The Journal of neuroscience : the official journal of the Society for Neuroscience
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Several distinct components of voltage-gated sodium current have been recorded from native dorsal root ganglion (DRG) neurons that display differences in gating and pharmacology. This study compares the electrophysiological properties of two peripheral nerve sodium channels that are expressed selectively in DRG neurons (Na(v)1.7 and Na(v)1.8). Recombinant Na(v)1.7 and Na(v)1.8 sodium channels were coexpressed with the auxiliary beta(1) subunit in Xenopus oocytes. ⋯ Consequently, the rapid entry into slow inactivation is believed to cause a frequency-dependent reduction of Na(v)1.8+beta(1) channel amplitudes, seen during repetitive pulsing between 1 and 2 Hz. However, at higher frequencies (>20 Hz) Na(v)1.8+beta(1) channels reach a steady state to approximately 42% of total current. The presence of this steady-state sodium channel activity, coupled with the high activation threshold (V(0.5) = -3.3 mV) of Na(v)1.8+beta(1), could enable the nociceptive fibers to fire spontaneously after nerve injury.
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The spinal dorsal horn is the first level of the CNS in which nociceptive input from sensory afferents is integrated and transmitted. Although inhibitory control in this region has a crucial impact on pain transmission, the respective contribution of GABA and glycine to this inhibition remains elusive. We have previously documented co-release of GABA and glycine at the same inhibitory synapse in spinal laminas I-II of adult rats [older than postnatal day 30 (P30)]. ⋯ Yet, at all developmental stages, benzodiazepine administration could unmask mixed mIPSCs. Together, these findings indicate that, although GABA and glycine are continually co-released throughout development, junctional codetection ceases by adulthood. This indicates an age-dependent postsynaptic tuning of inhibitory synapses that occurs in a region-specific manner.
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Regulation of protein phosphatase 2A (PP2A) activity and NMDA receptor (NMDAR) phosphorylation state contribute to the modulation of synaptic plasticity, yet these two mechanisms have not been functionally linked. The NMDAR subunit NR3A is equipped with a unique carboxyl domain that is different from other NMDAR subunits. We hypothesized that the NR3A C-terminal intracellular domain might serve as synaptic anchor for the phosphatase in the developing CNS. ⋯ A peptide corresponding to the PP2A-NR3A binding domain functioned as a negative regulator of PP2A activity. These data suggest that NMDARs are allosteric modulators of PP2A, which in turn controls their phosphorylation state. The data delineate a mechanistic model of the dynamic regulation of a PP2A-NMDAR signaling complex, mediated by the interaction of NR3A and PP2A, and suggest a novel NMDAR-mediated signaling mechanism in addition to the traditional ionotropic functions of NMDARs.
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Dopamine systems are intimately involved with opioid actions. Pharmacological studies suggest an important modulatory effect of dopamine and its receptors on opioid analgesia. We have now examined these interactions in a knock-out model in which the dopamine(2) (D(2)) receptor has been disrupted. ⋯ Antisense studies using a probe targeting the D(2) receptor revealed results similar to those observed in the knock-out model. The modulatory actions of D(2) receptors were independent of final sigma receptor systems because the final sigma agonist (+)-pentazocine lowered opioid analgesia in all mice, including the D(2) knock-out group. Thus, dopamine D(2) receptors represent an additional, significant modulatory system that inhibits analgesic responses to mu and kappa opioids.
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Opioid receptors are known to undergo complex regulatory changes in response to ligand exposure. In the present study, we examined the effect of morphine on the in vitro and in vivo density and trafficking of delta opioid receptors (deltaORs). Prolonged exposure (48 hr) of cortical neurons in culture to morphine (10 microm) resulted in a robust increase in the internalization of Fluo-deltorphin, a highly selective fluorescent deltaOR agonist. ⋯ Furthermore, this treatment markedly potentiated intrathecal d-[Ala(2)]deltorphin II-induced antinociception. Taken together, these results demonstrate that prolonged stimulation of neurons with morphine markedly increases recruitment of intracellular deltaORs to the cell surface, both in vitro and in vivo. We propose that this type of receptor subtype cross-mobilization may widen the transduction repertoire of G-protein-coupled receptors and offer new therapeutic strategies.