Mu- and kappa-opioid receptors selectively reduce the same transient components of high-threshold calcium current in rat dorsal root ganglion sensory neurons

Abstract

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.

κ-Opioid Receptor Activation Modulates Ca2+Currents and Secretion in Isolated Neuroendocrine Nerve Terminals

“…Somatic recordings obtained from rat peripheral sensory (Schroeder et al, 1991;Moises et al, 1994;Rusin and Moises, 1995) and nucleus tractus solitarius neurons (Rhim and Miller, 1994) have identified several high-threshold Ca 2ϩ channels that are modulated by opioid receptors. In these neurons, -opioids, and -selective agonists to a lesser extent, inhibit Ca 2ϩ current contributed by GVIA-sensitive N-type and pharmacologically distinct P-and Q-type channels but spare L-and T-type currents, thereby regulating the principal Ca 2ϩ channel types involved in exocytosis at central synapses and peripheral sites of release (Luebke et al, 1993;Takahashi and Momiyama, 1993;Wheeler et al, 1994;Dunlap et al, 1995).…”

“…Although it remains unclear how the presynaptic inhibitory effects of opioids are manifested, measurements from neuronal somata suggest that the depression of release may result from reductions in Ca 2ϩ influx through voltage-dependent Ca 2ϩ channels (North, 1993). Activation of -, ␦-, or -opioid receptors has been shown to inhibit somatic N-and P/Q-type Ca 2ϩ currents in several types of neurons (Schroeder et al, 1991;Moises et al, 1994;Rhim and Miller, 1994;Rusin and Moises, 1995) and clonal cells (Seward et al, 1991;Taussig et al, 1992). These same channel types have been implicated to play a pivotal role in mediating Ca 2ϩ influx that triggers depolarization-evoked neurotransmitter release from nerve endings in the periphery (Kongsamut et al, 1989;Toth et al, 1993) and CNS (Takahashi and Momiyama, 1993;Turner et al, 1993;Wheeler et al, 1994).…”

Modulation of pain transmission by G-protein-coupled receptors

“…The μ-, δ-, κ-, and ORL1 opioid receptor agonists inhibit neuronal activity through (1) inhibition of VGCCs in the DRG neurons (Moises et al, 1994a;Acosta and Lopez, 1999;Beedle et al, 2004;Wu et al, 2004), and (2) suppression of neuronal excitability through activation of GIRK channels in the postsynaptic neurons in the spinal cord (Schneider et al, 1998;Marker et al, 2006).…”

“…Activation of μ-, δ-, κ-, and ORL1-opioid receptors inhibits VGCCs in dissociated DRG neurons (Moises et al, 1994a;Moises et al, 1994b;Acosta and Lopez, 1999;Beedle et al, 2004). For example, both morphine and DAMGO have been demonstrated to selectively inhibit N-type and P/Q-type Ca 2+ channels in DRG neurons (Schroeder et al, 1991;Schroeder and McCleskey, 1993;Wu et al, 2004).…”

Characterizing the Site and Mode of Action of Dynorphin at Hippocampal Mossy Fiber Synapses in the Guinea Pig

“…A number of studies have found that dynorphin can inhibit both N-type (Werz and Macdonald, 1984;Gross and Macdonald, 1987;Moises et al, 1994) and L-type (Moises et al, 1994) Ca 2ϩ channels. Our studies show that mossy fiber synaptic transmission is mediated by N-and P-type Ca 2ϩ channels (Castillo et al, 1994b).…”