Opioid-Related (Orl1) Receptors Are Enriched In A Subpopulation Of Sensory Neurons And Prolonged Activation Produces No Functional Loss Of Surface N-Type Calcium Channels
JOURNAL OF PHYSIOLOGY-LONDON(2012)
Abstract
The opioid-related receptor, ORL1, is activated by the neuropeptide nociceptin/orphanin FQ (N/OFQ) and inhibits high-voltage-activated (HVA) calcium channel currents (I-Ca) via a G-protein-coupled mechanism. Endocytosis of ORL1 receptor during prolonged N/OFQ exposure was proposed to cause N-type voltage-gated calcium channel (VGCC) internalization via physical interaction between ORL1 and the N-type channel. However, there is no direct electrophysiological evidence for this mechanism in dorsal root ganglion (DRG) neurons or their central nerve terminals. The present study tested this using whole-cell patch-clamp recordings of HVA I-Ca in rat DRG neurons and primary afferent excitatory synaptic currents (eEPSCs) in spinal cord slices. DRG neurons were classified on the basis of diameter, isolectin-B4 (IB4) binding and responses to capsaicin, N/OFQ and a mu-opioid agonist, DAMGO. IB4-negative neurons less than 20 mu m diameter were selectively responsive to N/OFQ as well as DAMGO. In these neurons, ORL1 desensitization by a supramaximal concentration of N/OFQ was not followed by a decrease in HVA I-Ca current density or proportion of whole-cell HVA I-Ca contributed by N-type VGCC as determined using the N-type channel selective blocker, omega-conotoxin CVID. There was also no decrease in the proportion of N-type I-Ca when neurons were incubated at 37 degrees C with N/OFQ for 30 min prior to recording. In spinal cord slices, N/OFQ consistently inhibited eEPSCs onto dorsal horn neurons. As observed in DRG neurons, preincubation of slices in N/OFQ for 30 min produced no decrease in the proportion of eEPSCs inhibited by CVID. In conclusion, no internalization of the N-type VGCC occurs in either the soma or central nerve terminals of DRG neurons following prolonged exposure to high, desensitizing concentrations of N/OFQ.
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Key words
receptors,sensory neurons,orl1,opioid-related,n-type
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