RESUMO
RATIONALE: Tianeptine is a mu-opioid receptor (MOR) agonist with increasing reports of abuse in human populations. Preclinical data regarding the abuse potential and other opioid-like adverse effects of tianeptine at supratherapeutic doses are sparse. OBJECTIVES: The present study evaluated tianeptine in a rat model of abuse potential assessment and in mouse models of motor, gastrointestinal, and respiratory adverse effects. METHODS: Abuse potential was assessed in adult male Sprague-Dawley rats using an intracranial self-stimulation (ICSS) procedure to determine effects of acute and repeated tianeptine on responding for electrical brain stimulation. Male ICR mice were used to determine the effects of tianeptine in assays of locomotor behavior and gastrointestinal motility. Male Swiss-Webster mice were monitored for respiratory changes using whole-body plethysmography. RESULTS: In rats, acute tianeptine produced weak and delayed evidence for abuse-related ICSS facilitation at an intermediate dose (10 mg/kg, IP) and pronounced, naltrexone-preventable ICSS depression at a higher dose (32 mg/kg, IP). Repeated 7-day tianeptine (10 and 32 mg/kg/day, IP) produced no increase in abuse-related ICSS facilitation, only modest tolerance to ICSS depression, and no evidence of physical dependence. In mice, tianeptine produced dose-dependent, naltrexone-preventable locomotor activation. Tianeptine (100 mg/kg, SC) also significantly inhibited gastrointestinal motility and produced naloxone-reversible respiratory depression. CONCLUSIONS: Tianeptine presents as a MOR agonist with resistance to tolerance and dependence in our ICSS assay in rats, and it has lower abuse potential by this metric than many commonly abused opioids. Nonetheless, tianeptine produces MOR agonist-like acute adverse effects that include motor impairment, constipation, and respiratory depression.
Assuntos
Transtornos Relacionados ao Uso de Opioides , Insuficiência Respiratória , Analgésicos Opioides/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos ICR , Naltrexona/farmacologia , Ratos , Ratos Sprague-Dawley , Autoestimulação , TiazepinasRESUMO
Direct-acting cannabinoid receptor agonists are well known to reduce hyperalgesic responses and allodynia after nerve injury, although their psychoactive side effects have damped enthusiasm for their therapeutic development. Alternatively, inhibiting fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the principal enzymes responsible for the degradation of the respective endogenous cannabinoids, anandamide (AEA) and 2-arachydonylglycerol (2-AG), reduce nociception in a variety of nociceptive assays, with no or minimal behavioral effects. In the present study we tested whether inhibition of these enzymes attenuates mechanical allodynia, and acetone-induced cold allodynia in mice subjected to chronic constriction injury of the sciatic nerve. Acute administration of the irreversible FAAH inhibitor, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), or the reversible FAAH inhibitor, 1-oxo-1-[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL-135), decreased allodynia in both tests. This attenuation was completely blocked by pretreatment with either CB(1) or CB(2) receptor antagonists, but not by the TRPV1 receptor antagonist, capsazepine, or the opioid receptor antagonist, naltrexone. The novel MAGL inhibitor, 4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) also attenuated mechanical and cold allodynia via a CB(1), but not a CB(2), receptor mechanism of action. Whereas URB597 did not elicit antiallodynic effects in FAAH(-/-) mice, the effects of JZL184 were FAAH-independent. Finally, URB597 increased brain and spinal cord AEA levels, whereas JZL184 increased 2-AG levels in these tissues, but no differences in either endo-cannabinoid were found between nerve-injured and control mice. These data indicate that inhibition of FAAH and MAGL reduces neuropathic pain through distinct receptor mechanisms of action and present viable targets for the development of analgesic therapeutics.
