Resumen
Son conocidas las propiedades medicinales de la planta de cannabis a nivel mundial así como los efectos de sus derivados sintéticos en la terapéutica de diferentes enfermedades. En los países donde el consumo medicinal ha sido legalizado su utilidad en el tratamiento de enfermedades del sistema nervioso central ha generado amplios beneficios en los pacientes. En las últimas décadas ha tomado relevancia su efecto paliativo del dolor crónico en pacientes con patologías oncológicas o degenerativas y sus beneficios antiproliferativos e inmunomduladores. El sistema endocannabinoide está representado por ligandos endógenos, derivados de ácidos grasos, que tienen efectos sobre receptores expresados en distintas localizaciones del organismo. En el transcurso de los años se han descripto múltiples sitios target entre ellos los órganos del sistema endócrino. A pesar de estos avances sigue siendo un desafío determinar con certeza los efectos, la titulación de la dosis terapéutica para cada individuo y la detección de ligandos sintéticos agonistas y antagonistas selectivos para los diferentes receptores. En esta revisión describiremos los aspectos generales del sistema endocannabinoide y sus efectos sobre los órganos endócrinos haciendo foco en las implicancias sobre el metabolismo de los hidratos de carbono, el tejido adiposo y la función reproductiva.
Citas
Vera Rubin. Cannabis and Culture. Ed. De Gruyter Mouton (1975).
Crocq MA. History of cannabis and the endocannabinoid system. Dialogues Clin Neurosci. 2020;;22(3):223-228.
Mechoulam R, Gaoni Y. A total synthesis of dl-Δ1-tetrahydrocannabinol, the active constituent of hashish. J Am Chem Soc. 1965;87:3273–3275.
Devane WA, Dysarz FA, Johnson MR, Melvin LS. Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605–613.
Devane WA, Hanus L, Breuer A, et al Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–1949.
Lu HC, Mackie K. Review of the Endocannabinoid System. Biol Psychiatry Cogn Neurosci Neuroimaging. 2021; 6(6):607-615.
Oultram JMJ, Pegler JL, Bowser TA, Ney LJ, Eamens AL, Grof CPL. Cannabis sativa: Interdisciplinary Strategies and Avenues for Medical and Commercial Progression Outside of CBD and THC. Biomedicines. 2021; 9(3):234.
De Vito Eduardo. Argentina tiene su primera Lay sobre el uso medicinal de la Planta de Cannabis. Historia y Perspectivas. Medicina. 2017. Vo. 77 Nº 5
https://www.argentina.gob.ar/salud/cannabis-medicinal/reprocann
Valeria Salech. La historia de mamá cultiva argentina: el camino del cannabis terapéutico. 1 ed. Ediciones B, 2018.
Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali Renato. The Emerging Role of the Endocannabinoid System in Endocrine Regulation and Energy Balance. Endocrine Reviews. 2006; 27:73–100.
Wenger T, Fernandez-Ruiz JJ, Ramos JA. Immunocytochemical demonstration of CB1 cannabinoid receptors in the anterior lobe of the pituitary gland. J Neuroendocrinol 1999; 11:873– 878.
Pagotto U, Marsicano G, Fezza F, Theodoropoulou M, Gruebler Y, Stalla J, Arzberger T, Milone A, Losa M, Di Marzo V, Lutz B, Stalla GK Normal human pituitary gland and pituitary adenomas express cannabinoid receptor type 1 and synthesize endogenous cannabinoids: first evidence for a direct role of cannabinoids on hormone modulation at the human pituitary level. J Clin Endocrinol Metab. 2001; 86:2687–2696.
Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology. 2004 145:5431–5438.
Labad J, Ortega L,Cabezas A, Montalvo I, Arranz S, Algora MJ, et al. Hypothalamic-pituitary-adrenal axis function and exposure to stress factors and cannabis use in recent-onset psychosis.. The Word Journal of Biological Psychiatry. 2020. Vol 21, N°. 7, 564–571.
Tucci SA, Rogers EK, Korbonits M, Kirkham TC. The cannabinoid CB1 receptor antagonist SR141716 blocks the orexigenic effects of intrahypothalamic ghrelin. Br J Pharmacol. 2004; 143:520 –523
Porcella A, Marchese G, Casu MA, Rocchitta A, Lai ML, Gessa GL, Pani L Evidence for functional CB1 cannabinoid receptor expressed in the rat thyroid. Eur J Endocrinology. 2002; 147:255–261
Ranganathan M, Braley G, Pittman B, Cooper T, Perry E, Krystal J, Cyril D, Souza D. The effects of cannabinoids on serum cortisol and prolactin in humans.Psychopharmacology. 2009; 203:737–744
Gammon, C. M. et al. Regulation of gonadotropin releasing hormone secretion by cannabinoids. Endocrinology. 2005; 146, 4491–4499.
