Aley K O, Green P G, Levine J D
Department of Anatomy, University of California, San Francisco 94143, USA.
J Neurosci. 1995 Dec;15(12):8031-8. doi: 10.1523/JNEUROSCI.15-12-08031.1995.
The selective mu-opioid agonist, D-Ala2,N-Me-Phe4,Gly5-ol-enkephalin (DAMGO), or the selective A1-adenosine agonist N6-cyclopentyladenosine (CPA), when coinjected intradermally with prostaglandin E2 (PGE2), dose-dependently inhibited PGE2-induced mechanical hyperalgesia in the rat hindpaw, as determined by the Randall-Selitto paw-withdrawal test. Repeated (hourly x 3) intradermal injections of DAMGO or CPA produced tolerance to the antinociceptive effect of a fourth injection 1 hr later. Furthermore, repeated (hourly x 3) intradermal injections of DAMGO produced cross-tolerance to the antinociceptive effect of CPA, and repeated (hourly x 3) intradermal injection of CPA produced cross-tolerance to the antinociceptive effect of DAMGO. The demonstration of the bidirectional cross-tolerance between the peripheral antinociceptive effects of DAMGO and CPA supports the hypothesis that both these agents produced antinociception by acting on the same cell, presumably the primary afferent nociceptor, and that the development of tolerance involves changes downstream to activation of mu-opioid and A1-adenosine receptors. The opioid antagonist naloxone, which had no effect on paw-withdrawal threshold in normal paws, produced withdrawal threshold in normal paws, produced withdrawal hyperalgesia in DAMGO-tolerant paws. Furthermore, naloxone elicited a cross-withdrawal hyperalgesia response in CPA-tolerant paws. Similarly, the A1-adenosine antagonist 1,3-dipropyl-8-(2-amino-4- chlorophenyl)-xanthine (PACPX), which had no effect on paw-withdrawal threshold in normal paws, elicited a withdrawal hyperalgesia response in CPA-tolerant paws and cross-withdrawal hyperalgesia responses in DAMGO-tolerant paws. These cross-dependence and cross-withdrawal responses suggest that the development of dependence to mu-opioid and A1-adenosine agonists involves changes in the same second messenger system downstream to both mu-opioid and A1-adenosine receptor activation.
选择性μ阿片受体激动剂D - Ala2，N - Me - Phe4，Gly5 - ol - 脑啡肽（DAMGO）或选择性A1 - 腺苷激动剂N6 - 环戊基腺苷（CPA），与前列腺素E2（PGE2）皮内共注射时，根据Randall - Selitto足趾撤回试验测定，剂量依赖性地抑制大鼠后爪中PGE2诱导的机械性痛觉过敏。重复（每小时一次，共3次）皮内注射DAMGO或CPA会导致对1小时后第四次注射的抗伤害感受作用产生耐受性。此外，重复（每小时一次，共3次）皮内注射DAMGO会对CPA的抗伤害感受作用产生交叉耐受性，而重复（每小时一次，共3次）皮内注射CPA会对DAMGO的抗伤害感受作用产生交叉耐受性。DAMGO和CPA外周抗伤害感受作用之间双向交叉耐受性的证明支持了这样的假设，即这两种药物都是通过作用于同一细胞（大概是初级传入伤害感受器）产生抗伤害感受，并且耐受性的发展涉及μ阿片受体和A1 - 腺苷受体激活下游的变化。阿片拮抗剂纳洛酮对正常爪的足趾撤回阈值没有影响，但在DAMGO耐受的爪中产生撤回阈值，并产生撤回痛觉过敏。此外，纳洛酮在CPA耐受的爪中引发交叉撤回痛觉过敏反应。同样，A1 - 腺苷拮抗剂1,3 - 二丙基 - 8 -（2 - 氨基 - 4 - 氯苯基） - 黄嘌呤（PACPX）对正常爪的足趾撤回阈值没有影响，但在CPA耐受的爪中引发撤回痛觉过敏反应，在DAMGO耐受的爪中引发交叉撤回痛觉过敏反应。这些交叉依赖性和交叉撤回反应表明，对μ阿片受体和A1 - 腺苷激动剂的依赖性发展涉及μ阿片受体和A1 - 腺苷受体激活下游相同第二信使系统的变化。