Assuntos
Amidoidrolases/antagonistas & inibidores , Analgésicos não Narcóticos/farmacologia , Moduladores de Receptores de Canabinoides/metabolismo , Endocanabinoides , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Dor/tratamento farmacológico , Dor/etiologia , Doenças do Sistema Nervoso Periférico/complicações , Animais , Ácidos Araquidônicos/metabolismo , Benzamidas/farmacologia , Benzodioxóis/farmacologia , Moduladores de Receptores de Canabinoides/análise , Carbamatos/farmacologia , Temperatura Baixa , Glicerídeos/metabolismo , Hiperalgesia/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas de Entorpecentes , Medição da Dor/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/metabolismo , Piridinas/farmacologia , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB2 de Canabinoide/efeitos dos fármacos , Canais de Cátion TRPV/efeitos dos fármacosRESUMO
The reemergence on the debate of the use of marijuana for medicinal purposes has been the impetus for developing an acceptable delivery form of aerosolized cannabinoids. The goals of the present study were to: (1) develop and characterize the physical properties of an aerosolized form of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent present in marijuana; and (2) assess the pharmacological effects of cannabinoid inhalation in mice. A Small Particle Aerosol Generator (SPAG) nebulizer, used to generate the aerosol, had an output of approximately 0.154 mg/l of aerosolized Delta(9)-THC with a 2.0 microm mass median aerodynamic diameter and a 2.2 geometric standard deviation (GSD). Virtually all the particles were less than 5.0 microm in diameter suggesting that they were sufficiently small to penetrate deeply into the lungs. Inhalation exposure to aerosolized Delta(9)-THC in mice elicited antinociceptive effects that were dependent on concentration and exposure time with an estimated Delta(9)-THC dose of 1.8 mg/kg. On the other hand, inhalation exposure to Delta(9)-THC failed to produce two other indices indicative of cannabinoid activity, hypothermia and decreases in spontaneous locomotor activity. The antinociceptive effects occurred within 5 min of exposure and lasted approximately 40 min in duration. The cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), but not naloxone, blocked these antinociceptive effects (AD(50)=0.09 mg/kg) indicating a cannabinoid receptor mechanism of action. Similarly, inhalation exposure to a water soluble cannabinoid analog, 3-(5'-cyano-1', 1'dimethylheptyl)-1-(4-N-morpholinobutyrloxy)-Delta(8)-te trahydrocann abinol (O-1057), produced antinociception that was blocked by SR 141716A. These results demonstrate that the development of an aerosolized form of cannabinoids for human medicinal use is feasible.
Assuntos
Canabinoides/farmacologia , Administração por Inalação , Aerossóis , Animais , Canabinoides/antagonistas & inibidores , Relação Dose-Resposta a Droga , Dronabinol/sangue , Dronabinol/farmacologia , Alucinógenos/farmacologia , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Dor/prevenção & controle , Piperidinas/farmacologia , Pirazóis/farmacologia , RimonabantoRESUMO
Although the majority of cannabinoid users smoke marijuana, the preponderance of laboratory animal research is based on administration of Delta9-tetrahydrocannabinol (Delta9-THC) or other cannabinoid agents via injection. The aim of the present study was to evaluate the impact of inhaling marijuana, or ethanol-extracted placebo smoke in the mouse model of cannabinoid activity by assessing inhibition of spontaneous activity, antinociception, catalepsy, and body temperature. In order to determine dosimetry, blood levels of Delta9-THC were obtained following either marijuana exposure or intravenous injection of Delta(9)-THC. Inhalation exposure to marijuana produced dose-related increases in antinociception and catalepsy, with estimated ED50 doses of Delta9-THC of 2.4 and 3.8 mg/kg, respectively. However, hypothermia and locomotor depression occurred in both the placebo- and marijuana-exposed mice. The CB1 receptor antagonist, SR 141716A antagonized the antinociceptive effects of marijuana (AD50 = 0.6 mg/kg), but only slightly decreased marijuana-induced catalepsy, and failed to alter either the hypothermic or locomotor depressive effects. In contrast, SR 141716A antagonized the antinociceptive, cataleptic, and hypothermic effects of intravenously administered Delta9-THC in mice that were exposed to air alone, though all subjects exhibited locomotor depression, possibly related to the restraint. In accordance with reports of others, these data suggest that exposure to smoke alone has pharmacological consequences. Our findings also indicate that marijuana-induced antinociception is mediated through a CB1-receptor mechanism of action and are consistent with the notion that Delta9-THC is mainly responsible for this effect.
Assuntos
Canabinoides/farmacologia , Fumar Maconha/fisiopatologia , Administração por Inalação , Animais , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Regulação da Temperatura Corporal/efeitos dos fármacos , Regulação da Temperatura Corporal/fisiologia , Relação Dose-Resposta a Droga , Dronabinol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologiaRESUMO
The case history and toxicological findings of a fatal suicidal valproic acid overdose are presented. Valproic acid concentrations were determined in body tissues and fluids by gas-liquid chromatography (GLC) following both direct extraction and the method of standards addition and quantitative fluorescence polarization immunoassay. The quantitative results obtained by the three procedures were in good agreement. Qualitative identification of valproic acid as its methylated derivative was by ion-trap gas chromatography-mass spectrometry. Toxicological analysis by direct extraction GLC yielded the following valproate concentrations (mg/mL or mg/kg): blood, 1050; bile, 713; brain, 510; heart, 670; kidney, 1580; liver, 985; and vitreous, 516. A total of 15.1 g of valproate was recovered in the stomach contents. These findings far exceed those associated with valproate therapy and are similar to the limited valproate disposition data reported in prior fatal overdoses.