Sakoori Kazuto, Murphy Niall P
Neuronal Circuit Mechanisms Research Group, RIKEN Brain Science Institute, Wakoshi, Saitama, Japan.
Neuropsychopharmacology. 2008 Mar;33(4):877-91. doi: 10.1038/sj.npp.1301459. Epub 2007 May 23.
The opioid peptide nociceptin (orphanin FQ) suppresses drug reward, drug self-administration, and impedes some of the processes believed to underlie the transition to addiction. As virtually all previous studies have used administration of nociceptin receptor agonists to evaluate the role of nociceptin on addiction-like behavior, the current study used a pharmacological (nociceptin receptor antagonist) and genetic (nociceptin receptor knockout mice) approach to elucidate the role of endogenous nociceptin. The nociceptin receptor antagonist UFP-101 induced a modest place preference, and enhanced the conditioned place preference induced by methamphetamine. In agreement with this, nociceptin receptor knockout mice had slightly enhanced methamphetamine and ethanol conditioned place preferences compared to wild-type mice. This effect did not appear to depend on differences in learning ability, as nociceptin receptor knockout mice had slightly weaker-conditioned place aversions to lithium chloride, the kappa-opioid receptor agonist, U50488H, and the general opiate antagonist, naloxone. The development of behavioral sensitization to methamphetamine was lower in nociceptin receptor knockout mice, and attenuated by UFP-101 administration to wild-type mice. Additionally, ethanol consumption and preference in a two-bottle choice test was lower in nociceptin receptor knockout mice, though ethanol-stimulated locomotion was stronger. Whereas the rewarding effect of methamphetamine and ethanol following chronic treatment, as measured by place conditioning, strengthened in wild-type mice, this effect was absent in nociceptin receptor knockout mice. These results suggest that endogenous N/OFQ suppresses basal and drug-stimulated increases in hedonic state, and plays either a permissive or facilitatory role in the development of addiction.
阿片肽痛敏肽（孤啡肽FQ）可抑制药物奖赏、药物自我给药，并阻碍一些被认为是成瘾转变基础的过程。由于几乎所有先前的研究都使用痛敏肽受体激动剂给药来评估痛敏肽对成瘾样行为的作用，因此本研究采用药理学方法（痛敏肽受体拮抗剂）和遗传学方法（痛敏肽受体基因敲除小鼠）来阐明内源性痛敏肽的作用。痛敏肽受体拮抗剂UFP-101诱导了适度的位置偏爱，并增强了甲基苯丙胺诱导的条件性位置偏爱。与此一致的是，与野生型小鼠相比，痛敏肽受体基因敲除小鼠对甲基苯丙胺和乙醇的条件性位置偏爱略有增强。这种效应似乎并不取决于学习能力的差异，因为痛敏肽受体基因敲除小鼠对氯化锂、κ-阿片受体激动剂U50488H和通用阿片拮抗剂纳洛酮的条件性位置厌恶稍弱。痛敏肽受体基因敲除小鼠对甲基苯丙胺的行为敏化发展较低，而对野生型小鼠给予UFP-101可减弱这种敏化。此外，在双瓶选择试验中，痛敏肽受体基因敲除小鼠的乙醇消耗量和偏爱较低，尽管乙醇刺激的运动更强。通过位置条件反射测量，野生型小鼠慢性治疗后甲基苯丙胺和乙醇的奖赏效应增强，而痛敏肽受体基因敲除小鼠则没有这种效应。这些结果表明，内源性N/OFQ抑制基础和药物刺激引起的享乐状态增加，并在成瘾发展中起允许或促进作用。
