This study will investigate the cellular, molecular, and physiological mechanisms responsible for tolerance to ?9-THC. We have produced mutant mice (S426A/S430A) expressing a desensitization- resistant form of the cannabinoid receptor 1 (CB) that exhibit delayed tolerance for ?9-THC. 1 However S426A/S430A mutants eventually become completely tolerant to ?9-THC. Treatment of S426A/S430A mutant with an inhibitor of c-Jun N-terminal kinase (JNK) eliminates tolerance to the analgesic effects of ?9-THC suggesting that this signaling pathway might be responsible for the residual tolerance observed in S426A/S430A mutant mice. The specific JNK isoform involved in cannabinoid tolerance will be determined by measuring tolerance for the analgesic, hypothermic, and cataleptic effects of ?9-THC in wild-type, S426A/S430A x JNK1 knockout (KO), and S426A/S430A x JNK2 KO double mutant mice. A dose response curve for the preventative effects of SP600125 (JNK inhibitor) on hypothermic, cataleptic, and analgesic tolerance will be examined in S426A/S430A single mutant mice to determine an optimal dosage for this inhibitor. Microarray analyses examining differences in gene expression between vehicle and SP600125-treated S426A/S430A mutants as well between S426A/S430A single mutants and S426A/S430A x JNK1 and S426A/S430A x JNK2 KO double mutants will be done to determine the molecular targets responsible for JNK-mediated cannabinoid tolerance. All putative JNK targets identified by microarray analysis will be validated using quantitative real-time PCR. The goal of this study is to determine the form of JNK responsible for mediating tolerance to the analgesic effects of ?9-THC and also to identify the molecular and biochemical targets of JNK that are responsible for cannabinoid tolerance.
We have found that pharmacological inhibition of c-Jun N-terminal kinase (JNK) in mutant mice that are unable undergo G-protein coupled receptor kinase-mediated cannabinoid receptor 1 desensitization prevents tolerance to the analgesic effects of ?9-THC. This study will determine the form of JNK that is responsible for mediating tolerance to ?9-THC. This study will also identify and validate molecular targets involved in JNK-mediated cannabinoid tolerance.
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