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Vol. 59, Issue 1, 9-15, January 2001
Departments of Molecular Pharmacology (P.W., C.T.), Isotope
Chemistry (C.F.), and Molecular Genetics (S.T.), Novo Nordisk A/S,
Health Care Discovery, Maaloev, Bagsvaerd, Denmark
The highly potent vanilloid receptor (VR) agonist resiniferatoxin has
been radiolabeled with 125I, and the pharmacology to the
cloned rodent VR, VR1, and the endogenous VR in rat spinal cord
membranes has been characterized. [125I]RTX binding to
human embryonic kidney 293 cells expressing VR1 was reversible and with
high affinity (Kd = 4.3 nM) in an
apparent monophasic manner. In rat spinal cord membranes,
[125I]RTX bound with a similar high affinity
(Kd = 4.2 nM) to a limited number of
binding sites (Bmax = 51 ± 8 fmol/mg of protein). The pharmacology of recombinant rodent VR1 and the
endogenous rat VR1 was indistinguishable when measuring displacement of
[125I]RTX binding (i.e., the following rank order of
affinity was observed: RTX > I-RTX > olvanil > capsaicin > capsazepine). Capsaicin and RTX induced large
nondesensitizing currents in Xenopus laevis oocytes
expressing VR1 (EC50 values were 1300 nM and 0.2 nM,
respectively), whereas I-RTX induced no current per se at
concentrations up to 10 µM. However, I-RTX completely blocked
capsaicin-induced currents (IC50 = 3.9 nM). In vivo,
I-RTX effectively blocked the pain responses elicited by capsaicin
(ED50 = 16 ng/mouse, intrathecally). The present study
showed that I-RTX is at least 40-fold more potent than the previously
known VR antagonist, capsazepine. Thus, I-RTX as well as its
radiolabeled form, should be highly useful for further exploring the
physiological roles of VRs in the brain and periphery.
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