endothelin-1 and capsazepine

Noxious cold reduces pruritus and transient receptor potential ankyrin subfamily member 1 (TRPA1), a non-selective cation channel, is known as a noxious cold-activated ion channel. Recent findings implicated the involvement of TRPA1 in pain induced by endothelin-1 (ET-1). Therefore, we evaluated its potential role in pruritus induced by ET-1. We found that ruthenium red (RR; a nonselective TRP inhibitor) and AP18 (a TRPA1 antagonist) significantly increased scratching bouts caused by ET-1, while capsazepine (a TRPV1 antagonist) and morphine showed no effects in the ET-1-induced scratching response. However, RR and capsazepine significantly reduced scratching bouts caused by histamine. Our results suggested that activation of TRPA1 could suppress itch induced by ET-1 and this is not related to pain induced by ET-1.

Topics: Animals; Behavior, Animal; Capsaicin; Endothelin-1; Enzyme Inhibitors; Histamine; Irritants; Male; Mice; Mice, Inbred C57BL; Pruritus; Ruthenium Red; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

Increasing evidence indicates that endothelin-1 (ET-1) activates nociceptive neurons and sensitizes them to different noxious stimuli, but involvement of TRPV1-dependent mechanisms in mediation of such effects is not yet fully understood. Here we report that intraplantar (i.pl.) injection of ET-1 (10 pmol) into the hind paw of rats induced overt nociceptive behavior over the first hour, followed by a slowly developing thermal hyperalgesia, lasting from 3 to 8h after injection. Both effects were also induced by similar injections of capsaicin (10-1000 pmol), but these responses were shorter lasting than those caused by ET-1. Local pre-treatment with the TRPV1 antagonist capsazepine (30 nmol, i.pl.) reduced only the thermal hyperalgesia induced by ET-1, but fully suppressed both responses to capsaicin (1000 pmol). Injection of a sub-threshold dose of ET-1 (0.1 pmol, i.pl.) prior to capsaicin (1 pmol, i.pl.) markedly sensitized the hind paw to the overt nociceptive and thermal hyperalgesic effects of the later. The potentiation of capsaicin-induced nociception by ET-1 was abolished by prior i.pl. injection of BQ-123 (ET(A) receptor antagonist, 10 nmol), but unaffected by BQ-788 (ET(B) receptors antagonist, 10 nmol), whereas the enhancement of capsaicin-induced hyperalgesia by ET-1 was attenuated by both antagonists. Therefore, differently to what has been reported in mice, in rats TRPV1 receptors contribute selectively to thermal hyperalgesia, but not overt nociception, induced by ET-1. Importantly, although ET-1 augments capsaicin-induced overt nociception and thermal hyperalgesia, potentiation of the former relies solely on ET(A) receptor-mediated signaling mechanisms, whereas both receptors contribute to the latter.

Topics: Analysis of Variance; Animals; Capsaicin; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hindlimb; Hyperalgesia; Male; Oligopeptides; Pain Measurement; Peptides, Cyclic; Physical Stimulation; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Sensory System Agents; Temperature; TRPV Cation Channels

Subcutaneous endothelin-1 (ET-1; 200 microM, 2 nmoles/paw) injected into the rat hind paw, has been shown to cause robust hind paw flinching (HPF) and paw licking, and to induce impulses selectively in primary nociceptors. Here we report that a much lower [ET-1] sensitizes the paw to a nocifensive withdrawal response to tactile stimulation (by von Frey hairs, VFH), a sensitization that involves local TRPV1 receptors. Injection of 10 microM ET-1 (0.1 nmole/paw) causes only marginal HPF but rapidly (20 mins after injection) lowers the force threshold for paw withdrawal (PWT) to VFH, to approximately 30% of pre-injection baseline. Such tactile allodynia persists for 3 hrs. In rats pre-injected with the TRPV1-antagonists capsazepine (CPZ; 1.33 mM) or 5'-iodoresiniferatoxin (I-RTX; 0.13 microM), 15 min before ET-1, a fast initial drop in PWT, as with ET-1 alone, occurs (to 40% or to 19% of baseline, respectively), but this earliest reduction then regresses back to the pre-injection PWT value more rapidly than with ET-1 alone. The recovery of allodynia from the maximum value is about two times faster for ET-1+CPZ and about 4 times faster for ET-1+ I-RTX, compared with that from ET-1 +vehicle (t(1/2) = 130, 60, and 250 mins, respectively). In contrast, spontaneous pain indicated by overt HPF from ET-1 is not attenuated by TRPV1 antagonists. Tactile allodynia is similarly abbreviated by antagonists of both ET(A) (BQ-123, 32 nmoles/paw) and ET(B) (BQ-788, 30 nmoles/paw) receptors, whereas HPF is abolished by this ET(A) antagonist but enhanced by the ET(B) antagonist. We conclude that low ET-1 causes tactile allodynia, which is characterized by a different time-course and pharmacology than ET-1-induced nociception, and that local TRPV1 receptors are involved in the maintenance of this ET-1-induced allodynia but not in the overt algesic action of ET-1.

