title: Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control.
abstract: Control of cancer, neuropathic, and postoperative pain is frequently inadequate or compromised by debilitating side effects. Inhibition or removal of certain nociceptive neurons, while retaining all other sensory modalities and motor function, would represent a new therapeutic approach to control severe pain. The enriched expression of transient receptor potential cation channel, subfamily V, member 1 (TRPV1; also known as the vanilloid receptor, VR1) in nociceptive neurons of the dorsal root and trigeminal ganglia allowed us to test this concept. Administration of the potent TRPV1 agonist resiniferatoxin (RTX) to neuronal perikarya induces calcium cytotoxicity by opening the TRPV1 ion channel and selectively ablates nociceptive neurons. This treatment blocks experimental inflammatory hyperalgesia and neurogenic inflammation in rats and naturally occurring cancer and debilitating arthritic pain in dogs. Sensations of touch, proprioception, and high-threshold mechanosensitive nociception, as well as locomotor function, remained intact in both species. In separate experiments directed at postoperative pain control, subcutaneous administration of RTX transiently disrupted nociceptive nerve endings, yielding reversible analgesia. In human dorsal root ganglion cultures, RTX induced a prolonged increase in intracellular calcium in vanilloid-sensitive neurons, while leaving other, adjacent neurons unaffected. The results suggest that nociceptive neuronal or nerve terminal deletion will be effective and broadly applicable as strategies for pain management.
authors.affiliation: National Institute of Dental and Craniofacial Research, Bethesda, Maryland 20892, USA.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Karai
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Brown
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mannes
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Connelly
authors.forename: Jacob
authors.initials: J
authors.lastname: Brown
authors.forename: Michael
authors.initials: M
authors.lastname: Gandal
authors.forename: Ofer M
authors.initials: OM
authors.lastname: Wellisch
authors.forename: John K
authors.initials: JK
authors.lastname: Neubert
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Olah
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Iadarola
mesh_terms: D000328:Adult; D000698:Analgesia / Q000379:methods; D000818:Animals; D002118:Calcium / Q000633:toxicity; D002478:Cells, Cultured; D004224:Diterpenes / Q000008:administration & dosage* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000517:prevention & control; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D008845:Microinjections; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism; D059408:Pain Management; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000378:metabolism*; D013238:Stereotaxic Techniques; D013997:Time Factors; D012668:Trigeminal Ganglion / Q000187:drug effects
chemical_list: D004224:Diterpenes; D011955:Receptors, Drug; C024353:resiniferatoxin; D002118:Calcium