Critical role of the morphine-activated VTA neuron in pain relief

[Speaker] Naoko Kuzumaki:1
[Co-author] Moe Watanabe:1, Michiko Narita:1, Yusuke Hamada:1, Daisuke Sato:1, Vivianne L. Tawfik:2, Hideki Tamura:3, Akihiro Yamanaka:4, Minoru Narita:1,3
1:Dept. Pharmacol., Hoshi Univ., Tokyo, Japan, 2:Dept. Anesthesiol., Perioperative and Pain Med., Stanford Univ. Sch. Med., Palo Alto, USA, 3:L-StaR, Hoshi Univ., Tokyo, Japan, 4:Dept. Neurosci. II, RIEM, Nagoya Univ. Aichi, Japan

Morphine is a highly potent opiate analgesic drug and is frequently used for the treatment of cancer pain or moderate to severe non-cancer pain. On the other hand, morphine also induces rewarding behavior through the activation of the brain reward network, consisting of a dopaminergic projection from the ventral tegmental area (VTA) to nucleus accumbens (N.Acc.). The resent studies have shown that pain negatively correlates with pleasure. In this study, we performed activity-dependent cell labeling in combination with optogenetic methods to identify and determine the role of specific dopaminergic cells in the VTA. We generated the transgenic mice expressing enhanced natronomonas pharaonis halorhodopsin (eNpHR) or channelrhodopsin-2 (ChR2) under the control of the c-fos promoter using tamoxifen inducible Cre-loxP system. After in vivo treatment with morphine, c-fos expression was induced in some cells of the VTA and eNpHR-EYFP was co-induced in this same population of morphine-activated cells. The expression of tyrosine hydroxylase (TH), a marker for dopaminergic neurons, was found in these morphine-activated cells in the VTA. Furthermore, using cFos-targeted Recombination in Active Populations (TRAP) mice in which the tamoxifen-dependent recombinase CreERT2 is expressed in an activity-dependent manner from the loci of the cFos, we labeled the activated cell in the VTA by the stimulation of morphine. Using the cell sorting system, morphine-activated neurons showed highly expression of TH mRNA compared to morphine-inactivated neurons. On the other hand, Optical suppression of morphine-activated dopamine neurons in the VTA, which expressed eNpHR-EYFP, significantly inhibited morphine-induced analgesia. Furthermore, optical activation of morphine-sensitive neurons in the VTA alleviated thermal hyperalgesia in animal models of chronic pain. These findings provide further evidence that morphine-activated VTA dopamine neurons may, at least partially, contribute to morphine-induced analgesia and modulate pathological pain.
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