Peripheral neural blockade with local anesthetics is commonly used as a method of effective postoperative analgesia, however, the value of blockade is decreased by its non-selective nature. In this project, we will examine the mechanisms of neural blockade induced by vanilloid agonists with the aim of using these mechanisms in the search for an agent with selective, long-lasting, and spontaneously reversible local analgesic action. The main hypothesis of this project is that a single local application of a vanilloid agonist to a peripheral nerve can abolish pain behavior and hyperalgesia for the whole period of postincisional inflammation. We will also examine the cellular mechanisms of vanilloid-induced neural blockade. The following three Specific Aims are proposed: to determine, (1) if resiniferatoxin (RTX) applied locally to a peripheral nerve, provides a long-lasting suppression of the responses to noxious stimuli; in addition, it will be determined if this effect is mediated by vanilloid receptors and has a sufficient safety in relation to irreversible neural blockade and to disruption of other functions; (2) if selective neural blockade by RTX prevents and reverses pain behavior and hyperalgesia in carrageenan-induced inflammation and incisional injury; and (3) if the inactivation phase of the local effect of RTX on nerves is primarily dependent on abolition of voltage-gated, tetrodotoxin-resistant (TTX-R) sodium currents. To study the specific aims of the project the effects of RTX will be examined in rats by behavioral methods; and whole cell voltage-clamp technique will be used to identify a mechanism for impulse failure induced by RTX.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM065834-01A1
Application #
6731561
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$353,166
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Sugimoto, Kenji; Kissin, Igor; Strichartz, Gary (2008) A high concentration of resiniferatoxin inhibits ion channel function in clonal neuroendocrine cells. Anesth Analg 107:318-24
Kissin, Igor (2008) Vanilloid-induced conduction analgesia: selective, dose-dependent, long-lasting, with a low level of potential neurotoxicity. Anesth Analg 107:271-81
Kissin, Igor; Freitas, Cristina F; Mulhern, Howard L et al. (2007) Sciatic nerve block with resiniferatoxin: an electron microscopic study of unmyelinated fibers in the rat. Anesth Analg 105:825-31
Kissin, Igor; Freitas, Cristina F; Bradley Jr, Edwin L (2007) Perineural resiniferatoxin prevents the development of hyperalgesia produced by loose ligation of the sciatic nerve in rats. Anesth Analg 104:1210-6, tables of contents
Kissin, Igor; Freitas, Cristina F; Bradley Jr, Edwin L (2006) Memory of pain: the effect of perineural resiniferatoxin. Anesth Analg 103:721-8
Kissin, Eugene Y; Freitas, Cristina F; Kissin, Igor (2005) The effects of intraarticular resiniferatoxin in experimental knee-joint arthritis. Anesth Analg 101:1433-9
Kissin, Igor (2005) Preemptive analgesia at the crossroad. Anesth Analg 100:754-6
Kissin, Igor; Davison, Natasha; Bradley Jr, Edwin L (2005) Perineural resiniferatoxin prevents hyperalgesia in a rat model of postoperative pain. Anesth Analg 100:774-80, table of contents