Abstract
Inflammation enhances the peripheral analgesic efficacy of opioid drugs, but the mechanisms involved in this phenomenon have not been fully elucidated. Crotalphine (CRP), a peptide that was first isolated from South American rattlesnake C.d. terrificus venom, induces a potent and long-lasting anti-nociceptive effect that is mediated by the activation of peripheral opioid receptors. Because the high efficacy of CRP is only observed in the presence of inflammation, we aimed to elucidate the mechanisms involved in the CRP anti-nociceptive effect induced by inflammation. Using real-time RT-PCR, western blot analysis and ELISA assays, we demonstrate that the intraplantar injection of prostaglandin E2 (PGE2) increases the mRNA and protein levels of the µ- and κ-opioid receptors in the dorsal root ganglia (DRG) and paw tissue of rats within 3 h of the injection. Using conformation state-sensitive antibodies that recognize activated opioid receptors, we show that PGE2, alone does not increase the activation of these opioid receptors but that in the presence of PGE2, the activation of specific opioid receptors by CRP and selective µ- and κ-opioid receptor agonists (positive controls) increases. Furthermore, PGE2 down-regulated the expression and activation of the δ-opioid receptor. CRP increased the level of activated mitogen-activated protein kinases in cultured DRG neurons, and this increase was dependent on the activation of protein kinase Cζ. This CRP effect was much more prominent when the cells were pretreated with PGE2. These results indicate that the expression and activation of peripheral opioid receptors by opioid-like drugs can be up- or down-regulated in the presence of an acute injury and that acute tissue injury enhances the efficacy of peripheral opioids.
Highlights
Clinical and experimental results have shown that the peripheral analgesic efficacy of opioids is enhanced in the presence of inflammation and tissue injury [1,2]
We demonstrated that crotalphine (CRP), a structural analogue to a novel analgesic peptide that was first identified in the crude venom from the South American rattlesnake Crotalus durissus terrificus [11], induces a potent (0.008–25 mg/kg, p.o.) and long-lasting (2–5 days) anti-nociceptive effect that is mediated by the activation of the peripheral k-opioid receptor and the k- and d- opioid receptors [11,12,13]
The intraplantar injection of prostaglandin E2 (PGE2) caused a significant decrease in the nociceptive threshold, with a peak response occurring 3 h after the administration (Fig. 1B, checkered bar, and Fig. S1), compared with the basal values obtained before any treatment, which is a characteristic sign of hyperalgesia
Summary
Clinical and experimental results have shown that the peripheral analgesic efficacy of opioids is enhanced in the presence of inflammation and tissue injury [1,2]. Studies investigating the molecular mechanisms involved in the enhanced effects of opioid treatments in the periphery caused by inflammation mainly focus on the m-opioid receptor and the chronic inflammatory processes [2,5,6,7,9]. We demonstrated that crotalphine (CRP), a structural analogue to a novel analgesic peptide that was first identified in the crude venom from the South American rattlesnake Crotalus durissus terrificus [11], induces a potent (0.008–25 mg/kg, p.o.) and long-lasting (2–5 days) anti-nociceptive effect that is mediated by the activation of the peripheral k-opioid receptor (prostaglandin E2-induced hyperalgesia) and the k- and d- (chronic constriction injury of the rat sciatic nerve) opioid receptors [11,12,13]. The activation of opioid receptors regulates a variety of intracellular signaling cascades, including the PI3Kc/AKT signaling pathway [18], as well as the activation of mitogenactivated protein kinases (MAPKs) and protein kinase C (PKC) [19,20,21]
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