RESUMO
The antihyperalgesic properties of the opiate antidiarrheal agent loperamide (ADL 2-1294) were investigated in a variety of inflammatory pain models in rodents. Loperamide exhibited potent affinity and selectivity for the cloned micro (Ki = 3 nM) compared with the delta (Ki = 48 nM) and kappa (Ki = 1156 nM) human opioid receptors. Loperamide potently stimulated [35S]guanosine-5'-O-(3-thio)triphosphate binding (EC50 = 56 nM), and inhibited forskolin-stimulated cAMP accumulation (IC50 = 25 nM) in Chinese hamster ovary cells transfected with the human mu opioid receptor. The injection of 0.3 mg of loperamide into the intra-articular space of the inflamed rat knee joint resulted in potent antinociception to knee compression that was antagonized by naloxone, whereas injection into the contralateral knee joint or via the i.m. route failed to inhibit compression-induced changes in blood pressure. Loperamide potently inhibited late-phase formalin-induced flinching after intrapaw injection (A50 = 6 microgram) but was ineffective against early-phase flinching or after injection into the paw contralateral to the formalin-treated paw. Local injection of loperamide also produced antinociception against Freund's adjuvant- (ED50 = 21 microgram) or tape stripping- (ED50 = 71 microgram) induced hyperalgesia as demonstrated by increased paw pressure thresholds in the inflamed paw. In all animal models examined, the potency of loperamide after local administration was comparable to or better than that of morphine. Loperamide has potential therapeutic use as a peripherally selective opiate antihyperalgesic agent that lacks many of the side effects generally associated with administration of centrally acting opiates.
Assuntos
Analgésicos Opioides/farmacologia , Antidiarreicos/farmacologia , Hiperalgesia/tratamento farmacológico , Loperamida/farmacologia , Sistema Nervoso Periférico/efeitos dos fármacos , Analgésicos Opioides/metabolismo , Animais , Antidiarreicos/metabolismo , Clonagem Molecular , Colforsina/farmacologia , Cricetinae , AMP Cíclico/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Hiperalgesia/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Loperamida/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Opioides/efeitos dos fármacos , Receptores Opioides delta/efeitos dos fármacos , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/efeitos dos fármacos , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismoRESUMO
The influence of temperature on Paracoccidioides brasiliensis mycelium to yeast transformation was studied by sequential microscopic observations of slide cultures. When incubated at temperatures above 28 degrees C, the mycelial elements gradually produced round to oval chlamydospores and later on, exhibited multiple budding. A sizeable proportion of mycelial elements transformed at 34 degrees C; however, multiple budding was important only at 37 degrees C.
