Midbrain opioid circuit dynamics in pain and endogenous analgesia

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Pain represents our ability to detect noxious stimuli in the environment and engage in behaviors to reduce harm. This potentially life-saving function of pain can be disturbed by injury or illness leading to chronic pain that exceeds its biological utility. Chronic pain inflicts long-term suffering and is a common clinical problem that chal- lenges our health services and impairs the lives of millions in the United States. Although prescribed opioids remain an important option for the management of pain symptoms, their use presents substantial risk for abuse and overdose. Mu opioid receptors (MOR) in the brain are a crucial substrate for the analgesic action of exoge- nous opioid drugs, however, our understanding of the endogenous opioid system on which these drugs act remains incomplete and difficult to access. The discovery that the endogenous opioid system is recruited by placebo analgesia – expectation that a treatment or context is pain-relieving even when it is not – stands to vastly improve knowledge of pain-relevant opioid signaling mechanisms when applied to preclinical model systems. My previous postdoctoral work demonstrates that placebo analgesia can be achieved in an operant conditioning paradigm in rodents, which results in the suppression of nociceptive activity within MOR neurons in the ven- trolateral periaqueductal gray (vlPAG), indicating recruitment of opioid peptide release and antinociceptive sig- naling. This career development proposal aims to reveal, at the cellular and neural circuit levels, how the endog- enous opioid system is activated by pain and placebo analgesic behavioral states in two key midbrain structures, the vlPAG and ventral tegmental area (VTA) that have been implicated in pain processes and opioid drug func- tion. Training in advanced imaging technologies and rigorous opioid pharmacology, combined with mentoring/ad- visory team meetings and professional/career development activities will prepare me to completely attain and succeed in an independent faculty position. In Aim 1 (K99 phase), I will use two in vivo approaches, one-photon in vivo miniature endoscope (miniscope) calcium imaging for cellular resolution recordings of neural activity and optogenetic neurocircuit manipulation, to delineate the signaling dynamics and function of the enkephalinergic neural populations in the vlPAG in pain and placebo analgesia. Importantly, the vlPAG does not modulate pain in isolation, but sends pain-relevant signals to affective-motivational regions like the VTA. Therefore, in Aim 2 (R00 phase), I will investigate the functional relationship between the vlPAG MOR-expressing neural population and the VTA through optogenetics and miniscope recordings of VTA neural activity, to understand the role and dynamics of these connected circuits across pain states. The results of these studies will produce fundamental knowledge about the brain’s endogenous opioid system that can be applied to the development of future chronic pain therapies that are safe and efficacious. Completion of this mentored career development plan will advance my scientific skills and professional growth and lay the foundation for my independent research career.