title: Perineural resiniferatoxin selectively inhibits inflammatory hyperalgesia.
abstract: Resiniferatoxin (RTX) is an ultrapotent capsaicin analog that binds to the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1). There is a large body of evidence supporting a role for TRPV1 in noxious-mediated and inflammatory hyperalgesic responses. In this study, we evaluated low, graded, doses of perineural RTX as a method for regional pain control. We hypothesized that this approach can provide long-term, but reversible, blockade of a portion of nociceptive afferent fibers within peripheral nerves when given at a site remote from the neuronal perikarya in the dorsal root ganglia. Following perineural RTX application to the sciatic nerve, we demonstrated a significant inhibition of inflammatory nociception that was dose- and time-dependent. At the same time, treated animals maintained normal proprioceptive sensations and motor control, and other nociceptive responses were largely unaffected. Using a range of mechanical and thermal algesic tests, we found that the most sensitive measure following perineural RTX administration was inhibition of inflammatory hyperalgesia. Recovery studies showed that physiologic sensory function could return as early as two weeks post-RTX treatment, however, immunohistochemical examination of the DRG revealed a partial, but significant reduction in the number of the TRPV1-positive neurons. We propose that this method could represent a beneficial treatment for a range of chronic pain problems, including neuropathic and inflammatory pain not responding to other therapies.
authors.affiliation: College of Dentistry Department of Orthodontics, University of Florida, Gainesville, FL, USA. jneubert@dental.ufl.edu
authors.forename: John K
authors.initials: JK
authors.lastname: Neubert
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mannes
authors.forename: Laszlo J
authors.initials: LJ
authors.lastname: Karai
authors.forename: Alan C
authors.initials: AC
authors.lastname: Jenkins
authors.forename: Lanel
authors.initials: L
authors.lastname: Zawatski
authors.forename: Mones
authors.initials: M
authors.lastname: Abu-Asab
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Iadarola
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000517:prevention & control*; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D020078:Neurogenic Inflammation / Q000517:prevention & control; D010525:Peripheral Nerves / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D050916:TRPV Cation Channels / Q000378:metabolism; D013997:Time Factors
chemical_list: D004224:Diterpenes; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C024353:resiniferatoxin; D002211:Capsaicin