Orexin A and B, also named hypocretin 1 and 2, are two potent hypothalamic neuropeptides. There are two orexin receptors, OX1Rs and OX2Rs and both are Gq protein coupled receptors. Orexins have been implicated in several neuropsychatric controls involving arousal, feeding, reward and pain regulations. In 2011, we found that orexins given in the ventrolateral periaqueductal gray (vlPAG), a midbrain region crucial for initiating descending pain inhibition, can reduce nociceptive responses in mice via a novel analgesic mechanism. Specifically, orexin induces analgesia via activating postsynaptic OX1Rs in vlPAG neurons to generate 2-arachidonoylglycerol (2-AG) via an enzymatic cascade mediated by phospholipase C (PLC) and diacylglycerol lipase (DAGL). 2-AG is an endocannabinoid that is well-known to be able to produce retrograde inhibition of neurotransmitter release, namely 2-AG produced from the postsynaptic site diffuses back to presynaptic GABAergic terminals where type 1 cannabinoid receptors (CB1Rs) are located and then, via activating CB1Rs, attenuates the release of GABA, an inhibitory neurotransmitter. Inhibition of GABAergic transmission, i.e. disinhibition, can lead to vlPAG excitation and activating the descending pain inhibitory pathway.1
　　Thereafter, we further explored the physiological significance of this orexin-induced endocannabinoid retrograde disinhibition cascade, i.e. when endogenous orexins can be released to produce disinhibition in the vlPAG via this OX1R- PLC-DAGL-2-AG-CB1R cascade. Interestingly, we found that this orexin-initiated and endocannabinoid-mediated disinhibition mechanism in the vlPAG can contribute to not only stress-induced analgesia2 but also median nerve stimulation at the Neiguan (PC6) acupoint.3 Given that this acupuncture-induced analgesic effect is opioid-independent, we have completed a proof-of-concept study supporting that MNS-PC6 can successful relieve neuropathic pain in mice tolerant to escalating doses of morphine.4 This suggests that we MNS-PCs can serve as an alternative pain reliving management for combating opioid crisis or in patients with morphine tolerance, such as in cancer terminal patients.
　　In addition, we also substantiated that this orexin-initiated and endocannabinoid-mediated disinhibition mechanism exists in dopaminergic neurons of the ventral tegmental area, an area important for reward regulation. Importantly, this mechanism can contribute to stress-induced reinstatement of extinguished cocaine seeking in animals,5 which mimics cocaine relapse in human. Environmental stress is a vital factor leading to drug relapse that fails habitation programs in abstinent cocaine addicts, causing a huge socioeconomic burden. This study hopefully sheds light on the way to success in the treatment of this unmet medical need.
1.Ho YC, Lee HJ, Tung LW, Liao YY, Fu SY, Teng SF, Liao HT, Mackie K and Chiou LC (2011). Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition. J Neurosci 31:14600-14610.
2.Lee HJ, Chang LY, Ho YC, Teng SF, Hwang LL, Mackie K and Chiou LC (2016). Stress induces analgesia via orexin 1 receptor-initiated endocannabinoid/CB1 signaling in the mouse periaqueductal gray. Neuropharmacology 105:577-586.
3.Chen YH, Lee HJ, Lee MT, Wu YT, Lee YH, Hwang LL, Hung MS, Zimmer A, Mackie K and Chiou LC (2018) Median nerve stimulation induces analgesia via orexin-initiated endocannabinoid disinhibition in the periaqueductal gray. Proc Natl Acad Sci USA 115 (45): E10720-10729
4. Lee MT, Chen YH, Mackie K and Chiou LC (2020) Median nerve stimulation as a non-pharmacological approach to bypass analgesic tolerance to morphine: a proof-of-concept study in mice. J Pain (Accepted).
5. Tung LW, Lu GL, Lee YH, Yu L, Lee HJ, Leishman E, Bradshaw H, Hwang LL, Hung MS, Mackie K, Zimmer A and Chiou LC (2016) Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons. Nature Comm. 7:12199.