Stress induces analgesia via orexin 1 receptor-initiated endocannabinoid/CB1 signaling in the mouse periaqueductal gray.

Neuropharmacology
Hsin-Jung LeeLih-Chu Chiou

Abstract

The orexin system consists of orexin A/hypocretin 1 and orexin B/hypocretin 2, and OX1 and OX2 receptors. Our previous electrophysiological study showed that orexin A in the rat ventrolateral periaqueductal gray (vlPAG) induced antinociception via an OX1 receptor-initiated and endocannabinoid-mediated disinhibition mechanism. Here, we further characterized antinociceptive effects of orexins in the mouse vlPAG and investigated whether this mechanism in the vlPAG can contribute to stress-induced analgesia (SIA) in mice. Intra-vlPAG (i.pag.) microinjection of orexin A in the mouse vlPAG increased the hot-plate latency. This effect was mimicked by i.pag. injection of WIN 55,212-2, a CB1 agonist, and antagonized by i.pag. injection of the antagonist of OX1 (SB 334867) or CB1 (AM 251), but not OX2 (TCS-OX2-29) or opioid (naloxone), receptors. [Ala(11), D-Leu(15)]-orexin B (i.pag.), an OX2 selective agonist, also induced antinociception in a manner blocked by i.pag. injection of TCS-OX2-29, but not SB 334867 or AM 251. Mice receiving restraint stress for 30 min showed significantly longer hot-plate latency, more c-Fos-expressing orexin neurons in the lateral hypothalamus and higher orexin levels in the vlPAG than unrestrained mice. Re...Continue Reading

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