State-dependent control of nociception in opioid circuits - ABSTRACT │ The perception of pain does not scale linearly with peripheral nociception. This highly modifiable feature of pain is tuned by a range of contexts: internal emotional or interoceptive states, as well as expectations and beliefs involving future outcomes that might make pain worse or better. One form of pain modulation is placebo analgesia—an endogenous antinociception process in which perceived pain is reduced by a treatment that has no pharmacological effect but relies on expectations of pain-relief. While fMRI has provided a roadmap of distributed brain circuits involved in placebo analgesia, in particular associative cortical areas, the amygdala, and the ventrolateral periaqueductal gray (vlPAG), the dynamic role of distinct cell-types and neuropeptides for placebo mechanisms involved in endogenous antinociception are unknown. The vlPAG is enriched in mu opioid receptors (MORs) and opioid peptides, such as enkephalin (ENK). While the vlPAG is a principal site of morphine antinociception, fundamental gaps in knowledge remain regarding nociception-related endogenous opioid signaling mechanisms: are there coordinated and opposing activities between different opioid cell-types during pain-relief; under what noxious conditions and learned expectation contexts is ENK released and what are the temporal dynamics of ENK release? Our preliminary results find that vlPAG MOR+ neurons projecting to forebrain areas broadly respond to noxious stimuli and may be modulated by endogenous ENK release arising from local and reciprocal afferent structures, such as the central amygdala. The proposed experiments, across 3 Specific Aims, will build greatly from these findings by combining a new model of rodent placebo-like analgesia, optogenetic control of functional-genetic cell-types, single-neuron resolution dual-color calcium + biosensor imaging, and development of a new red-fluorescent ENK biosensor. Our overall approach will permit the investigation of vlPAG local and long-range circuits with single-cell resolution and millisecond timescales to link the rapid dynamics of this pain modulation system with behavioral metrics of analgesia under contexts of instrumental pain-relief. Uncovering placebo analgesia mechanisms provides important opportunities to understand this clinically-relevant phenomena at the level of functional ensembles and cell-types, and to launch efforts that aim to harness this endogenous pain modulation system for effective chronic pain management.
