resiniferatoxin and cinnamaldehyde

Acetaminophen (APAP) is an effective antipyretic and one of the most commonly used analgesic drugs. Unlike antipyretic non-steroidal anti-inflammatory drugs, APAP elicits hypothermia in addition to its antipyretic effect. Here we have examined the mechanisms responsible for the hypothermic activity of APAP. Subcutaneous, but not intrathecal, administration of APAP elicited a dose dependent decrease in body temperature in wildtype mice. Hypothermia was abolished in mice pre-treated with resiniferatoxin to destroy or defunctionalize peripheral TRPV1-expressing terminals, but resistant to inhibition of cyclo-oxygenases. The hypothermic activity was independent of TRPV1 since APAP evoked hypothermia was identical in wildtype and Trpv1(-/-) mice, and not reduced by administration of a maximally effective dose of a TRPV1 antagonist. In contrast, a TRPA1 antagonist inhibited APAP induced hypothermia and APAP was without effect on body temperature in Trpa1(-/-) mice. In a model of yeast induced pyrexia, administration of APAP evoked a marked hypothermia in wildtype and Trpv1(-/-) mice, but only restored normal body temperature in Trpa1(-/-) and Trpa1(-/-)/Trpv1(-/-) mice. We conclude that TRPA1 mediates APAP evoked hypothermia.

Topics: Acetaminophen; Acrolein; Animals; Antipyretics; Benzoquinones; Diterpenes; Female; Hypothermia; Hypothermia, Induced; Imines; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Sensory Receptor Cells; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

Two tachykinin peptides, substance P (SP) and hemokinin-1 (HK-1), and three transient receptor potential (TRP) channels, TRPV1, TRPA1 and TRPM8, are similarly localized in the spinal dorsal horn and dorsal root ganglion, suggesting that TRP channels may be related or modulated by these tachykinin peptides. Thus, to clarify whether the responses of TRP channels are modulated by SP or HK-1, the effects of pretreatment with SP or HK-1 on the induction of scratching behavior by TRP channel agonists were examined. Pretreatment with SP or HK-1 enhanced the induction of scratching behavior by resiniferatoxin, a TRPV1 agonist, whereas scratching behavior induced by menthol, a TRPM8 agonist, was suppressed by pretreatment with these peptides. On the other hand, pretreatment with SP, but not HK-1, suppressed the induction of scratching behavior by cinnamaldehyde, a TRPA1 agonist. Taken together, the present results indicate that SP or HK-1 differentially modulated the response of TRPV1, TRPA1 or TRPM8 channel.

Topics: Acrolein; Animals; Ankyrins; Behavior, Animal; Calcium Channels; Diterpenes; Injections, Spinal; Male; Menthol; Pruritus; Rats; Rats, Sprague-Dawley; Spinal Cord; Substance P; Tachykinins; TRPA1 Cation Channel; TRPC Cation Channels; TRPM Cation Channels; TRPV Cation Channels

TRPA1 is a member of the transient receptor potential (TRP) channel family present in sensory neurons. Here we show that vanilloid receptor (TRPV1) stimulation with capsaicin and activation of TRPA1 with allyl isothiocyanate or cinnamaldehyde cause a graded contraction of the rat urinary bladder in vitro. Repeated applications of maximal concentrations of the agonists produce desensitization to their contractile effects. Moreover, contraction caused by TRPA1 agonists generates cross-desensitization with capsaicin. The TRP receptor antagonist ruthenium red (10-100 microM) inhibits capsaicin (0.03 microM), allyl isothiocyanate (100 microM) and cinnamaldehyde (300 microM)-induced contractions in the rat urinary bladder. The selective TRPV1 receptor antagonist SB 366791 (10 microM) blocks capsaicin-induced contraction, but partially reduces allyl isothiocyanate- or cinnamaldehyde-mediated contraction. However, allyl isothiocyanate and cinnamaldehyde (10-1000 microM) completely fail to interfere with the specific binding sites for the TRPV1 agonist [(3)H]-resiniferatoxin. Allyl isothiocyanate or cinnamaldehyde-mediated contractions of rat urinary bladder, which rely on external Ca(2+) influx, are significantly inhibited by tachykinin receptor antagonists as well as by tetrodotoxin (1 microM) or indomethacin (1 microM). Allyl isothiocyanate-induced contraction is not changed by atropine (1 microM) or suramin (300 microM). The exposure of urinary bladders to allyl isothiocyanate (100 microM) causes an increase in the prostaglandin E(2) and substance P levels. Taken together, these results indicate that TRPA1 agonists contract rat urinary bladder through sensory fibre stimulation, depending on extracellular Ca(2+) influx and release of tachykinins and cyclooxygenase metabolites, probably prostaglandin E(2). Thus, TRPA1 appears to exert an important role in urinary bladder function.

Topics: Acrolein; Anilides; Animals; Ankyrins; Binding Sites; Calcium Channels; Capsaicin; Cinnamates; Diterpenes; Dose-Response Relationship, Drug; Drug Antagonism; In Vitro Techniques; Isothiocyanates; Male; Muscle Contraction; Muscle, Smooth; Rats; Rats, Wistar; Ruthenium Red; TRPA1 Cation Channel; TRPC Cation Channels; TRPV Cation Channels; Urinary Bladder