title: Mechanism Underlying the Analgesic Effect Exerted by Endomorphin-1 in the rat Ventrolateral Periaqueductal Gray.
abstract: The ventrolateral periaqueductal gray (vlPAG) is an important brain area, in which 5-HTergic neurons play key roles in descending pain modulation. It has been proposed that opioid peptides within the vlPAG can excite the 5-HTergic neurons by alleviating tonic inhibition from GABAergic neurons, the so-called disinhibitory effect. However, no direct morphological evidence has been observed for the micro-circuitry among the opioid peptide-, GABA-, and 5-HT-immunoreactive (ir) profiles nor for the functional involvement of the opioid peptides in the intrinsic properties of GABAergic and 5-HTergic neurons. In the present study, through microscopic observation of triple-immunofluorescence, we firstly identified the circuitry among the endomorphin-1 (EM1, an endogenous ligand for the μ-opioid receptor)-ir terminals and GABA-ir and 5-HT-ir neurons within the rat vlPAG. The synaptic connections of these neurons were further confirmed by electron microscopy. Through the in vitro whole-cell patch-clamp method, we showed that EM1 has strong inhibitory effects on the spiking of GABAergic neurons. However, although the resting membrane potential was hyperpolarized, EM1 actually increased the firing of 5-HTergic neurons. More interestingly, EM1 strongly inhibited the excitatory input to GABAergic neurons, as well as the inhibitory input to 5-HTergic neurons. Finally, behavioral results showed that pretreatment with a GABA(A) receptor antagonist potentiated the analgesic effect of EM1, while treatment with a GABA(A) receptor agonist blocked its analgesic effect. In summary, by utilizing morphological and functional methods, we found that the analgesic effect of EM1 is largely dependent on its potent inhibition on the inhibitory inputs to 5-HTergic neurons, which overwhelms EM1's direct inhibitory effect on 5-HTergic neurons.
authors: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, 710032, China.
authors: Tao
authors: T
authors: Chen
authors: Department of Physiology and Pathophysiology, College of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China.
authors: Jing
authors: J
authors: Li
authors: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, 710032, China.
authors: Ban
authors: B
authors: Feng
authors: Department of Neurosurgery, Navy General Hospital, Beijing, 100048, China.
authors: Rui
authors: R
authors: Hui
authors: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, 710032, China.
authors: Yu-Lin
authors: YL
authors: Dong
authors: Department of Physiology and Pathophysiology, College of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China.
authors: Fu-Quan
authors: FQ
authors: Huo
authors: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, 710032, China.
authors: Ting
authors: T
authors: Zhang
authors: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, 710032, China.
authors: Jun-Bin
authors: JB
authors: Yin
authors: Department of Physiology and Pathophysiology, College of Medicine, Xi'an Jiaotong University, Xi'an, 710061, China.
authors: Jian-Qing
authors: JQ
authors: Du
authors: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, 710032, China. deptanat@fmmu.edu.cn.|Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, 200032, China. deptanat@fmmu.edu.cn.
authors: Yun-Qing
authors: YQ
authors: Li
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008845:Microinjections; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000700:Analgesics; D009842:Oligopeptides; D010455:Peptides; D018079:Receptors, GABA; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D012701:Serotonin; D009271:Naltrexone; C024524:beta-funaltrexamine
keywords: 5-HT; Disinhibition; Endomorphin; GABA; Rat; Ventrolateral periaqueductal gray