254) Functional and Anatomical Characterization of Descending Periaqueductal Gray (PAG) Projections and their Role in Pain Modulation

Endogenous analgesic pathways embody an alternative target for the development for chronic pain therapies. Previous studies have demonstrated the role of the ventrolateral periaqueductal gray (vlPAG) in descending pain modulation. It has been proposed that tonic GABAergic neurotransmission at the level of the vlPAG serves to inhibit efferent excitatory projections that mediate descending analgesia. Disinhibition of these projection neurons allows subsequent activation of rostral ventromedial medulla (RVM) neurons that inhibit nociception at the level of the spinal cord. However, lack of cell-type specificity in these studies has prevented the determination of the role of specific subsets of vlPAG neurons in analgesia. We have utilized recently developed genetic tools to selectively manipulate the activity of subclasses of vlPAG neurons to identify the circuit components critical for analgesia. Our data suggest that increasing the activity of glutamatergic vlPAG neurons or decreasing the activity of GABAergic vlPAG neurons results in increases in sensory thresholds in uninjured animals, while ameliorating hyperalgesia associated with chronic pain states. To further characterize descending pain circuitry at the level of the vlPAG, we decided to focus on efferent projections to the RVM. We hypothesize that these projections are partially responsible for the observed analgesia in our previous study. Population-specific anatomical tracing revealed that most of these projections are glutamatergic and originate from the ventrolateral columns of the PAG. Optogenetic stimulation of these PAG-RVM neurons results in elevation of thermal thresholds in uninjured animals and seems to reverse thermal hyperalgesia associated with inflammatory states. However, this is not the case in a model of neuropathic pain. In brief, our results provide direct experimental evidence supporting the GABA disinhibition hypothesis, highlighting the role of descending glutamatergic neurotransmission at the level of the PAG-RVM as a key component of endogenous analgesic pathways. This work is supported by NINDS F31NS103472 to JGGR.