한빛사논문
- 조회1,700
Jong-Hyun Kima,b,c, Gireesh Gangadharana, Junweon Byuna,d, Eui-Ju Choib, C. Justin Leec, and Hee-Sup Shina,d,1
aCenter for Cognition and Sociality, Institute for Basic Science, 34141 Daejeon, Korea; bDivision of Life Sciences, Korea University, 02841 Seoul, Korea; cCenter for Glia-Neuron Interaction, Brain Science Institute, Korea Institute of Science and Technology, 02792 Seoul, Korea; and dDepartment of Basic Science, Korea University of Science and Technology, 34141 Daejeon, Korea
1To whom correspondence should be addressed.
Abstract
In the descending analgesia pathway, opioids are known to disinhibit the projections from the periaqueductal gray (PAG) to the rostral ventromedial medulla (RVM), leading to suppression of pain signals at the spinal cord level. The locus coeruleus (LC) has been proposed to engage in the descending pathway through noradrenergic inputs to the spinal cord. Nevertheless, how the LC is integrated in the descending analgesia circuit has remained unknown. Here, we show that the opioidergic analgesia pathway is bifurcated in structure and function at the PAG. A knockout as well as a PAG-specific knockdown of phospholipase C β4 (PLCβ4), a signaling molecule for G protein-coupled receptors, enhanced swim stress-induced and morphine-induced analgesia in mice. Immunostaining after simultaneous retrograde labeling from the RVM and the LC revealed two mutually exclusive neuronal populations at the PAG, each projecting either to the LC or the RVM, with PLCβ4 expression only in the PAG-LC projecting cells that provide a direct synaptic input to LC-spinal cord (SC) projection neurons. The PAG-LC projection neurons in wild-type mice turned quiescent in response to opiates, but remained active in the PLCβ4 mutant, suggesting a possibility that an increased adrenergic function induced by the persistent PAG-LC activity underlies the enhanced opioid analgesia in the mutant. Indeed, the enhanced analgesia in the mutant was reversed by blocking α2-noradrenergic receptors. These findings indicate that opioids suppress descending analgesia through the PAG-LC pathway, while enhancing it through the PAG-RVM pathway, i.e., two distinct pathways with opposing effects on opioid analgesia. These results point to a therapeutic target in pain control.
descending analgesia pathway, opioid, periaqueductal gray, locus coeruleus, phopholipase C
논문정보
- Research article
- 2018년 10월 (BRIC 등록일 2018-10-17)
- 국내 연구진
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