Morgan M M, Clayton C C, Lane D A
Department of Psychology, WA State University Vancouver, 14204 NE Salmon Creek Avenue, Vancouver, WA 98686, USA.
Neuroscience. 2003;118(1):227-32. doi: 10.1016/s0306-4522(02)00822-9.
Tolerance develops to the antinociceptive effects of morphine with repeated microinjections into the ventrolateral periaqueductal gray (PAG). This tolerance could be caused by adaptations within the PAG or anywhere along the descending pathway (rostral ventromedial medulla to spinal cord). If tolerance is caused by a change along the descending pathway, then tolerance should develop to direct activation of PAG output neurons. However, if tolerance is caused by a change to neurons within the PAG, then tolerance will not occur with repeated direct activation of PAG output neurons. This hypothesis was tested by assessing antinociception following repeated microinjections of the GABA antagonist bicuculline and the excitatory amino acid kainate into the ventrolateral PAG. Microinjection of bicuculline and kainate produces antinociception by disinhibition and direct excitation of ventrolateral PAG output neurons, respectively. Repeated administration of these drugs into the ventrolateral PAG produced antinociception with no evidence of tolerance. That is, the hot-plate latency and responsiveness to intraplantar formalin administration was comparable whether rats received the drug for the first or fifth time. Moreover, microinjection of bicuculline or kainate produced comparable antinociception in rats pretreated with these drugs and saline-treated control rats. These data demonstrate that repeated activation of ventrolateral PAG output neurons is not sufficient to produce tolerance. Thus, tolerance must be caused by a change in neurons preceding output neurons in this circuit, presumably opioid-sensitive GABAergic neurons.
通过反复向腹外侧导水管周围灰质（PAG）微量注射吗啡，可产生对其抗伤害感受作用的耐受性。这种耐受性可能是由PAG内或下行通路（从延髓头端腹内侧到脊髓）任何部位的适应性变化引起的。如果耐受性是由下行通路的变化引起的，那么对PAG输出神经元的直接激活也应产生耐受性。然而，如果耐受性是由PAG内神经元的变化引起的，那么反复直接激活PAG输出神经元将不会产生耐受性。通过评估向腹外侧PAG反复微量注射GABA拮抗剂荷包牡丹碱和兴奋性氨基酸海藻酸后的抗伤害感受作用，对这一假设进行了验证。微量注射荷包牡丹碱和海藻酸分别通过解除对腹外侧PAG输出神经元的抑制和直接兴奋这些神经元来产生抗伤害感受作用。向腹外侧PAG反复注射这些药物会产生抗伤害感受作用，且没有耐受性的证据。也就是说，无论大鼠是首次还是第五次接受药物，热板潜伏期和对足底注射福尔马林的反应性都是可比的。此外，在预先用这些药物处理的大鼠和生理盐水处理的对照大鼠中，微量注射荷包牡丹碱或海藻酸产生的抗伤害感受作用相当。这些数据表明，反复激活腹外侧PAG输出神经元不足以产生耐受性。因此，耐受性必定是由该回路中输出神经元之前的神经元变化引起的，推测是对阿片类敏感的GABA能神经元。
