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

Abstract

The present study demonstrates that perikaryal ␦-opioid receptors (␦ORs) 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 ␦ORs and, by way of consequence, receptor-mediated internalization of the fluorescent deltorphin (DLT) analog -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 -opioid receptor (OR) knock-out mice, it may be assumed that the enhanced membrane recruitment of ␦ORs observed after sustained morphine is attributable to stimulation of ORs. 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 A␦ fibers. Indeed, stimulation by capsaicin of transient receptor potential vanilloid 1 receptors, which are selectively expressed by small diameter (Ͻ 600 m 2 ) DRG neurons, increased Fluo-DLT internalization exclusively in this cell population. The present results, therefore, demonstrate that DRG neurons express perikaryal ␦ORs 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 OR agonists.

Morphine priming in rats with chronic inflammation reveals a dichotomy between antihyperalgesic and antinociceptive properties of deltorphin

“…Likewise, CFA injection in the hindlimb selectively affected trafficking as opposed to expression of ␦OR in rat lumbar DRGs (Gendron et al, 2006). However, we previously observed a bilateral increase in ␦OR mRNA in a discrete subpopulation of the dorsal horn neurons of CFA-treated animals using quantitative in situ hybridization , suggesting that a small number of neurons exhibiting enhanced ␦OR availability, diluted in the sample assayed here, might be up-regulating ␦OR.…”

“…These results suggest that the antihyperalgesic effects of deltorphin in the CFA model are unrelated to the increase in the cell surface availability of ␦OR in neurons of the dorsal horn. Alternatively, they might be related to the increase in ␦OR cell surface density observed in small-and medium-sized DRG neurons following CFA injection (Gendron et al, 2006). The enhancement of ␦OR's functional competence recently reported in trigeminal nociceptors following activation of bradykinin B2 receptors supports this interpretation (Patwardhan et al, 2005).…”

“…This is not to say, however, that both regimens affect the same neuronal populations. Indeed, in dorsal root ganglia (DRG), morphine treatment increases cell surface ␦OR in neurons of all types and sizes, whereas CFA injection selectively up-regulates cell surface ␦OR in small-and medium-sized ganglion cells (Gendron et al, 2006).…”

Antihyperalgesic effects of loperamide in a model of rat neuropathic pain are mediated by peripheral δ-opioid receptors

“…Although the reason why loperamide was effective only in neuropathic rats is not known, it is possible that expression of δ-opioid receptors in PNS may be altered after nerve injury. Recent reports showed that inflammatory stimulation, capsaicin treatment, and morphine treatment increased cell surface δ-opioid receptors in the dorsal root ganglia neurons or primary culture of sensory neurons [5,29]. Although δ-opioid receptors in the spinal cord were shown to decrease after nerve injury [30,31], it is possible that peripheral δ-opioid receptors may increase after nerve injury.…”

Disruption of δ-opioid receptor phosphorylation at Threonine 161 attenuates morphine tolerance in rats with CFA-induced inflammatory hypersensitivity

“…Gendron et al found a similar effect on DOR trafficking in small DRG neurons following injection of capsaicin into rat hindpaw [42] . Constitutive receptor activity has been reported to increase in animals treated chronically with morphine.…”