RESUMEN
The nociceptin/orphanin FQ peptide (NOP) receptor is believed to have an integral modulatory function in the stress response system. We evaluated the highly selective NOP antagonist J-113397 (7.5 and 20.0 mg/kg), using a predator exposure in which rats were exposed to predator cats as a stressor. A single dose of J-113397 or vehicle was administered (intraperitoneally) shortly before exposure to the predators or a sham exposure. Behavioral impact was measured using elevated plus maze (EPM), open field activity (OFA), and an olfactory discrimination (OD). The predator exposure produced a relatively long-lasting deficit (decreased time in open arms, decreased basic activity) on the EPM while having little effect on performance on the OFA or OD. J-113397 mitigated the performance deficits on the EPM in a dose-dependent manner while having little effect on performance on the OFA or OD. The largest dose of J-113397, administered with a sham exposure, was essentially devoid of effects on the EPM, OFA, and OD. These results demonstrate that J-113397 can significantly and selectively mitigate the effects of a stressor typically used in a preclinical model of post-traumatic stress disorder. Furthermore, these results are consistent with and extend previous results showing that the NOP receptor has an important role in the response to stress and that NOP antagonism may, potentially, have therapeutic benefit in stress disorders.
Asunto(s)
Bencimidazoles/farmacología , Piperidinas/farmacología , Receptores Opioides/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacos , Animales , Ansiedad/tratamiento farmacológico , Bencimidazoles/metabolismo , Gatos , Masculino , Antagonistas de Narcóticos/uso terapéutico , Péptidos Opioides/antagonistas & inhibidores , Péptidos Opioides/metabolismo , Fragmentos de Péptidos/metabolismo , Piperidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Opioides/metabolismo , Trastornos por Estrés Postraumático/tratamiento farmacológico , Estrés Fisiológico/fisiología , Estrés Psicológico/fisiopatología , Receptor de Nociceptina , NociceptinaRESUMEN
Essential survival signals within hematopoietic stem cell (HSC) and thymic niches are mediated by receptor tyrosine kinases, which can be reversibly inhibited using clinically available drugs. We studied whether sunitinib, a multityrosine kinase inhibitor that inhibits KIT, enhances engraftment after bone marrow transplantation (BMT) in mice. Sunitinib diminished hematopoietic progenitor cell numbers, and sunitinib enhanced marrow, peripheral myeloid, and lymphoid engraftment after BMT in Rag1(-/-) mice. Sunitinib augmented HSC engraftment because recipients displayed increased myeloid and lymphoid engraftment and because sunitinib-treated recipients of purified HSCs showed enhanced engraftment of secondary hosts. However, sunitinib preferentially augmented T-cell engraftment with lesser effects on myeloid and HSC engraftment. Consistent with this, sunitinib preferentially depleted the early thymic progenitor subset in the thymus. Sunitinib did not increase engraftment in mice with deficient KIT signaling, and the pattern of more potent effects on T cell compared with HSC engraftment observed in sunitinib-treated hosts was also observed after BMT into KIT(W/Wv) mice. These results implicate KIT as a critical modulator of thymic niches. We conclude that transient, pharmacologic inhibition of KIT enhances accessibility of marrow and thymic niches, and provides a novel, noncytotoxic approach to accomplish engraftment after stem cell transplantation.