Department of Psychology, Washington State University, Pullman, WA 99164-4820, USA.
J Pharmacol Exp Ther. 2012 Mar;340(3):787-800. doi: 10.1124/jpet.111.188540. Epub 2011 Dec 19.
The purpose of this study was to determine whether sex differences in cannabinoid (CB)-induced antinociception and motoric effects can be attributed to differential activation of CB(1) or CB(2) receptors. Rats were injected intraperitoneally with vehicle, rimonabant [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (SR141716A), a putative CB(1) receptor-selective antagonist; 0.1-10 mg/kg] or 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528) (a putative CB(2) receptor-selective antagonist; 1.0-10 mg/kg). Thirty minutes later, Δ(9)-tetrahydrocannabinol (THC; 1.25-40 mg/kg) or 5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol (CP55,940) (0.05-1.6 mg/kg) was injected. Paw pressure and tail withdrawal antinociception, locomotor activity, and catalepsy were measured. Rimonabant dose-dependently antagonized THC and CP55,940 in each test, but was up to 10 times more potent in female than male rats on the nociceptive tests; estimates of rimonabant affinity (apparent pK(B)) for the CB(1) receptor were approximately 0.5 to 1 mol/kg higher in female than male rats. SR144528 partially antagonized THC-induced tail withdrawal antinociception and locomotor activity in females, but this antagonism was not dose-dependent or consistent; no SR144528 antagonism was observed in either sex tested with CP55,940. Neither the time course of rimonabant antagonism nor the plasma levels of rimonabant differed between the sexes. Rimonabant and SR144528 did not antagonize morphine-induced antinociception, and naloxone did not antagonize THC-induced antinociception in either sex. These results suggest that THC produces acute antinociceptive and motoric effects via activation of CB(1), and perhaps under some conditions, CB(2) receptors, in female rats, whereas THC acts primarily at CB(1) receptors in male rats. Higher apparent pK(B) for rimonabant in female rats suggests that cannabinoid drugs bind with greater affinity to CB(1) receptors in female than male rats, probably contributing to greater antinociceptive effects observed in female compared with male rats.
本研究旨在确定大麻素（CB）诱导的镇痛和运动效应的性别差异是否归因于 CB（1）或 CB（2）受体的不同激活。大鼠腹腔注射给予载体、利莫那班[5-（4-氯苯基）-1-（2,4-二氯苯基）-4-甲基-N-1-哌啶基-1H-吡唑-3-甲酰胺（SR141716A），一种假定的 CB（1）受体选择性拮抗剂；0.1-10mg/kg]或 5-（4-氯-3-甲基苯基）-1-[[4-甲基苯基]甲基]-N-[[1S,2S,4R]-1,3,3-三甲基双环[2.2.1]庚-2-基]-1H-吡唑-3-甲酰胺（SR144528）（一种假定的 CB（2）受体选择性拮抗剂；1.0-10mg/kg）。30 分钟后，注射 Δ（9）-四氢大麻酚（THC；1.25-40mg/kg）或 5-（1,1-二甲基庚基）-2-[5-羟基-2-（3-羟基丙基）环己基]苯酚（CP55,940）（0.05-1.6mg/kg）。测量爪压力和尾部撤回镇痛、运动活动和僵住。利莫那班剂量依赖性拮抗 THC 和 CP55,940 在每个测试中，但在雌性大鼠中的镇痛测试中，其效力比雄性大鼠高 10 倍；利莫那班对 CB（1）受体的亲和力（表观 pK（B））估计在雌性大鼠中比雄性大鼠高约 0.5 至 1mol/kg。SR144528 部分拮抗 THC 诱导的尾部撤回镇痛和雌性大鼠的运动活动，但这种拮抗作用不是剂量依赖性或一致的；在雄性大鼠中用 CP55,940 进行测试时，未观察到 SR144528 拮抗作用。利莫那班拮抗作用的时间过程和利莫那班的血浆水平在两性之间没有差异。利莫那班和 SR144528 不拮抗吗啡诱导的镇痛作用，纳洛酮也不拮抗 THC 诱导的镇痛作用在两性中。这些结果表明，THC 通过激活 CB（1）受体，并且在某些条件下可能通过激活 CB（2）受体，在雌性大鼠中产生急性镇痛和运动效应，而在雄性大鼠中，THC 主要作用于 CB（1）受体。雌性大鼠中利莫那班的表观 pK（B）较高表明，大麻素药物与雌性大鼠的 CB（1）受体的结合亲和力大于雄性大鼠，这可能导致雌性大鼠比雄性大鼠观察到更大的镇痛作用。