Scorticati, C. et al. The inhibitory effect of anandamide on luteinizing hormone-releasing hormone secretion is reversed by estrogen. Proc. Natl Acad. Sci. USA. 2004; 101, 11891–11896.
Watanabe, M., Fukuda, A. & Nabekura, J. The role of GABA in the regulation of GnRH neurons. Front. Neurosci. 2014; 8, 387.
Gauthier, B. R. et al.Advances in Genetics of Regeneration in Metabesity. Genes 2019; 10, 383.
Lu, T. T. et al. The polycomb-dependent epigenome controls cell dysfunction, dedifferentiation, and diabetes. Cell Metab. 2018; 27, 1294–1308.
Katarzyna M, Keimpemaa E, Piscitellid F, Calvigionia D, Björklunde P, Mackief K, et al Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture. PNAS Proc Natl Acad Sci U S A. 2015;10;112(45)
González-Mariscal I, Krzysik-Walker SM, Doyle ME, Liu Q-R, Cimbro R, Santa-Cruz Calvo S, et al. Human CB1 receptor isoforms, present in hepatocytes and -cells, are involved in regulating metabolism. Sci Rep 2016; 6: 3330
Kim W, Lao Q, Shin Y-K, Carlson OD, Lee EK, Gorospe M, et al. Cannabinoids induce pancreatic -cell death by directly inhibiting insulin receptor activation. Sci Signal 2012; 5: ra23.
Hanho Shin, Ji Hye Han, Juhwan Yoon, Hyo Jung Sim, Tae Joo Park, Siyoung Yang, et al. Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells. J Cell Mol Med. 2018;22:2337–2345.
Kirkham TC. Endogenous cannabinoids: a new target in the treatment of obesity. Am J Physiol Regul Integr Comp Physiol 2003;284:R343–4.
Robert Ettaro, Lucas Laudermilk, Stewart D. Clark, Rangan Maitra. Behavioral assessment of rimonabant under acute and chronic conditions. Behav Brain Res. 2020 July 15; 390.
Scheyer AF, Melis M, Trezza V, Manzoni OJJ. Consequences of perinatal cannabis exposure. Trends Neurosci. 2019; 42(12):871–884.
Maia J, Fonseca BM, Teixeira N, Correia-da-Silva G. The fundamental role of the endocannabinoid system in endometrium and placenta: implications in pathophysiological aspects of uterine and pregnancy disorders Human Reproduction Update. 2020; Vol.26, No.2, 586–602.
Innocenzi E, De Domenico E, Ciccarone F, Zampieri M, Rossi G, Cicconi R et al Paternal activation of CB2 cannabinoid receptor impairs placental and embryonic growth via an epigenetic mechanism. Sci Rep 2019; 9(1):17034
Wang H, Guo Y, Wang D, Kingsley PJ, Marnett LJ, Das SK et al. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nat Med 2004; 10(10):1074–1080
Cecconi S, Rossi G, Castellucci A, D’Andrea G, Maccarrone M. Endocannabinoid signaling in mammalian ovary. Eur J Obstet Gynecol Reprod Biol. 2014; 178:6–11
Castel P, Barbier M, Poumerol E, Mandon‑Pépin B, Tassistro V, Lepidi H, et al Prenatal cannabinoid exposure alters the ovarian reserve in adult ofspring of rats. Archives of Toxicology. 2020; 94:4131–4141
Cacciola, G. et al. Expression of type-1 cannabinoid receptor during rat postnatal testicular development: possible involvement in adult Leydig cell differentiation. Biol. Reprod. 2008; 79, 758–765.
Hedges J, Hanna C, Bash J, Boniface ER, Burch FC, Mahalingaiah S, et al. Chronic exposure to delta-9-tetrahydrocannabinol impacts testicular volume and male reproductive health in rhesus macaques. Fertility and Sterility. 2022; Vol117, N° 4.
Banerjee, A., Singh, A., Srivastava, P., Turner, H. & Krishna, A. Effects of chronic bhang (cannabis) administration on the reproductive system of male mice. Birth Defects Res. B Dev. Reprod. Toxicol. 2011; 92, 195–205.
Maccarrone M, Rapino C, Francavilla F, Barbonettina A. Cannabinoid signalling and effects of cannabis on the male reproductive system Urology. 2021; Vol 18 (19-32)
Zufferey F, Donzé N, Rahban R, Senn A, Stettler E, Serge R, et al. Semen endocannabinoids are correlated to sperm quality in a cohort of 200 young Swiss men. Andrology. 2020;00:1–10.