagonist beta-funaltrexamine but not the kappa-opioid antagonist nor-binaltorphimine, while responses to kappa-opioid agonists showed the opposite pattern of antagonist sensitivity. In addition, many cells responded to both PLO17 and dynorphin A (or U69,593), and in these neurons the inhibitory response to one agonist was occluded when tested in the presence of the other. These data suggest that mu- and kappa-opioid receptors are coexpressed on at least some DRG neurons and appear to be functionally coupled to a common pool of calcium channels. Both rapidly inactivating (transient) and sustained components of high-threshold current, arising from pharmacologically distinct types of calcium channels, were identified in our neurons. Activation of mu-opioid receptors selectively reduced the transient component of currents evoked at +10 mV from Vh = -80 mV, while sparing the sustained component. The transient component was irreversibly blocked by the N-type channel antagonist omega-conotoxin GVIA (omega-CgTx), and in one-half of the neurons there was a concomitant loss of the response to PLO17. In the remaining neurons, PLO17 continued to reduce a small fraction of omega-CgTx-insensitive current and subsequent administration of the L-type channel blocker nifedipine in saturating concentrations failed to reduce the opioid-induced inhibitory effect. These data demonstrate that mu-opioid receptors are negatively coupled to several pharmacologically distinct types of calcium channels in DRG sensory neurons, one that was blocked by omega-CgTx and thus likely to be N-type, and a second that was resistant to blockade by N- and L-type channel blockers.
Moises
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HC
Department of Physiology, University of Michigan, Ann Arbor 48109-0622.
Rusin
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KI
Macdonald
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RL
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D004399:Dynorphins / Q000494:pharmacology; D004723:Endorphins / Q000494:pharmacology*; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D012680:Sensitivity and Specificity
D000700:Analgesics; D044482:Benzeneacetamides; D015220:Calcium Channels; D004723:Endorphins; D004745:Enkephalins; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009271:Naltrexone; C024524:beta-funaltrexamine; D004399:Dynorphins; C044708:morphiceptin, N-Me-Phe(3)-; D020881:Enkephalin, D-Penicillamine (2,5)-; C045444:U 69593; D002118:Calcium