Antihyperalgesic effects of δ opioid agonists in a rat model of chronic inflammation

Abstract

1 Opioid receptors in the brain activate descending pain pathways to inhibit the nociceptive response to acute noxious stimuli. The aim of the present study was to clarify the role of supraspinal opioid receptors in modulating the nociceptive response to persistent in¯ammation in rats. 2 Subcutaneous administration of 50 ml of complete Freund's Adjuvant (CFA) into the plantar surface of the hindpaw induced a signi®cant decrease in paw withdrawal latency to thermal stimuli (P50.01) at 24 h post-injection. 3 Intracerebroventricular (i.c.v.) administration of the m opioid receptor agonists, DAMGO and morphine, and the d opioid receptor agonists, deltorphin II and SNC80, signi®cantly reversed the hyperalgesic response associated with peripheral in¯ammation in a dose-dependent manner (P50.0001). 4 The m and d agonists also signi®cantly attenuated the antinociceptive response to acute thermal stimulation in rats (P50.001). However, deltorphin II and SNC80 were less potent, and in the case of SNC80 less e cacious, in modulating the response to acute thermal nociception in comparison to hyperalgesia associated with persistent in¯ammation. 5 These results indicate that m and d opioid receptors in the brain modulate descending pain pathways to attenuate the nociceptive response to acute thermal stimuli in both normal and in¯amed tissues. The heightened response to d agonists in the hyperalgesia model suggests that d opioid receptors in the brain are promising targets for the treatment of pain arising from chronic in¯ammation.

Coexpression of δ- and μ-opioid receptors in nociceptive sensory neurons

“…Moreover, DORs and MORs were found to be transported to afferent fibers in laminae I-II of the spinal cord and to mediate presynaptic inhibition of glutamate release. This is consistent with early reports of DOR-and MOR-mediated analgesic effects on thermal nociceptive responses (45,46). Interaction between DORs and MORs has been considered to be an important mechanism for modulating opioid analgesia.…”

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.…”