Up-regulation and trafficking of δ opioid receptor in a model of chronic inflammation: implications for pain control

Abstract

Pharmacological and physiological evidence supports a role for delta (delta) opioid receptors in the nociceptive mechanisms of inflammation. However, few data exist regarding delta opioid receptor expression and localization in such conditions. In this study, we have assessed the distribution and function of delta opioid receptors in the rat spinal cord following induction of chronic inflammation by intraplantar injection of complete Freund's adjuvant (CFA). Intrathecal administration of the selective delta opioid receptor agonist, D-[Ala(2), Glu(4)] deltorphin, dose-dependently reversed thermal hyperalgesia induced by CFA. In situ hybridization and Western blotting experiments revealed an increase in delta opioid receptor mRNA and protein levels, respectively, in the dorsal lumbar spinal cord ipsilateral to the CFA injection site compared to the contralateral side and sham-injected controls. By electron microscopy, immunopositive delta opioid receptors were evident in neuronal perikarya, dendrites, unmyelinated axons and axon terminals. Quantification of immunopositive signal in dendrites revealed a twofold increase in the number of immunogold particles in the ipsilateral dorsal spinal cord of CFA-injected rats compared to the contralateral side and to sham-injected rats. Moreover, the relative frequency of immunogold particles associated with or in close proximity to the plasma membrane was increased in the ipsilateral dorsal spinal cord, indicating a more efficient targeting of delta opioid receptors to neuronal plasma membranes. These data demonstrate that CFA induces an up-regulation and increased membrane targeting of delta opioid receptors in the dorsal spinal cord which may account for the enhanced antinociceptive effects of delta opioid receptor agonists in chronic inflammatory pain models.

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

“…However, under conditions of chronic inflammation, such as produced in rodents by injection of complete Freund's adjuvant (CFA) in the hind paw, we observed a massive recruitment of ␦OR from intracellular stores to the plasma membrane in neurons of the dorsal horn of the spinal cord Morinville et al, 2004b). This increase in the pharmacological availability of ␦OR was postulated to account for the enhanced antihyperalgesic efficacy of the centrally administered ␦OR agonists reported in conditions of chronic inflammation (Hylden et al, 1991;Stewart and Hammond, 1994;Fraser et al, 2000;Hurley and Hammond, 2000;Cahill et al, 2003;Morinville et al, 2004b). The CFA-induced up-regulation of cell surface ␦OR in spinal cord neurons involves the participation of OR as it can no longer be elicited in OR knockout mice (Morinville et al, 2004b).…”

“…By contrast, drugs acting on ␦OR produce more limited analgesia, but also give rise to considerably less undesirable side-effects and induce virtually no tolerance (Porreca et al, 1984;May et al, 1989; Sheldon et al, 1990;Szeto et al, 1999;Gallantine and Meert, 2005). For these reasons, ␦OR agonists have been proposed as possible alternatives to OR agonists for the treatment of chronic pain, including neuropathic (Mika et al, 2001;Petrillo et al, 2003;Morinville et al, 2004a) and chronic inflammatory pain (Desmeules et al, 1993;Stewart and Hammond, 1994;Fraser et al, 2000;Hurley and Hammond, 2000;Qiu et al, 2000;Cahill et al, 2003;Petrillo et al, 2003).One of the reasons for the relatively poor analgesic efficiency of ␦OR agonists may be that only a small proportion of ␦OR is actually present on neuronal plasma membranes under baseline conditions (Cheng et al, 1995(Cheng et al, , 1997Elde et al, 1995;Zhang et al, 1998;Cahill et al, 2001a). However, under conditions of chronic inflammation, such as produced in rodents by injection of complete Freund's adjuvant (CFA) in the hind paw, we observed a massive recruitment of ␦OR from intracellular stores to the plasma membrane in neurons of the dorsal horn of the spinal cord Morinville et al, 2004b).…”

“…By contrast, drugs acting on ␦OR produce more limited analgesia, but also give rise to considerably less undesirable side-effects and induce virtually no tolerance (Porreca et al, 1984;May et al, 1989; Sheldon et al, 1990;Szeto et al, 1999;Gallantine and Meert, 2005). For these reasons, ␦OR agonists have been proposed as possible alternatives to OR agonists for the treatment of chronic pain, including neuropathic (Mika et al, 2001;Petrillo et al, 2003;Morinville et al, 2004a) and chronic inflammatory pain (Desmeules et al, 1993;Stewart and Hammond, 1994;Fraser et al, 2000;Hurley and Hammond, 2000;Qiu et al, 2000;Cahill et al, 2003;Petrillo et al, 2003).…”

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

“…In DOR mutants, the increased hypersensitivity response seems to occur in both early and late phases after formalin injection, however, in MOR mutants this only happens in the early phase with no effects in the late phase [25] . These results indicate that both [23,[26][27][28][29][30][31][32] . The present study provides evidence that phosphorylation of Thr-161-DOR attenuates CFA-induced heat hypersensitivity.…”

“…or capsaicin also promotes the trafficking of DORs to the plasma membrane [19] . Under conditions of inflammatory injury, the levels of DOR and MOR mRNA and protein are increased in the ipsilateral dorsal horn [20][21][22][23] . Visceral inflammation also similarly increases the levels of DOR mRNA in the dorsal horn, but the levels of protein are not significantly increased [24] .…”