Nicotinic modulation of descending pain control circuitry /

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Bibliographic Details
Author / Creator:Umana, Iboro Charles, author.
Imprint:2015.
Ann Arbor : ProQuest Dissertations & Theses, 2015
Description:1 electronic resource (145 pages)
Language:English
Format: E-Resource Dissertations
Local Note:School code: 0330
URL for this record:http://pi.lib.uchicago.edu/1001/cat/bib/10773283
Hidden Bibliographic Details
Other authors / contributors:University of Chicago. degree granting institution.
ISBN:9781339080741
Notes:Advisors: Daniel S. McGehee; Peggy Mason Committee members: William McDade; Wei Wei; Xiaoxi Zhuang.
Dissertation Abstracts International, Volume: 77-02(E), Section: B.
English
Summary:Chronic pain is an illness that affects a substantial proportion of people in the United States. Unfortunately, treatments for persistent pain have had mixed results. Thus, there is a need to explore alternative treatment strategies. Recent research in animal models has implicated alpha7 nicotinic acetylcholine receptors (nAChRs) as a potential analgesic target. Intracerebroventricular administration of alpha7 nAChR agonists decreases nociceptive behavior in chronic pain models, suggesting supraspinal sites of action. A strong candidate site of action is the periaqueductal gray (PAG), which is part of the descending pain control pathway. The PAG integrates inputs from higher centers and sends projections to the rostral ventromedial medulla (RVM), which in turn projects to the spinal cord to modulate incoming nociceptive signaling. We recently found functional alpha7 nAChR expression in 63% of recorded vlPAG-RVM projection neurons. In addition, somatic mu-opioid receptor (MOR) expression was rare in neurons containing nAChRs, suggesting segregation of these two receptor classes. Therefore, our working model is that activity of vlPAG alpha7 nAChR-expressing neurons suppresses ascending nociception ("pain-inhibiting") and activity of MOR-expressing vlPAG neurons facilitates nociceptive signaling ("pain-facilitating"). Because nAChRs are also expressed at the presynaptic terminal, we explored how nAChR modulation of excitatory and inhibitory drive affects vlPAG-RVM projection neuronal excitability. In neurons lacking somatic nAChRs, nicotine enhanced spontaneous inhibitory postsynaptic current (sIPSC) frequency in 63% of neurons, whereas in alpha7 nAChR-expressing neurons, sIPSC frequency increase was less prevalent. Finally, the prevalence of nicotine-induced increase in excitatory drive among alpha7 nAChR-expressing and alpha7 nAChR-lacking neurons was identical. Thus, nicotine enhances excitatory, but not inhibitory drive to alpha7 nAChR-expressing neurons. We also used the formalin test to assay acute and chronic antinociceptive potential of vlPAG alpha7 nAChRs. Administration of the selective alpha7 nAChR agonist, PHA-543613, into the vlPAG substantially reduced Phase II nociceptive responses. This antinociception was completely blocked by intra-vlPAG administration of alpha-bungarotoxin, an alpha7 nAChR selective antagonist. In addition, systemic PHA-543613 antinociception was completely blocked by focal alpha-bungarotoxin pretreatment. Our findings demonstrate vlPAG alpha7 nAChR is a promising target for analgesic drug development.
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