Resiniferatoxin: an ultrapotent selective modulator of capsaicin-sensitive primary afferent neurons.
Resiniferatoxin (RTX) has been shown to function as an ultrapotent analog of capsaicin. It is reported here that RTX, like capsaicin, acts selectively on primary sensory neurons in rats to produce ultrastructural alterations and calcitonin gene-related peptide depletion. To evaluate RTX actions on capsaicin-sensitive nociceptors of vagal origin in the lung, the activation and desensitization of the pulmonary chemoreflex in both rats and cats were examined. In rats, RTX (2 ng-5 micrograms/kg i.v.) failed to elicit the full reflex triad (apnea, systemic hypotension and bradycardia); RTX did, however, desensitize the pulmonary chemosensitive receptors to capsaicin and phenyldiguanide. This effect is not achievable upon acute capsaicin treatment. RTX pretreatment (300 micrograms/kg s.c.) of rats also abolished the neurogenic edema formation, another response mediated via capsaicin-sensitive vagal fibers, in rat trachea to challenge either by capsaicin or ether. The effect of electrical stimulation of vagal nerve was not impaired after RTX injection, indicating that RTX desensitized only the capsaicin-sensitive pathway whereas the parasympathetic pathway remained unaltered. In cats, unlike in the rat, the full pulmonary chemoreflex occurred in response to 0.1 micrograms/kg RTX. It is concluded that RTX is a selective probe for capsaicin-sensitive neural pathways but the spectrum of action of the two compounds is not identical. The failure of RTX to provoke the pulmonary chemoreflex in the rat, which is the main limiting factor in the use of capsaicin, suggests a further advantage to the use of RTX for probing capsaicin-sensitive neural pathways.
Szolcsanyi
J
J
Department of Pharmacology, University Medical School, Pecs, Hungary.
Szallasi
A
A
Szallasi
Z
Z
Joo
F
F
Blumberg
P M
PM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology*; D002415:Cats; D004224:Diterpenes / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D009475:Neurons, Afferent / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains; D012119:Respiration / Q000187:drug effects
D004224:Diterpenes; C024353:resiniferatoxin; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin