RESUMO
Dopamine replacement therapy in Parkinson's disease (PD) using L-dopa is invariably associated with a loss of drug efficacy ("wearing off") and the onset of dyskinesia. The use of dopamine receptor partial agonists might improve therapeutic benefit without increased dyskinesia expression but may antagonise the effects of L-dopa. We now examine the effects of the novel high affinity, dopamine D(2) receptor partial agonist, aplindore alone and in combination with L-dopa in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. In non-dyskinetic MPTP treated animals, aplindore (0.05-1.0 mg/kg p.o.) produced a dose-dependent reversal of motor disability and an increase in locomotor activity that was maximal at doses of 0.2 mg/kg and above. In animals previously exposed to L: -dopa to induce dyskinesia, escalating and repeated dosing of aplindore (0.05-0.5 mg/kg p.o.) produced a sustained, dose-related improvement in motor disability and an increase in locomotor activity. The effects were maximal at a dose of 0.1 mg/kg and above and not different from those produced by L-dopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o.). Aplindore administration also led to dose-dependent expression of dyskinesia but at 0.1 mg/kg, this was significantly less intense than that produced by L-dopa. Administration of aplindore (1.0 mg/kg p.o.) in combination with L-dopa (2.5 mg/kg plus carbidopa 12.5 mg/kg p.o.) did not inhibit the reversal of motor deficits but improved motor disability and increased both locomotor activity and dyskinesia expression equivalent to that produced by L-dopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o.). These data suggest that dopamine receptor partial agonists would be effective in the treatment of Parkinson's disease and would not inhibit the beneficial actions of L-dopa.
Assuntos
Antiparkinsonianos/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Indóis/uso terapêutico , Levodopa/uso terapêutico , Intoxicação por MPTP/tratamento farmacológico , Animais , Antiparkinsonianos/administração & dosagem , Callithrix , Avaliação da Deficiência , Agonistas de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/metabolismo , Feminino , Indóis/administração & dosagem , Levodopa/administração & dosagem , Locomoção/efeitos dos fármacos , Intoxicação por MPTP/metabolismo , Masculino , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Fatores de Tempo , Resultado do TratamentoRESUMO
Corticotropin releasing factor receptor 1 (CRF1) is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF1 antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 µg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67-87% and decreased WAS-induced-FPO by 23-53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD.