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Evaluation of the effects of opiates agonists in isolated corpus cavernosum from rabbit and rat: does opiate system have role on erectile function?

Grant number: 13/13907-4
Support type:Regular Research Grants
Duration: October 01, 2013 - September 30, 2015
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Gilberto de Nucci
Grantee:Gilberto de Nucci
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The most well characterized pathways in the control of erection are the noradrenergic and nitric oxide. The endogenous opiates are formed by proteolysis of larger precursor molecules. There are three precursors: proenkephalin A that gives rise to the family of enkefalins, prodynorphin which is processed into dynorphin A and B and propriomelanocortin that yields, among others, ²-endorphins. Five types of classical opioids receptors have been identified, being the ¼ (MOR ou OP3, ¼1, ¼2 e ¼3) delta (´ ou DOR ou OP1, ´1 e ´2) e kappa (º ou KOR ou OP2, º1 e º2) the most studied. The peripheral effects of opiates are well known in the gastrointestinal and cardiovascular systems, where its activation cn lead to constipation and drop in the blood pressure. Regarding its role in the erection, the majority of the studies focus on its actions on the central nervous system, where the chronic usage can lead to erectile dysfunction mainly due to hypogonadism hypogonadotropic. The peripheral effects of opiates in the corpus cavernosum are controversial. Thus, in a male patient detumescence of an isquemic priaprism was obtained following an inadvertent intra-cavernosal injection of fentanyl mistaken for phenylrphrine. On the other hand, clinical studies showed priaprism in patients undergoing surgery who received fentanyl or dihydrocodein or morphine. Preliminary data of our group show that fentanyl produced a concentration dependent relaxation in isolated corpus cavernosum from rabbit (pEC50: 5.14 e Emax: 93%, n=2) and monkey (pEC50: 5.54 ± 0,09 e Emax: 89 ± 12%, n=3) and the presence of the nitric oxide inhibitor L-NAME (100 ¼M) did not interfere on this response. Prior incubation of fentanyl (10 ¼M) reduced by, approximately, 58 and 74% the contractions induced by the alpha-1 agonist (phenylephrine) or electrical field stimulation in all studied frequencies (4, 8 e 16 Hz) in isolated corpus cavernosum from Callithirx sp. Intracavernous administration of fentanyl (8 ¼g/Kg) in rats increased by 50% the basal pressure. Thus, we aim to carry out in vitro assays (evaluation of the effects of agonists and/or antagonists by using organ bath techniques and neurotransmitter outflow in isolated corpus cavernosum from rabbit) and in vivo (measurement of intracavernous pressure in anaesthetized rats as an index of penile erection before and after intracavernous administration of opiates agonists/antagonist). The expression of the subtypes of opiates receptors (mu, delta and kappa) will be assessed by immunohistochemistry and RT-PCR. To date, there are no studies that evaluated the role of opiates agonists and/or antagonists in isolated corpus cavernosum. (AU)

Scientific publications (4)
(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)
DE OLIVEIRA, MARIANA G.; ROJAS-MOSCOSO, JULIO ALEJANDRO; BERTOLLOTTO, GABRIELA M.; CANDIDO, TUANY Z.; KIGUTI, LUIZ RICARDO DE A.; PUPO, ANDRE S.; ANTUNES, EDSON; DE NUCCI, GILBERTO; MONICA, FABIOLA Z. Mirabegron elicits rat corpus cavernosum relaxation and increases in vivo erectile response. European Journal of Pharmacology, v. 858, SEP 5 2019. Web of Science Citations: 1.
MENDES-SILVERIO, CAMILA BITENCOURT; ALEXANDRE, EVANDRO MARCOS; LESCANO, CAROLINE HONAISER; ANTUNES, EDSON; MONICA, FABIOLA ZAKIA. Mirabegron, a beta(3)-adrenoceptor agonist reduced platelet aggregation through cyclic adenosine monophosphate accumulation. European Journal of Pharmacology, v. 829, p. 79-84, JUN 15 2018. Web of Science Citations: 2.
CALMASINI, FABIANO B.; DE OLIVEIRA, MARIANA G.; ALEXANDRE, EDUARDO C.; DA SILVA, FABIO H.; DA SILVA, CARMEM P. V.; CANDIDO, TUANY Z.; ANTUNES, EDSON; MONICA, FABIOLA Z. Long-term treatment with the beta-3 adrenoceptor agonist, mirabegron ameliorates detrusor overactivity and restores cyclic adenosine monophosphate (cAMP) levels in obese mice. NEUROUROLOGY AND URODYNAMICS, v. 36, n. 6, p. 1511-1518, AUG 2017. Web of Science Citations: 13.
CALMASINI, FABIANO B.; ALEXANDRE, EDUARDO C.; SILVA, FABIO HENRIQUE; DE NUCCI, GILBERTO; ANTUNES, EDSON; D'ANCONA, CARLOS A.; MONICA, FABIOLA Z. Soluble Guanylate Cyclase Modulators, BAY 41-2272 and BAY 60-2770, Inhibit Human and Rabbit Prostate Contractility. UROLOGY, v. 94, p. 312-U392, AUG 2016. Web of Science Citations: 3.

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