Department of Psychology, University of Wisconsin Green Bay, Green Bay, Wisconsin (T.M.H., P.O.K.); Department of Pharmacology and Edward F. Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (K.M.O., J.E.H., L.G.R., B.F.S., C.M., J.W., E.M.J., J.R.T.); Department of Pharmacy and Pharmacology, and Center for Therapeutic Innovation, University of Bath, Bath, United Kingdom (M.O., S.M.H.); and Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.R.T.).
Department of Psychology, University of Wisconsin Green Bay, Green Bay, Wisconsin (T.M.H., P.O.K.); Department of Pharmacology and Edward F. Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (K.M.O., J.E.H., L.G.R., B.F.S., C.M., J.W., E.M.J., J.R.T.); Department of Pharmacy and Pharmacology, and Center for Therapeutic Innovation, University of Bath, Bath, United Kingdom (M.O., S.M.H.); and Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (J.R.T.)
J Pharmacol Exp Ther. 2021 Sep;378(3):287-299. doi: 10.1124/jpet.121.000524. Epub 2021 Jun 28.
There are no Food and Drug Administration-approved medications for cocaine use disorder, including relapse. The -opioid receptor (MOPr) partial agonist buprenorphine alone or in combination with naltrexone has been shown to reduce cocaine-positive urine tests and cocaine seeking in rodents. However, there are concerns over the abuse liability of buprenorphine. Buprenorphine's partial agonist and antagonist activity at the nociception receptor (NOPr) and -opioid receptor (KOPr), respectively, may contribute to its ability to inhibit cocaine seeking. Thus, we hypothesized that a buprenorphine derivative that exhibits antagonist activity at MOPr and KOPr with enhanced agonist activity at the NOPr could provide a more effective treatment. Here we compare the pharmacology of buprenorphine and two analogs, BU10119 and BU12004, in assays for antinociception and for cocaine- and stress-primed reinstatement in the conditioned place preference paradigm. In vitro and in vivo assays showed that BU10119 acts as an antagonist at MOPr, KOPr, and -opioid receptor (DOPr) and a partial agonist at NOPr, whereas BU12004 showed MOPr partial agonist activity and DOPr, KOPr, and NOPr antagonism. BU10119 and buprenorphine but not BU12004 lessened cocaine-primed reinstatement. In contrast, BU10119, BU12004, and buprenorphine blocked stress-primed reinstatement. The selective NOPr agonist SCH221510 but not naloxone decreased cocaine-primed reinstatement. Together, these findings are consistent with the concept that NOPr agonism contributes to the ability of BU10119 and buprenorphine to attenuate reinstatement of cocaine-conditioned place preference in mice. The findings support the development of buprenorphine analogs lacking MOPr agonism with increased NOPr agonism for relapse prevention to cocaine addiction. SIGNIFICANCE STATEMENT: There are no Food and Drug Administration-approved medications for cocaine use disorder. Buprenorphine has shown promise as a treatment for cocaine relapse prevention; however, there are concerns over the abuse liability of buprenorphine. Here we show a buprenorphine analogue, BU10119, which lacks -opioid receptor agonism and inhibits cocaine-primed and stress-primed reinstatement in a conditioned place-preference paradigm. The results suggest the development of BU10119 for the management of relapse to cocaine seeking.
目前，尚无美国食品和药物管理局批准的用于可卡因使用障碍（包括复发）的药物。单独使用或与纳曲酮联合使用的μ-阿片受体（MOPr）部分激动剂丁丙诺啡已被证明可减少啮齿动物可卡因阳性尿检和可卡因觅药行为。然而，人们对丁丙诺啡的滥用倾向存在担忧。丁丙诺啡对伤害感受受体（NOPr）和μ-阿片受体（KOPr）具有部分激动剂和拮抗剂活性，分别可能有助于其抑制可卡因觅药行为。因此，我们假设，一种对 MOPr 和 KOPr 表现出拮抗活性，对 NOPr 表现出增强的激动活性的丁丙诺啡衍生物可能提供更有效的治疗方法。在这里，我们比较了丁丙诺啡及其两种类似物 BU10119 和 BU12004 在痛觉测定和条件性位置偏爱范式中可卡因和应激引发复吸的药理学。体外和体内测定表明，BU10119 对 MOPr、KOPr 和 μ-阿片受体（DOPr）表现为拮抗剂，对 NOPr 表现为部分激动剂，而 BU12004 对 MOPr 表现为部分激动剂活性，对 DOPr、KOPr 和 NOPr 表现为拮抗剂。BU10119 和丁丙诺啡而非 BU12004 减轻了可卡因引发的复吸。相比之下，BU10119、BU12004 和丁丙诺啡阻断了应激引发的复吸。选择性 NOPr 激动剂 SCH221510 而非纳洛酮降低了可卡因引发的复吸。总的来说，这些发现与这样的概念一致，即 NOPr 激动作用有助于 BU10119 和丁丙诺啡减弱可卡因条件性位置偏爱在小鼠中的复吸。这些发现支持开发缺乏 MOPr 激动作用而增加 NOPr 激动作用的丁丙诺啡类似物，以预防可卡因成瘾的复发。
