RESUMO
Morphine (MOR) withdrawal signs are more marked in males than in females. Considering that the influence of the dopaminergic system on these differences is unclear, we analyzed dopamine (DA) and dihydroxyphenylacetic-acid (DOPAC) brain levels during naloxone (NAL)-precipitated withdrawal as well as the involvement of D(1) and D(2) receptors in the expression of MOR withdrawal in either sex. Prepubertal Swiss-Webster mice received MOR (2 mg/kg, i.p.) twice daily for 9 days. On the tenth day, dependent animals received NAL (6 mg/kg, i.p.) after MOR and were sacrificed 30 min later. DA and DOPAC concentrations were determined in different brain areas using HPLC with electrochemical detection. Other pool of mice received either a D(1) (SCH 23390; 0.2 mg/kg, i.p.) or D(2) (raclopride; 0.3 mg/kg, i.p.) receptor antagonist before NAL and withdrawal signs were evaluated. DA and DOPAC levels only decreased in striatum and cortex of withdrawn males. Conversely, both DA receptor antagonists decreased the expression of MOR withdrawal signs in either sex. The neurochemical sex differences described here could partially explain the behavioral sex differences observed during MOR withdrawal. Additionally, SCH-23390 and raclopride effects suggest an important role of both DA receptors in the expression of MOR withdrawal in males and females.
Assuntos
Dopamina/fisiologia , Morfina/efeitos adversos , Síndrome de Abstinência a Substâncias/fisiopatologia , Animais , Comportamento Animal , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Feminino , Masculino , Camundongos , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Maturidade Sexual/fisiologia , Síndrome de Abstinência a Substâncias/metabolismoRESUMO
We have previously shown that the GABA(B) agonist baclofen (BAC) prevents the expression of morphine (MOR) withdrawal syndrome in male as well as female mice. In addition, we have demonstrated that BAC reestablishes the dopamine levels modified by MOR withdrawal syndrome in male mice. The aim of the present study was to evaluate the micro-opioid receptor binding parameters in striatum and frontal cortex of male and female mice during MOR withdrawal and its prevention with BAC. Prepubertal Swiss-Webster mice of either sex were rendered dependent by intraperitoneal (i.p.) injection of MOR (2 mg/kg) twice daily for 9 days. On the tenth day, dependent animals received naloxone (NAL) (6 mg/kg, i.p.) 60 min after the last dose of MOR and another pool of dependent mice received BAC (2 mg/kg, i.p.) previous to NAL injection. Thirty min after NAL or saline injection mice were sacrificed, brains were collected, and the striatum and frontal cortex were dissected in order to perform binding studies with [(3)H][DAMGO]. The density of micro-opioid receptor increased significantly during MOR withdrawal in male and female striatum as well as in male cortex. In addition, in both brain areas the B(max) was higher in male than in female mice during MOR withdrawal. Finally, BAC pretreatment of MOR withdrawn mice reestablished the levels of micro-opioid receptor by significantly decreasing the B(max) in either sex. In conclusion, although there were sex differences in the micro-opioid receptor density during MOR withdrawal syndrome, BAC was able to reestablish the changes in binding parameters induced by the NAL-precipitated withdrawal in female and male mice.
Assuntos
Baclofeno/farmacologia , Agonistas GABAérgicos/farmacologia , Entorpecentes/farmacologia , Receptores Opioides mu/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ala(2)-MePhe(4)-Gly(5)-Encefalina , Feminino , Masculino , Camundongos , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Fatores Sexuais , Síndrome de Abstinência a Substâncias/tratamento farmacológicoRESUMO
The present study analyzes the effects of baclofen (BAC) on mice brain neurochemical alterations during the morphine (MOR) withdrawal syndrome. Male Swiss-Webster albino mice (27-33 g) were rendered dependent by intraperitoneal (i.p.) injection of MOR (2mg/kg), twice daily for 9 days. On day 10, the dependent animals were divided into two groups: one receiving naloxone (NAL; 6 mg/kg i.p.) to precipitate the withdrawal syndrome 60 min after the last dose of MOR and the other received BAC (2mg/kg, i.p.) followed by NAL (6 mg/kg, i.p.), injected 30 and 60 min after the last dose of MOR, respectively. Ten minutes after these treatments, mice were killed by decapitation and the striatum, cortex and hippocampus were dissected to determine endogenous concentrations of dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites using HPLC with electrochemical detection. Striatal DA, dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) concentrations as well as cortical DA concentrations of the withdrawal groups decreased significantly with respect to the control groups. BAC attenuated the decrease in DA and DOPAC concentrations observed during the withdrawal, without modifying per se the control DA concentrations. No changes on 5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) concentrations were observed during the MOR abstinence syndrome. The prevention caused by BAC on the decreased concentrations of DA induced by MOR withdrawal could have a therapeutic interest for the management of withdrawal syndrome.