Peripheral Sensitization Increases Opioid Receptor Expression and Activation by Crotalphine in Rats

Author(s)

Zambelli, Vanessa Olzon ^[1] ; de Oliveira Fernandes, Ana Carolina ^[1] ; Gutierrez, Vanessa Pacciari ^[1] ; Batista Ferreira, Julio Cesar ^[2] ; Parada, Carlos Amilcar ^[3] ; Mochly-Rosen, Daria ^[4] ; Cury, Yara ^[1]

Affiliation

^[1] Inst Butantan, Lab Especial Dor & Sinalizacao, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Anat, BR-05508 Sao Paulo - Brazil

^[3] Inst Biociencias UNICAMP, Dept Fisiol & Biofis, Campinas, SP - Brazil

^[4] Stanford Univ, Dept Chem & Syst Biol, Sch Med, Stanford, CA 94305 - USA

• Document type: Journal article
• Source: PLoS One; v. 9, n. 3 MAR 4 2014.
• Web of Science Citations: 10

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 (PGE(2)) increases the mRNA and protein levels of the mu-and kappa-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 PGE(2), alone does not increase the activation of these opioid receptors but that in the presence of PGE(2), the activation of specific opioid receptors by CRP and selective mu-and kappa-opioid receptor agonists (positive controls) increases. Furthermore, PGE2 down-regulated the expression and activation of the delta-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 C zeta. This CRP effect was much more prominent when the cells were pretreated with PGE(2). 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. (AU)

• FAPESP's process: 08/57898-0 - National Institute of Science and Technology on Toxins
• Grantee: Osvaldo Augusto Brazil Esteves Sant'Anna
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 07/00135-2 - Evaluation of expression and activation of opioid receptors after peripheral injury in rats
• Grantee: Vanessa Olzon Zambelli
• Support Opportunities: Scholarships in Brazil - Doctorate