Morphine and Pain-Related Stimuli Enhance Cell Surface Availability of Somatic δ-Opioid Receptors in Rat Dorsal Root Ganglia

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Abstract
The present study demonstrates that perikaryalδ-opioid receptors (δORs) in rat dorsal root ganglion (DRG) neurons bind and internalize opioid ligands circulating in the CSF. Using confocal and electron microscopy, we found that prolonged morphine treatment increased the cell surface density of these perikaryal δORs and, by way of consequence, receptor-mediated internalization of the fluorescent deltorphin (DLT) analog ω-Bodipy 576/589 deltorphin-I 5-aminopentylamide (Fluo-DLT) in all three types of DRG neurons (small, medium, and large). In contrast, chronic inflammatory pain induced by the injection of complete Freund's adjuvant (CFA) into one hindpaw selectively increased Fluo-DLT internalization in small and medium-sized DRG neurons ipsilateral to the inflammation. Based on our previous studies in the spinal cord of μ-opioid receptor (μOR) knock-out mice, it may be assumed that the enhanced membrane recruitment of δORs observed after sustained morphine is attributable to stimulation of μORs. However, the selectivity of the effect induced by inflammatory pain suggests that it involves a different mechanism, namely a modality-specific and pain-related activation of C and Aδ fibers. Indeed, stimulation by capsaicin of transient receptor potential vanilloid 1 receptors, which are selectively expressed by small diameter (< 600 μm2) DRG neurons, increased Fluo-DLT internalization exclusively in this cell population. The present results, therefore, demonstrate that DRG neurons express perikaryal δORs accessible to CSF-circulating ligands and that the density and, hence, presumably also the responsiveness, of these receptors may be modulated by both pain-related stimuli and sustained exposure to μOR agonists.