Peripheral interactions between cannabinoid and opioid systems contribute to the antinociceptive effect of crotalphine

Abstract

BACKGROUND AND PURPOSECrotalphine is an antinociceptive peptide that, despite its opioid-like activity, does not induce some of the characteristic side effects of opioids, and its amino acid sequence has no homology to any known opioid peptide. Here, we evaluated the involvement of the peripheral cannabinoid system in the crotalphine effect and its interaction with the opioid system. EXPERIMENTAL APPROACHHyperalgesia was evaluated using the rat paw pressure test. Involvement of the cannabinoid system was determined using a selective cannabinoid receptor antagonist. Cannabinoid and opioid receptor activation were evaluated in paw slices by immunofluorescence assays using conformation state-sensitive antibodies. The release of endogenous opioid peptides from skin tissue was measured using a commercial enzyme immunoassay (EIA). ) was blocked by AM630 (50 μg per paw), a CB2 receptor antagonist, and by antiserum anti-dynorphin A (1 μg per paw). Immunoassay studies confirmed that crotalphine increased the activation of both κ-opioid (51.7%) and CB2 (28.5%) receptors in paw tissue. The local release of dynorphin A from paw skin was confirmed by in vitro EIA and blocked by AM630. KEY RESULTS CONCLUSIONS AND IMPLICATIONSCrotalphine-induced antinociception involves peripheral CB2 cannabinoid receptors and local release of dynorphin A, which is dependent on CB2 receptor activation. These results enhance our understanding of the mechanisms involved in the peripheral effect of crotalphine, as well as the interaction between the opioid and cannabinoid systems. Abbreviations

A spider derived peptide, PnPP-19, induces central antinociception mediated by opioid and cannabinoid systems

“…These authors demonstrated that crotalphine-induced antinociception stimulates local release of dynorphin A, which is dependent on CB 2 receptor activation [32]. In contrast, we observed the participation of the CB 1 receptor in PnPP-19-induced central antinociception, and as previously reported, μ and δ opioids receptors are also involved [17].…”

“…Recently, it was shown that peripheral interactions between cannabinoid and opioid systems contribute to the antinociceptive effect of the peptide crotalphine [32]. These authors demonstrated that crotalphine-induced antinociception stimulates local release of dynorphin A, which is dependent on CB 2 receptor activation [32].…”

Prostamide F2α receptor antagonism combined with inhibition of FAAH may block the pro‐inflammatory mediators formed following selective FAAH inhibition

“…The contribution from Machado et al (2014) assessed cross-talk between the cannabinoid and opioid systems in pain management. The authors investigated the cannabinoid-mediated anti-nociceptive activity of crotalphine, a synthetic peptide with opioid-like activity, following induction of hyperalgesia in rats via intraplantar administration of prostaglandin E2.…”

Toxins and Drug Discovery

“…Konno et al, 2008;Zambelli et al, 2014). Some of its actions are mediated through k-opioid receptors, with an involvement of pathways including nitric oxide (Gutierrez et al, 2012) and cannabinoids (Machado et al, 2014). Crotalphine is being treated as a possible development candidate (US Patent Application, 2009) and is currently in the pre-clinical phase with the Brazilian company Biolab Farmaceutica.…”