Rady J J, Roerig S C, Fujimoto J M
Research Service, VA Medical Center, Milwaukee, Wisconsin.
J Pharmacol Exp Ther. 1991 Feb;256(2):448-57.
The opioid receptor types involved in supraspinal and spinal heroin-induced analgesia in Swiss Webster and ICR mice were determined by intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration of opioid agonists and antagonists. Also, comparisons were made with morphine. Antinociception was measured by changes in tail-flick latency. In Swiss Webster mice, i.c.v. heroin like [D-Pen2-D-Pen5]enkephalin, a delta receptor opioid agonist, activated supraspinal delta opioid receptors as evidenced by inhibition of analgesia by coadministration of naltrindole, a delta receptor antagonist. Lack of effect of i.t. yohimbine and methysergide vs. i.c.v. heroin indicated that spinal descending noradrenergic and serotonergic systems were not involved. Heroin and [D-Pen2-D-Pen5]enkephalin were also matched in producing additive interactions with i.t. opioids. Also, i.c.v. heroin like [D-Pen2-D-Pen5]enkephalin did not activate a dynorphin-mediated antianalgesic system. In ICR mice, i.c.v. heroin receptor selectivity matched that of i.c.v. Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5, a selective mu receptor opioid agonist. Analgesia was inhibited by pretreatment with i.c.v. beta-funaltrexamine, a nonequilibrium mu receptor antagonist. Intrathecal administration of methysergide inhibited i.c.v. heroin-induced analgesia whereas i.t. yohimbine had no effect, which indicated that a descending serotonergic system but not a noradrenergic system was involved. Low doses of i.t. naloxone and nor-binaltorphimine increased the analgesic effect. This effect was consistent with activation of an antianalgesic system by i.c.v. heroin, which was mediated by dynorphin A in the spinal cord. Desensitization of the antianalgesic system also resulted in increased analgesia. In both Swiss Webster and ICR mice, i.t. heroin-induced analgesia involved spinal mu receptors like those stimulated by Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5. Analgesia was inhibited by i.t. naloxone. In both strains, i.t. heroin, like i.t. Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5, produced an additive interaction with i.t. clonidine. In conclusion, the supraspinal receptors activated by heroin are different between Swiss Webster and ICR mice. In both strains, the receptor selectivities assigned to heroin did not match those for morphine. Heroin did not act by being biotransformed to morphine.
通过向瑞士 Webster 小鼠和 ICR 小鼠脑室内（i.c.v.）和鞘内（i.t.）注射阿片类激动剂和拮抗剂，确定了参与海洛因诱导的脊髓上和脊髓镇痛的阿片受体类型。此外，还与吗啡进行了比较。通过甩尾潜伏期的变化来测量镇痛作用。在瑞士 Webster 小鼠中，脑室内注射海洛因与 δ 受体阿片类激动剂[D-Pen2-D-Pen5]脑啡肽一样，激活了脊髓上的 δ 阿片受体，δ 受体拮抗剂纳曲吲哚共同给药可抑制镇痛作用，这证明了这一点。鞘内注射育亨宾和麦角新碱与脑室内注射海洛因相比没有效果，表明脊髓下行去甲肾上腺素能和 5-羟色胺能系统未参与其中。海洛因和[D-Pen2-D-Pen5]脑啡肽在与鞘内阿片类药物产生相加相互作用方面也相当。此外，脑室内注射海洛因与[D-Pen2-D-Pen5]脑啡肽一样，并未激活强啡肽介导的抗镇痛系统。在 ICR 小鼠中，脑室内注射海洛因的受体选择性与脑室内注射选择性 μ 受体阿片类激动剂 Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5 的受体选择性相当。用脑室内注射 β-芬太尼环已胺（一种非平衡 μ 受体拮抗剂）预处理可抑制镇痛作用。鞘内注射麦角新碱可抑制脑室内注射海洛因诱导的镇痛作用，而鞘内注射育亨宾则没有效果，这表明涉及下行 5-羟色胺能系统而非去甲肾上腺素能系统。低剂量的鞘内注射纳洛酮和去甲二氢吗啡酮可增强镇痛作用。这种作用与脑室内注射海洛因激活脊髓中由强啡肽 A 介导的抗镇痛系统一致。抗镇痛系统的脱敏也导致镇痛作用增强。在瑞士 Webster 小鼠和 ICR 小鼠中，鞘内注射海洛因诱导的镇痛作用都涉及脊髓 μ 受体，就像 Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5 刺激的那些受体一样。鞘内注射纳洛酮可抑制镇痛作用。在这两个品系中，鞘内注射海洛因与鞘内注射 Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5 一样，与鞘内注射可乐定产生相加相互作用。总之，瑞士 Webster 小鼠和 ICR 小鼠中被海洛因激活的脊髓上受体不同。在这两个品系中，归因于海洛因的受体选择性与吗啡的受体选择性不匹配。海洛因不是通过生物转化为吗啡起作用的。
