Mechanisms and treatment of pain-depressed behavior

疼痛抑郁行为的机制和治疗

• 批准号: 10238775
• 负责人: Clare Diester
• 金额: $ 3.14万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-25 至 2022-05-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238775
• 关键词: 2-arachidonylglycerol; 2-arachidonylglycerol signaling; Abdomen; Acids; Acute; Acute Pain; Acute inflammatory pain; Adult; Affective; Agonist; American; Amphetamines; Analgesics; Anatomy; Antibodies; Arachidonic Acids; Area; Back; Behavior; Behavioral; CNR1 gene; CNR2 gene; Cannabinoids; Chemicals; Clinic; Clinical; Complement; Cyclooxygenase Inhibitors; Depressed mood; Development; Diazepam; Dopamine; Effectiveness; Endocannabinoids; Enzymes; Evaluation; Face; Fatty Acids; Feedback; Female; Fluorescent in Situ Hybridization; GABA-A Receptor; Grooming; High Pressure Liquid Chromatography; Immunohistochemistry; Inbred ICR Mice; Intraperitoneal Injections; Ketoprofen; Label; Lactic acid; Lipids; MAGL inhibitor; Mediating; Mental Depression; Monoacylglycerol Lipases; Morphine; Mus; Neural Pathways; Neuraxis; Neurons; Neurotransmitters; Nociceptors; Nucleus Accumbens; Opioid; Opioid agonist; Oxycodone; Pain; Pain Measurement; Pain management; Pathway interactions; Pharmacology; Phenotype; Physiological; Production; Prostaglandins; Proto-Oncogenes; Public Health; Receptor Activation; Receptor Signaling; Reflex action; Research; Role; Sensory; Signal Transduction; Site; Slice; Somatosensory Cortex; Source; Spinal; Spinal Cord; Spine pain; Stimulus; Stretching; Synapses; Testing; Tetrahydrocannabinol; Thalamic structure; Tissues; Training; Travel; United States; Ventilatory Depression; Ventral Tegmental Area; Visceral; anandamide; behavioral response; cannabinoid receptor; career development; central pain; chronic pain; clinically relevant; comparative; dorsal horn; driving force; effectiveness evaluation; effectiveness testing; endocannabinoid signaling; endogenous cannabinoid system; experience; health care service utilization; improved; inhibitor/antagonist; intraperitoneal; lipidomics; liquid chromatography mass spectrometry; male; mu opioid receptors; neural circuit; neurochemistry; neurotransmitter release; non-opioid analgesic; noradrenaline transporter; novel; opioid epidemic; pain behavior; pain inhibition; pain processing; pain signal; parabrachial nucleus; positive allosteric modulator; pre-clinical; preclinical study; presynaptic; transmission process

PROJECT SUMMARY  Pain management is a major public health problem in the United States. Opioids like morphine are widely used  to treat severe pain, but they possess limitations such as abuse liability and potentially lethal respiratory  depression that have fed into the current opioid public health crisis. The endocannabinoid system, which  includes cannabinoid receptors (CBRs), endogenous cannabinoid (eCB) lipid neurotransmitters, and enzymes  responsible for the synthesis and degradation of eCBs, has emerged as a promising source of targets for  development of candidate non-­opioid analgesics.  In particular, the enzyme monoacylglycerol lipase (MAGL)  breaks down the eCB agonist 2-­arachidonoylglycerol (2-­AG), and MAGL inhibition can increase 2-­AG levels,  increase CBR activation, and potentially inhibit pain-­related activity in neural pathways that mediate different  pain behaviors.  This F31 application proposes research that will evaluate the effectiveness of the MAGL   inhibitor MJN110 to alleviate a battery of pain-­related behavioral and neurochemical endpoints in adult male  and female mice following intraperitoneal administration of dilute lactic acid (IP acid) as an acute, visceral, and  physiologically relevant noxious stimulus.  Aim 1 will determine MJN110 effectiveness to alleviate IP acid-­ induced sensory and affective pain-­related behaviors mediated by spinal and central pain-­processing  pathways.  The effects of MJN110 will be compared to clinically effective positive-­control analgesics (the mu  opioid receptor agonist oxycodone and the cyclooxygenase inhibitor ketoprofen), non-­analgesic negative  controls that nonspecifically depress or stimulate general behavior (the GABA-­A receptor positive allosteric  modulator diazepam and dopamine/norepinephrine transporter inhibitor amphetamine), and the direct CBR  agonist ∆9-­tetrahydrocannabinol (THC).  Aim 2 will determine MJN110 effectiveness to inhibit IP acid-­induced  activation of sensory and affective pain pathways.  Neuronal activation will be assessed with  immunohistochemical and fluorescent in situ hybridization of the proto-­oncogene cFos, and the chemical  phenotype of cFos-­positive neurons will be determined using double-­labeling with antibodies selective for  markers in glutamaterigic vs. GABAergic neurons.  Aim 3 will use high-­performance liquid chromatography-­ mass spectrometry to determine MJN110 effectiveness to modulate pain-­related changes lipidomic profiles of  fatty acids, oxilipins, and N-­acylethanolimines in sensory and affective pain pathways.  Overall, the proposed  research will provide a detailed evaluation of the antinocicpetive effectiveness of MJN110 for acute noxious  stimuli, as well as improve our understanding of the eCB system’s role in acute inflammatory pain signaling  and antinociception through comparative analyses of clinically-­relevant pain-­related behaviors and  neurochemical and lipidomic correlates.

项目总结