Author Type

Graduate Student

Date of Award

Spring 4-13-2026

Document Type

Dissertation

Publication Status

Version of Record

Submission Date

April 2026

Department

Biological Sciences

College Granting Degree

Charles E. Schmidt College of Science

Department Granting Degree

Biological Sciences

Degree Name

Doctor of Philosophy (PhD)

Thesis/Dissertation Advisor [Chair]

Lawrence Toll

Abstract

Chronic neuropathic pain severely diminishes quality of life, yet the supraspinal neural circuits that sustain pain perception and mediate analgesic relief remain incompletely characterized. While peripheral and spinal pain pathways are well established, relatively few studies have mapped pain- or opioid-related neuronal activation across the entire brain. This dissertation employed activity-dependent genetic labeling (TRAP2/Ai9), whole-brain tissue clearing, light sheet microscopy, and graph-theoretic network analysis to characterize brain-wide activation patterns across chronic pain and analgesic conditions in mice.

In Chapter 1, we mapped supraspinal neuronal activation in a bilateral spared nerve injury model of chronic neuropathic pain. Although no individual region survived correction for multiple comparisons, network-level analyses revealed widespread reorganization of interregional co-activation structure, with the medullary reticular formation emerging as the most consistent locus of nerve injury-specific modulation. Biological sex was the dominant source of regional variance.

In Chapter 2, we compared brain-wide activation across four pharmacological conditions: vehicle, acute morphine, morphine-dependent, and the selective NOP receptor agonist Ro 64-6198. Morphine produced robust activation concentrated in the preoptic area and hypothalamus that was amplified with repeated exposure. Ro 64-6198 did not recruit these circuits, demonstrating that NOP receptor agonism engages pharmacologically distinct neural substrates. Sex differences in opioid response emerged at the network level rather than at individual regions.

In Chapter 3, we tested whether chemogenetic reactivation of morphine-activated periaqueductal gray neurons was sufficient to alter nociceptive or locomotor behavior. No significant behavioral effects were detected, suggesting that the analgesic actions of morphine require coordinated engagement of distributed circuits rather than activation of a single node.

In conclusion, the present findings demonstrate that the supraspinal signatures of both chronic pain and opioid exposure are expressed primarily through altered network architecture rather than through drastic regional activation changes, supporting a shift toward network-oriented frameworks in preclinical pain and addiction research.

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