The purpose of this renewal proposal, for a third cycle of funding, is to test specific hypotheses concerning the relevance of animal studies to the spinal pharmacology of pain and analgesia in humans. The goal for the next project period is to concentrate on adenosine as a potential agent for the relief of neuropathic pain. In preliminary animal studies, adenosine has been found to be selectively effective in allodynia versus acute pain.
Two specific aims relate to this: (1) in human studies, define the dose-response and time course of intrathecal adenosine alone and with clonidine for side effects, analgesia to an acute thermal stimulus, and inhibition of capsaicin-induced mechanical allodynia and hyperalgesia in volunteers, and adenosine's efficacy as an analgesic in patients with chronic neuropathic pain; (2) in animal studies, test pharmacokinetic and pharmacodynamic mechanisms for adenosine's greater potency to remove allodynia than to block acute nociceptive stimuli, and examine pharmacologic mechanisms for the interaction between adenosine and a2 adrenoceptor-mediated neurotransmission in spinal cord. Hypotheses to be tested for pharmacodynamic mechanisms include allodynia-induced changes in adenosine receptor number or affinity, in adenosine-induced norepinephrine release, and in adenosine inhibition of excitatory amino acid release. Although only the animal studies are described in detail, a test of the adenosine-clonidine combination in human subjects is apparently also envisioned. A third specific aim is to complete preclinical neurotoxicity screening for preservative-free ketorolac in animals prior to human intrathecal testing.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM048085-09
Application #
6329734
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
1992-08-01
Project End
2002-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
9
Fiscal Year
2001
Total Cost
$272,461
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Gutierrez, Silvia; Boada, M Danilo (2018) Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+). Cancer Cell Int 18:216
Boada, M Danilo; Eisenach, James C; Ririe, Douglas G (2016) Mechanical sensibility of nociceptive and non-nociceptive fast-conducting afferents is modulated by skin temperature. J Neurophysiol 115:546-53
Booth, Jessica L; Harris, Lynnette C; Eisenach, James C et al. (2016) A Randomized Controlled Trial Comparing Two Multimodal Analgesic Techniques in Patients Predicted to Have Severe Pain After Cesarean Delivery. Anesth Analg 122:1114-9
Arora, Vipin; Morado-Urbina, Carlos Eduardo; Aschenbrenner, Carol A et al. (2016) Disruption of Spinal Noradrenergic Activation Delays Recovery of Acute Incision-Induced Hypersensitivity and Increases Spinal Glial Activation in the Rat. J Pain 17:190-202
Boada, M Danilo; Martin, Thomas J; Peters, Christopher M et al. (2014) Fast-conducting mechanoreceptors contribute to withdrawal behavior in normal and nerve injured rats. Pain 155:2646-55
Yaksh, Tony L; Hobo, Shotaro; Peters, Christopher et al. (2014) Preclinical toxicity screening of intrathecal oxytocin in rats and dogs. Anesthesiology 120:951-61
Wang, Lu; Bauer, Maria; Curry, Regina et al. (2014) Intrathecal ketorolac does not improve acute or chronic pain after hip arthroplasty: a randomized controlled trial. J Anesth 28:790-3
Pan, Peter H; Tonidandel, Ashley M; Aschenbrenner, Carol A et al. (2013) Predicting acute pain after cesarean delivery using three simple questions. Anesthesiology 118:1170-9
Gutierrez, S; Hayashida, K; Eisenach, J C (2013) The puerperium alters spinal cord plasticity following peripheral nerve injury. Neuroscience 228:301-8
Gutierrez, Silvia; Liu, Baogang; Hayashida, Ken-ichiro et al. (2013) Reversal of peripheral nerve injury-induced hypersensitivity in the postpartum period: role of spinal oxytocin. Anesthesiology 118:152-9

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