title: TRPV1 antagonist, A-889425, inhibits mechanotransmission in a subclass of rat primary afferent neurons following peripheral inflammation.
abstract: TRPV1 (transient receptor potential vanilloid family type 1) is a nonselective cation channel that is activated and/or sensitized by noxious heat, protons, and other endogenous molecules released following tissue injury. In addition, a role for TRPV1 in mechanotransmission is emerging. We have recently reported that a selective TRPV1 receptor antagonist, A-889425, reduces mechanical allodynia and spinal neuron responses to mechanical stimulation of complete Freund's adjuvant (CFA)-inflamed rat hind paws. The population of peripheral nerve fibers through which TRPV1 antagonists mediate their effect on mechanotransmission have not yet been described. The objective of this study was to characterize TRPV1-mediated modulation of mechanically evoked activity in sensory axons innervating rat hind paws. We used an in vitro skin-nerve preparation to record neural activity from single axons isolated from rat tibial nerve. Single fibers were classified by conduction velocity, mechanical threshold, and stimulus-response relationships. We used A-889425 to investigate uninjured and inflamed skin afferent neuron populations to evoked mechanical stimulation. Application of A-889425 had no effect on the mechanical responsiveness of Aδ and C-fiber units innervating uninjured skin. In contrast, A-889425 inhibited responses of slowly conducting Aδ fiber units to noxious mechanical stimulation in a population of axons innervating CFA-inflamed hind paws. These data support a role for TRPV1 in mechanotransmission following peripheral inflammation, and highlight the importance of a distinct subclass of primary afferent neurons in mediating this effect.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6123, USA. jill-desiree.brederson@abbott.com
authors.forename: Jill-Desiree
authors.initials: JD
authors.lastname: Brederson
authors.forename: Katharine L
authors.initials: KL
authors.lastname: Chu
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Brian S
authors.initials: BS
authors.lastname: Brown
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Steve
authors.initials: S
authors.lastname: McGaraughty
mesh_terms: D000818:Animals; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D040542:Mechanotransduction, Cellular / Q000187:drug effects / Q000502:physiology*; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D020078:Neurogenic Inflammation / Q000503:physiopathology*; D009475:Neurons, Afferent / Q000502:physiology*; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000293:injuries / Q000294:innervation; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013979:Tibial Nerve / Q000502:physiology
chemical_list: C540006:A-889425; D011725:Pyridines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor