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Sex differences in nociception and in the antinociceptive effect of CNF 021.03, an opioid analgesic

Grant number: 06/02708-7
Support type:Scholarships in Brazil - Master
Effective date (Start): September 01, 2006
Effective date (End): August 31, 2008
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Yara Cury
Grantee:Luciana de Britto Pedroso
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Sex differences in pain sensation and in the response to analgesics, particularly opioids, have been described for humans and animals. Our group has been studying a new opioid drug, named CNF 021.03, obtained from the venom of the South American rattlesnake Crotalus durissus terrificus. Due to its potent and long-lasting antinociceptive effect and its effectiveness in chronic pain models, pre-clinical trials have been developed aiming the use of this peptide as a new therapeutic analgesic. These pre-clinical trials include pharmacodynamic, pharmacokinetic and toxicological studies. However, it is important to point out that the studies about the analgesic properties of CNF 021.03 have been always developed in male animals, with no information about its effectiveness in female rodents.The purpose of the present study is to evaluate the differences in pain sensation and in the antinociceptive response to CNF021.03 between male and female Wistar rats. These goals will be assessed by the investigation of:-the differences between male and female rats to the hypernociceptive effect of carrageenin and prostaglandin E2 and to the chronic constriction of sciatic nerve. Persistent hyperalgesia, allodynia and spontaneous pain will be considered for characterization of neuropathic pain. Hyperalgesia and allodynia will be determined using the rat paw pressure test and von Frey hair filaments, respectively. Spontaneous pain will be evaluated by the determination of the cumulative duration of the lifting and licking of the hind limbs. The onset, peak, intensity and duration of the nociceptive responses will be presently analysed; -the differences between male and female rats to the antinociceptive effect of CNF021.03, regarding the onset, peak, intensity and duration of the antinociceptive response. Antinociception will be evaluated in the acute (hyperalgesia induced by carrageenin or prostaglandin E2) and persistent pain (neurophatic pain) models. -the role of female steroid hormones and estrous cycle on pain threshold and CNF021.03 effectiveness. To confirm the influence of female steroids, female rats will be ovariectomized. If this procedure modifies the antinociceptive effect of CNF 021.03, estradiol and progesterone will be replaced immediately after surgery. To verify the influence of estrous cycle, vaginal cytology analysis will be done. -the involvement of kappa and delta opioid receptors, the L-arginine-nitric oxide cGMP and potassium channels in the antinociceptive effect of CNF 021.03 in females. For this purpose, opioid receptor antagonists, nitric oxide synthase inhibitors and potassium channels blockers will be used.