Investigating Neuroinflammation and Opioid Receptor Signaling Mechanisms in Chronic Pain Pathology

Chronic pain represents a substantial burden to society and is difficult to manage for both physicians and patients due to lack of effective therapies. There are multiple dimensions of chronic pain, with symptoms such as anxiety, depression, fatigue, anhedonia, etc. Collectively known as negative affect, these symptoms exacerbate the pain experience and results in decreased efficacy of opioid analgesics. Endotoxins known to induce neuroinflammation produce anhedonia and depression in humans. Similarly, activation of kappa opioid receptors produces dysphoric and depressive symptoms in humans. This work investigates the contribution of neuroinflammation and kappa opioid receptors in multiple rodent models of chronic pain and the manifestation of negative affect in these models. We identified that kappa opioid receptors are upregulated within limbic brain regions of neuropathic pain animals and upregulation within ventral tegmental area dopamine neurons is responsible for the tonic-aversive component of pain. This effect was sex dependent where blocking or elimination of kappa opioid receptors in male but not female mice prevented pain-induced aversion. Our lab previously identified that neuroinflammation within the ventral tegmental area in a model of neuropathic pain was responsible for altered reward signaling and dopamine release. We show that peripheral nerve injury model of neuropathic pain causes microglial activation in many brain structures but is not ubiquitous, and neuroinflammation is primarily restricted to limbic brain structures. Because neuroinflammation is a hallmark of traumatic brain injury, we asked whether neuroinflammation is also causative to chronic pain following head injury. Using a model of repeated mild traumatic brain injury (rmTBI), we show that blocking microglial activation one month after injury reverses cold hypersensitivity and affective-like behaviors but has no effect on rmTBI-induced hyper-locomotion or risk-taking behavior. Together, we provide insight to the complexity and importance of a global neuroinflammatory response and kappa opioid receptors to pain