Titre du document / Document title

Central and peripheral mechanisms contribute to the antiemetic actions of delta-9-tetrahydrocannabinol against 5-hydroxytryptophan-induced emesis

Auteur(s) / Author(s)

DARMANI Nissar A. ⁽¹⁾ ; JOHNSON Jane C. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Department of Pharmacology. Kirksville College of Osteopathic Medicine. A.T. Still University of Health Sciences. 800 West Jefferson Street, Kirksville, MO 63501, ETATS-UNIS

Résumé / Abstract

Delta-9-tetrahydrocannabinol (delta-9-THC) prevents cisplatin-induced emesis via cannabinoid CB₁ receptor. Whether central and/or peripheral cannabinoid CB₁ receptors account for the antiemetic action(s) of delta-9-THC remains to be investigated. The 5-hydroxytryptamine (5-HT=serotonin) precursor, 5-hydroxytryptophan (5-HTP), is an indirect 5-HT agonist and simultaneously produces the head-twitch response (a centrally mediated serotonin 5-HT_2A receptor-induced behavior) and emesis (a serotonin 5-HT₃ receptor-induced response, mediated by both peripheral and central mechanisms) in the least shrew (Cryptotis parva). The peripheral amino acid decarboxylase inhibitor, carbidopa, prevents the conversion of 5-HTP to 5-HT in the periphery and elevates 5-HTP levels in the central nervous system (CNS). When administered i.p. alone, a 50 mg/kg dose of 5-HTP failed to induce either behaviour while its 100 mg/kg dose produced robust frequencies of both head-twitch response and emesis. Pretreatment with carbidopa (0, 10, 20 and 40 mg/kg) potentiated the ability of both doses of 5-HTP to produce the head-twitch response in a dose-dependent but bell-shaped manner, with maximal potentiation occurring at 20 mg/kg carbidopa. Carbidopa dose-dependently reduced the frequency of 5-HTP (100 mg/kg)-induced emesis, whereas the 10 mg/kg dose potentiated, and the 20 and 40 mg/kg doses suppressed the frequency of vomits produced by the 50 mg/kg dose of 5-HTP. The peripheral and/or central antiemetic action(s) of delta-9-THC (0, 1, 2.5, 5, 10 and 20 mg/kg) against 5-HTP (100 mg/kg)-induced head-twitch response and emesis were investigated in different groups of carbidopa (0, 10 and 20 mg/kg) pretreated shrews, Irrespective of carbidopa treatment, delta-9-THC attenuated the frequency of 5-HTP-induced head-twitch response in a dose-dependent manner with similar ID₅₀ values. Although delta-9-THC also reduced the frequency of 5-HTP-induced emesis with similar ID_50s, at the 5 mg/kg delta-9-THC dose however, 5-HTP induced significantly less vomits in the 10 and 20 mg/kg carbidopa-treated groups relative to its 0 mg/kg control group. Moreover, increasing doses of carbidopa significantly shifted the inhibitory dose-response effect of delta-9-THC in protecting shrews from 5-HTP-induced emesis to the left. Relatively, a large dose of delta-9-THC (20 mg/kg) was required to significantly reduce the number of vomits produced by direct acting serotonergic 5-HT₃ receptor agonists, serotonin and 2-methylserotonin. Low doses of delta-9-THC (0.1-1I mg/kg) nearly completely prevented 2-methylserotonin-induced, centrally mediated, head-twitch and ear-scratch responses. The results indicate that delta-9-THC probably acts pre- and postsynaptically to attenuate emesis produced by indirect and direct acting 5-HT₃ receptor agonists via both central and peripheral mechanisms. In addition, delta-9-THC prevents 5-HTP-induced head-twitch and emesis via cannabinoid CB₁ receptors since the CB₁ receptor antagonist, SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], countered the inhibitory actions of an effective dose of delta-9-THC against both behaviours.

Revue / Journal Title

European journal of pharmacology   ISSN 0014-2999   CODEN EJPHAZ 

Source / Source

2004, vol. 488, n^o1-3, pp. 201-212 [12 page(s) (article)] (1 p.1/4)

Langue / Language

Anglais

Editeur / Publisher

Elsevier, Amsterdam, PAYS-BAS  (1967) (Revue)

Mots-clés anglais / English Keywords

Enzyme inhibitor ; Enzyme ; Lyases ; Carbon-carbon lyases ; Carboxy-lyases ; Decarboxylase ; Neurotransmitter ; Antiparkinson agent ; Antidepressant agent ; Psychotropic ; CB1 cannabinoid receptor ; Ear ; Carbidopa ; Serotonin ; Antiemetic ; Mechanism of action ; Oxitriptan ;

Mots-clés français / French Keywords

Inhibiteur enzyme ; Enzyme ; Lyases ; Carbon-carbon lyases ; Carboxy-lyases ; Decarboxylase ; Neurotransmetteur ; Antiparkinsonien ; Antidépresseur ; Psychotrope ; Récepteur cannabinoïde CB1 ; Oreille ; Carbidopa ; Sérotonine ; Antiémétique ; Mécanisme action ; Oxitriptan ;

Mots-clés espagnols / Spanish Keywords

Inhibidor enzima ; Enzima ; Lyases ; Carbon-carbon lyases ; Carboxy-lyases ; Decarboxylase ; Neurotransmisor ; Antiparkinsoniano ; Antidepresor ; Psicotropo ; Receptor canabinoide CB1 ; Oido ; Carbidopa ; Serotonina ; Antiemético ; Mecanismo acción ; Oxitriptán ;

Localisation / Location

INIST-CNRS, Cote INIST : 13322, 35400011700847.0240