Lane D A, Tortorici V, Morgan M M
Washington State University Vancouver, 14204 Northeast Salmon Creek Avenue, Vancouver, WA 98686, USA.
Neuroscience. 2004;125(1):63-9. doi: 10.1016/j.neuroscience.2004.01.023.
Repeated microinjections of morphine into the ventrolateral periaqueductal gray (vPAG) produce tolerance to the antinociceptive effect of morphine [Behav Neurosci 113 (1999) 833]. These results may be a direct effect of morphine on cells within the vPAG or be caused by cues linked to the microinjection procedure (i.e. associative tolerance). The objective of this paper was to determine whether continuous administration of morphine into the vPAG (i.e. no cues) would produce tolerance. Tolerance was assessed by measuring changes in behavior and changes in the activity of neurons in the rostral ventromedial medulla (RVM), the primary output target of the PAG. Rats were implanted with an osmotic minipump that released morphine (2.5 or 5 microg/h) or saline into the vPAG continuously. Continuous administration of morphine produced an increase in hotplate latency when measured 6 h after initiation of treatment. Tolerance to this antinociception was evident within 24 h. After 3 days, rats were anesthetized and the activity of RVM neurons was assessed. Although acute morphine administration into the RVM inhibits the activity of RVM on-cells and enhances the activity of off-cells, these neurons appeared normal following 3 days of continuous morphine administration. Systemic naloxone administration produced hyperalgesia that was associated with a marked increase in on-cell activity and a complete cessation of off-cell activity. The loss of morphine inhibition of nociception, measured behaviorally and electrophysiologically, demonstrates that tolerance is caused by a direct action of morphine on vPAG neurons.
向腹外侧导水管周围灰质（vPAG）反复微量注射吗啡会导致对吗啡的抗伤害感受作用产生耐受性[《行为神经科学》113（1999）833]。这些结果可能是吗啡对vPAG内细胞的直接作用，也可能是与微量注射程序相关的线索（即联合耐受性）所致。本文的目的是确定持续向vPAG注射吗啡（即无相关线索）是否会产生耐受性。通过测量行为变化和延髓头端腹内侧（RVM）神经元的活动变化来评估耐受性，RVM是PAG的主要输出靶点。给大鼠植入渗透微型泵，使其持续向vPAG释放吗啡（2.5或5微克/小时）或生理盐水。治疗开始6小时后测量发现，持续注射吗啡会使热板潜伏期延长。在24小时内对这种抗伤害感受的耐受性就很明显。3天后，将大鼠麻醉并评估RVM神经元的活动。虽然向RVM急性注射吗啡会抑制RVM开细胞的活动并增强关细胞的活动，但在持续注射吗啡3天后，这些神经元看起来正常。全身注射纳洛酮会产生痛觉过敏，这与开细胞活动显著增加和关细胞活动完全停止有关。从行为学和电生理学测量结果来看，吗啡对伤害感受的抑制作用丧失，表明耐受性是由吗啡对vPAG神经元的直接作用引起的。
