Development of mechanical hypersensitivity in rats during heroin and ethanol dependence: alleviation by CRF₁ receptor antagonism.
Development of mechanical hypersensitivity in rats during heroin and ethanol dependence: alleviation by CRF₁ receptor antagonism.
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DOI：
10.1016/j.neuropharm.2011.11.006
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发表时间：
2012-02
影响因子：
4.7
通讯作者：
Koob GF
中科院分区：
文献类型：
--
作者：
Edwards S;Vendruscolo LF;Schlosburg JE;Misra KK;Wee S;Park PE;Schulteis G;Koob GF
药物依赖的动物模型描述了大脑奖励过程的减少和应激样（或反奖励）机制的增强，包括促肾上腺皮质激素释放因子（CRF）信号的募集。因此，长期暴露于阿片类药物往往导致机械超敏反应的发展。我们测量了有限（短时间接触组：ShA）或延长（长时间接触组：LgA）自我给药海洛因或可卡因的雄性Wistar大鼠，或通过乙醇蒸气暴露依赖乙醇的大鼠（乙醇依赖组）的爪子戒断阈值（PWTs）。在海洛因自我给药的动物中，在过渡到LgA条件后，阈值降低到基线时观察到的水平的50%左右，并且也显著低于继续使用ShA计划的动物的阈值。相比之下，在ShA（1小时）或LgA（6小时）条件下自行服用可卡因的动物的阈值没有改变。与海洛因LgA大鼠相似，与非依赖大鼠相比，乙醇依赖大鼠在暴露于乙醇蒸气8周后也出现了机械超敏反应。全身给予CRF1R拮抗剂MPZP可显著减轻海洛因或乙醇依赖大鼠的超敏反应。因此，海洛因和乙醇依赖的机械性超敏反应的出现可能代表了一种与药物相关的关键负面情绪状态，驱动对这些物质的依赖。这些结果还表明，crf调节的伤害性通路的募集与摄入和依赖的增加有关。更深入地了解慢性药物暴露与疼痛相关状态之间的关系，可能有助于深入了解过渡到药物成瘾的机制，并揭示新的治疗机会。
Animal models of drug dependence have described both reductions in brain reward processes and potentiation of stress-like (or anti-reward) mechanisms, including a recruitment of corticotropin-releasing factor (CRF) signaling. Accordingly, chronic exposure to opiates often leads to the development of mechanical hypersensitivity. We measured paw withdrawal thresholds (PWTs) in male Wistar rats allowed limited (short access group: ShA) or extended (long access group: LgA) access to heroin or cocaine self-administration, or in rats made dependent on ethanol via ethanol vapor exposure (ethanol-dependent group). In heroin self-administering animals, after transition to LgA conditions, thresholds were reduced to around 50% of levels observed at baseline, and were also significantly lower than thresholds measured in animals remaining on the ShA schedule. In contrast, thresholds in animals self-administering cocaine under either ShA (1 h) or LgA (6 h) conditions were unaltered. Similar to heroin LgA rats, ethanol-dependent rats also developed mechanical hypersensitivity after eight weeks of ethanol vapor exposure compared to non-dependent animals. Systemic administration of the CRF1R antagonist MPZP significantly alleviated the hypersensitivity observed in rats dependent on heroin or ethanol. The emergence of mechanical hypersensitivity with heroin and ethanol dependence may thus represent one critical drug-associated negative emotional state driving dependence on these substances. These results also suggest a recruitment of CRF-regulated nociceptive pathways associated with escalation of intake and dependence. A greater understanding of relationships between chronic drug exposure and pain-related states may provide insight into mechanisms underlying the transition to drug addiction, as well as reveal new treatment opportunities.