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Contribution of cannabinoid system to the antinociceptive effect of crotalphine and its interation with opioid system

Grant number: 10/12917-8
Support type:Scholarships in Brazil - Master
Effective date (Start): March 01, 2011
Effective date (End): June 30, 2013
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Gisele Picolo
Grantee:Franciele Corrêa Machado
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated scholarship(s):12/01423-0 - Effect of crotalphine on the cannabinoid system: release of endocannabinoids or binding to the CB2 receptors, BE.EP.MS


Pain is a multidimensional sensory experience and multiple mechanisms are involved in the generation of pathophysiological nociceptive pain. Identification of mechanisms and molecular components responsible for pain generation has contributed to the advance in understanding of pain and its control. However, despite the increase in the number of options for pain treatment, many patients continue to experience inadequate pain relief and/or intolerable side effects that limit their usefulness. Morphine and other opioid-like drugs are widely used analgesics for patients with both acute and chronic pain. Although being considered the main option for the treatment of moderate to severe pain, the use of opioids is limited because of the observed undesirable effects. Therefore, efforts have been made on the search of new analgesic compounds.Recently, our group demonstrated that crotalphine, a 14 amino acid- peptide synthesized based on the structure of the natural analgesic factor isolated from the venom of the South American rattlesnake Crotalus durissus terrificus, features analgesic activity. In these studies, crotalphine induced a long-lasting antinociceptive effect in mice and rats, in experimental models of acute and chronic pain. This effect involves the participation of peripheral k- and d-opioid receptors, the activation of the L-arginine-nitric oxide-cGMP-PKG pathway and opening of ATP-sensitive K+ channels. Despite the presence of opioid activity, prolonged treatment with crude venom does not cause the development of tolerance to the analgesic effect observed in the chronic constriction injury of the rat sciatic nerve. Despite presenting opioid activity, the amino acid sequence of crotalphine displays no homology to any known opioid peptide. In addition, preliminary results indicate that crotalphine does not directly activate opioid receptors, since the peptide did not displace binding of [3H] naloxone to opioid receptors in rat brain membrane homogenates. Data from Literature have demonstrated a great interaction between opioid and cannabinoid systems. Both opioids and cannabinoids bind to distinct receptors. Moreover, it seems that one system may potentialize the other one, presenting evidence that these two systems may operate synergistically. In agreement, behavioral and molecular studies demonstrated that cannabinoids induce the release of endogenous opioids in the same manner that opioids may induce the release of endocannabinoids.The aim of this project is to further characterize the molecular mechanisms involved in the antinociceptive effect of crotalphine, evaluating the involvement of cannabinoid receptors in the antinociceptive effect of crotalphine as well as the possible interaction of the cannabinoid receptors with the opioid system.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MACHADO, F. C.; ZAMBELLI, V. O.; FERNANDES, A. C. O.; HEIMANN, A. S.; CURY, Y.; PICOLO, G. Peripheral interactions between cannabinoid and opioid systems contribute to the antinociceptive effect of crotalphine. British Journal of Pharmacology, v. 171, n. 4, SI, p. 961-972, FEB 2014. Web of Science Citations: 19.

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