Topics: Animals; Behavior, Animal; Capsaicin; Diterpenes; Dose-Response Relationship, Drug; Endothelin-1; Injections, Subcutaneous; Male; Nociceptors; Pain; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Endothelin A; Touch; TRPV Cation Channels

The infrared (IR) receptors in the pit organ of crotaline snakes are very sensitive to temperature. The vasculature of the pit organs, which is located in close proximity to IR-sensitive terminal nerve masses (IR receptors), is finer, flatter, and more convoluted than that of other sensory organs. Using extracellular recording in vivo from IR-sensitive primary afferent trigeminal ganglion (TG) neurons of the crotaline snake Trimeresurus flavoviridis, I studied the response to IR warming (24-25 degrees C) and to various chemicals: an exogenous vasoactive substance nitric oxide donor (sodium nitroprusside, SNP), endothelin-1 (ET-1), a transient receptor potential vanilloid (TRPV)1 agonist (capsaicin, CAP) and antagonist (capsazepine, CZP), and Ruthenium Red (RR), an antagonist of the TRPV family. IR-sensitive primary afferent TG neurons display regular background firing at 10-25 impulses per second at 24-25 degrees C. At this temperature, Ruthenium Red and endothelin-1 clearly suppressed the frequency of background firing, while sodium nitroprusside injected into the bloodstream significantly increased the frequency of discharges (P<0.01) and caused regular bursts of firing in IR-sensitive TG neurons. By contrast, capsaicin and capsazepine had no effect on the infrared responses. The possibility that these opposite responses result from their vasoactive effects on the unusual pit vasculature or from their chemical effects on the thermoreceptors of IR-sensitive nerve terminals in the pit organ, like those of the TRPV family, is discussed.

Topics: Animals; Blood Vessels; Capsaicin; Electrophysiology; Endothelin-1; Female; Male; Nitric Oxide Donors; Nitroprusside; Receptors, Drug; Ruthenium Red; Temperature; Thermoreceptors; Trimeresurus

Chronic exposure to beta(2)-adrenoceptor agonists, especially fenoterol, has been shown to increase smooth muscle contraction to endothelin-1 in human bronchi partly through tachykinin-mediated pathways. The purpose of this work was to further investigate the role of sensory nerves in fenoterol-induced sensitization of human airways and the effect of nociceptin, a nociceptin/orphanin FQ (NOP) receptor agonist, on the increase in contraction after fenoterol exposure. Human bronchi from 62 patients were sensitized to endothelin-1 by prolonged incubation with fenoterol (0.1 microM, 15 h). The sensitizing effect of fenoterol was inhibited by high concentration of capsaicin (10 microM, 30 min before fenoterol sensitization), which induces depletion of mediators from sensory nerves, or co-incubation of fenoterol and capsazepine (1 microM), a vanilloid TRPV-1 receptor antagonist. Moreover, short pretreatment of bronchi with capsaicin (10 microM) or capsazepine (1 microM) after sensitization by fenoterol decreased the rise in smooth muscle contraction to endothelin-1. Nociceptin (1 microM) also inhibited the increased contraction in fenoterol-sensitized bronchi. Tertiapin (10 microM), an inhibitor of the inward-rectifier K(+) channels, but not naloxone (0.1 microM), a DOP/KOP/MOP receptor antagonist, prevented the inhibitory effect of nociceptin. In conclusion, fenoterol induces sensitization of human isolated bronchi to endothelin-1 in part through the stimulation of the vanilloid TRPV-1 receptor on tachykininergic sensory nerves. Nociceptin inhibits airway hyperresponsiveness via NOP receptor activation. This effect involves inward-rectifier K(+) channels.

Topics: Adrenergic beta-Agonists; Bronchi; Bronchoconstriction; Capsaicin; Drug Interactions; Endothelin-1; Female; Fenoterol; Humans; Ion Channels; Male; Middle Aged; Nociceptin; Opioid Peptides; Receptors, Drug; TRPV Cation Channels; Vasodilator Agents