Date of Award
Doctor of Philosophy (PhD)
Endogenous analgesic pathways embody a potential 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 and monitor the activity of subclasses of vlPAG neurons to identify the circuit components critical for analgesia. Our data suggest that increasing the activity of glutamatergic (excitatory) vlPAG neurons or decreasing the activity of GABAergic (inhibitory) vlPAG neurons results in increases in sensory thresholds in uninjured animals, while ameliorating hyperalgesia associated with chronic pain states. In addition, preliminary anatomical analysis of vlPAG circuitry suggested that excitatory glutamatergic neurons composed the majority of efferent projections onto the RVM. We therefore hypothesized that vlPAG excitatory projections to the RVM are partially responsible for the antinociception and analgesia observed after stimulation of glutamatergic neurons in the vlPAG and proposed that such manipulation could result in analgesia during chronic pain states. Population-specific fiber photometry revealed evoked calcium transients in both glutamatergic and GABAergic vlPAG neurons after a variety of acute sensory stimuli, suggesting engagement of both populations during acute nociception. However, anatomical tracing confirmed that the nearly all neurons projecting from vlPAG to the RVM are glutamatergic. Optogenetic stimulation of these glutamatergic vlPAG-RVM neurons results in elevation of thermal thresholds in uninjured animals and had no effect on anxiety-like behaviors. In addition, we demonstrated that stimulation of glutamatergic vlPAG-RVM neurons is sufficient to reverse heat hyperalgesia associated with the induction of an inflammatory state but had minimal effect in conditions of neuropathic injury. Our results provide further support for the GABA disinhibition hypothesis, highlighting the role of descending glutamatergic neurotransmission at the level of the RVM as a key component of endogenous analgesic pathways. This work was supported by funds from the Medical Scientist Training Program (MSTP) Grant T32 GM07200 and the NINDS F31NS103472.
Chair and Committee
Robert W. Gereau
Jose A. Moron-Concepción
Grajales, Jose Gabriel, "Functional and anatomical characterization of descending periaqueductal gray (PAG) projections and their role in pain modulation" (2022). Arts & Sciences Electronic Theses and Dissertations. 2643.
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