The contribution of descending pain facilitation to the maintenance of neuropathic pain
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractThis dissertation will examine the likelihood that tonic activation of descending facilitatory pathways may underlie chronic pain states arising from injuries to peripheral nerves, and that this activation is what maintains neuropathic pain. Activation of these pathways might be the result of plasticity in the RVM that is driven, in part, by release of CCK in response to pain signals from the injured nerve. Hyperactivity of facilitatory ON cells in the RVM may contribute to neuropathic pain and lesions of these cells via the targeted toxin, DERM-SAP, may prevent or reverse neuropathic pain states in the injured animal. Rats treated with DERM or SAP and undergoing SNL exhibited tactile and thermal hypersensitivity. Rats receiving DERM-SAP showed similar responses to sham-operated controls. Administration of RVM DERM-SAP to SNL rats fully reversed established allodynia/hyperalgesia by day 14. Thus, the targeted loss of cells expressing the MOR both prevents and reverses SNL-induced neuropathic pain. Acutely, RVM lidocaine blocked tactile and thermal hypersensitivity on day 6 out to day 12 after SNL, but not on day 3. DERM-SAP pretreatment and DLF lesions did not prevent the onset of tactile and thermal hypersensitivity, but these neuropathic pain signs reversed toward baseline levels beginning on day 4 after SNL. These findings differentiate the mechanisms that initiate neuropathic pain as being independent of supraspinal influences needed to maintain such pain. These descending influences may underlie some of the SNL-induced changes at the spinal level, such as the upregulation of dynorphin and may be key to the maintenance of neuropathic pain. Administration of RVM CCK produces hypersensitivity in naive rats. Pretreatment with RVM DERM-SAP completely blocks the ability of RVM CCK to produce hypersensitivity. These results suggest that the action of CCK in the RVM may be mediated by activation of MOR expressing cells. Enhanced release of CCK in the RVM or upregulation of CCK receptors in RVM neurons after SNL may represent a mechanism of descending pain facilitation to maintain chronic pain states. An observed loss of both MOR and CCK2 receptors after DERM-SAP treatment gives support to the notion that both receptor types may be co-expressed in RVM neurons, and these neurons may be critical for descending facilitatory input from the RVM to maintain neuropathic pain. Understanding the mechanisms of descending facilitation and the spinal effects of, CCK-activated discharge could provide new insight into the modulation of chronic pain, and, furthermore, provide new targets for the development of novel drug therapies.
Degree ProgramGraduate College
Pharmacology and Toxicology