μ Opioid receptors and analgesia at the site of a peripheral nerve injury

Abstract

Opioid ligands may exert antinociception through receptors expressed on peripheral afferent axons. Whether local opioid receptors might attenuate neuropathic pain is uncertain. In this work, we examined the function and expression of local mu opioid receptors (MORs) associated with the chronic constriction injury (CCI) model of sciatic neuropathic pain in rats. Low-dose morphine or its carrier were percutaneously superfused over the CCI site with the injector blinded to the identity of the injectate. Morphine, but not its carrier, and not equimolar systemic doses of morphine reversed thermal hyperalgesia in a dose-related, naloxone-sensitive fashion. Moreover, analgesia was conferred at both 48 hours and 14 days after CCI, times associated with very different stages of nerve repair. Equimolar local DAGO ([D-Ala2, N-Me-Phe4, Gly5-(ol)] enkephalin), a selective MOR ligand, provided similar analgesia. Local morphine also attenuated mechanical allodynia. MOR protein was expressed in axonal endbulbs of Cajal just proximal to the injury site, in aberrantly regenerating small axons in the epineurial sheath around the CCI site and in residual small axons distal to the CCI lesion. Sensory neurons ipsilateral to CCI had an increase in the proportion of neurons expressing MOR. We suggest that local MOR expressed in axons may be exploited to modulate some forms of neuropathic pain.

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…Similar effects were observed after PSL (Rashid et al, 2004;Pol et al, 2006), although -receptor immunoreactivity (analyzed by Western blot) was enhanced in another study (Walczak et al, 2005). After CCI, there was no strict correlation between -receptor mRNA and protein levels, in that mRNA was unchanged (Truong et al, 2003) or down-regulated (Obara et al, 2009(Obara et al, , 2010, whereas the number of -receptor-expressing neurons was enhanced (Truong et al, 2003) or unaltered (Kolesnikov et al, 2007). In the same model, a reduction (by 37-39%) of the stimulation of G protein coupling to -receptors by morphine, but not by endomorphins, was reported (Obara et al, 2010).…”

“…All three opioid receptors were detected using immunohistochemistry in PERIPHERAL PAIN INHIBITION sensory fibers coexpressing CGRP at the CCI site of the sciatic nerve trunk . Furthermore, an up-regulation of -and ␦-receptors was detected by Western blot at the nerve injury site (Truong et al, 2003;Kabli and Cahill, 2007), and enhanced -receptor-immunoreactivity was found in hindpaw skin innervated by the damaged saphenous nerve after PSL or CCI (Walczak et al, 2005(Walczak et al, , 2006. All these alterations were demonstrated 1 to 14 days after nerve injury.…”

“…␦-Receptor mRNA was not altered after PSL or down-regulated after CCI (Obara et al, 2009). All these changes were observed 2 to 28 days after surgeries in lumbar DRG ipsilateral to the nerve injury compared with the contralateral DRG of injured animals (Zhang et al, 1998b;Truong et al, 2003;Pol et al, 2006) or to DRG of naive or sham-operated animals (Zhang et al, 1998b;Sung et al, 2000;Rashid et al, 2004;Kohno et al, 2005;Walczak et al, 2005;Pol et al, 2006;Obara et al, 2009Obara et al, , 2010. ␦-Receptor protein was examined in a CCI-resembling model, in which a loose polyethylene cuff is placed around the sciatic nerve (Mosconi and Kruger model) (Kabli and Cahill, 2007).…”

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

“…Although it has been suggested that neuropathic pain may be attenuated by opioids at higher doses than those effective in acute pain [11], this is accompanied by aggravation of central side effects and studies show that even neuropathic pain patients that acknowledge medical benefit with opioids drop out of therapy within months due to such side effects [12]. Although recent studies have demonstrated local administration of μ-opioid agonists reduced mechanical allodynia in models of rat neuropathic pain [13][14][15][16], possible beneficial effects of systemically administered opioids which are peripherally restricted have not been well studied.…”

Ausência de efeito antinociceptivo decorrente da administração intravenosa de crotalfina em comparação com morfina, U50-488H ou fenilbutazona em equinos submetidos à estimulação térmica da pele íntegra

“…Isso corrobora STEIN (1993) e ANTONIJEVIC et al (1995 que inferem que a ação antinociceptiva dos agonistas opioides é pronunciada no tecido infl amado, mas pouco evidente em tecidos íntegros em diversas espécies animais. O sistema opioidérgico é efi ciente para modular a resposta nociceptiva no tecido infl amado (TRUONG et al, 2003) conforme a natureza do estímulo e o estágio da reação infl amatória tecidual (MILLAN, 1986) que podem ativar os receptores opioides periféricos (STEIN & LANG, 2009). Também nos tecidos periféricos é necessário haver infl amação tecidual para que a morfi na promova adequado efeito analgésico (LIKAR et al, 2001).…”