Inhibition of low pH evoked activation of airway sensory nerves by capsazepine, a novel capsaicin-receptor antagonist

Lou, Ya‐Ping; Lundberg, Jan M.

doi:10.1016/0006-291x(92)91591-d

Cited by 80 publications

(38 citation statements)

References 18 publications

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“…These results correlate with the finding that capsazepine is able to block acid-induced activation of guinea pig VR1 in vitro (Lou and Lundberg, 1992;Satoh et al, 1993;Fox et al, 1995;Savidge et al, 2002), a property shared with human VR1 but absent from rat VR1 (McIntyre et al, 2001). Together, these data raise the possibility that blockade of VR1 responses activated by low pH, or dual blockade of capsaicin site and pH site-mediated responses, may be important for antihyperalgesic efficacy in vivo.…”

Section: Discussionsupporting

confidence: 87%

N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties

Valenzano¹,

Grant

et al. 2003

J Pharmacol Exp Ther

203

129

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Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ϳ1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than capsazepine for testing the role played by VR1 in rat models of human disease.

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Section: Discussionsupporting

confidence: 87%

N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties

Valenzano¹,

Grant

et al. 2003

J Pharmacol Exp Ther

203

129

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“…However, both in vitro and in vivo studies have indicated that capsazepine also has species-dependent activity. In vitro, capsazepine has been shown to block low pH mediated activation of human or guinea pig, but not rat VR1 (Lou and Lundberg, 1992;Satoh et al, 1993;Fox et al, 1995;McIntyre et al, 2001;Savidge et al, 2002). These in vitro results correlate with the finding that capsazepine reverses inflammatory and neuropathic hyperalgesia in the guinea pig, but not in the rat (Walker et al, 2003).…”

supporting

confidence: 67%

“…However, recent studies have revealed species-specific pharmacological actions of capsazepine that may limit its applicability in some animal models (Lou and Lundberg, 1992;Satoh et al, 1993;Fox et al, 1995;McIntyre et al, 2001;Savidge et al, 2002;Walker et al, 2003). Although capsazepine can inhibit activation of rat VR1 by capsaicin, Valenzano et al (2003) found it to be ineffective at blocking acid-mediated VR1 currents, and is similarly ineffective at reversing pain behaviors associated with inflammation in rats (Walker et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: II. In Vivo Characterization in Rat Models of Inflammatory and Neuropathic Pain

Pomonis¹,

Harrison²,

Mark³

et al. 2003

J Pharmacol Exp Ther

254

167

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The vanilloid receptor 1 (VR1) is a cation channel expressed predominantly by nociceptive sensory neurons and is activated by a wide array of pain-producing stimuli, including capsaicin, noxious heat, and low pH. Although the behavioral effects of injected capsaicin and the VR1 antagonist capsazepine have indicated a potential role for VR1 in the generation and maintenance of persistent pain states, species differences in the molecular pharmacology of VR1 and a limited number of selective ligands have made VR1 difficult to study in vivo. N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropryazine-1(2H)-carbox-amide (BCTC) is a recently described inhibitor of capsaicin-and acidmediated currents at rat VR1. Here, we report the effects of BCTC on acute, inflammatory, and neuropathic pain in rats. Administration of BCTC (30 mg/kg p.o.) significantly reduced both mechanical and thermal hyperalgesia induced by intraplantar injection of 30 g of capsaicin. In rats with Freund's complete adjuvantinduced inflammation, BCTC significantly reduced the accompanying thermal and mechanical hyperalgesia (3 mg/kg and 10 mg/kg p.o., respectively). BCTC also reduced mechanical hyperalgesia and tactile allodynia 2 weeks after partial sciatic nerve injury (10 and 30 mg/kg p.o.). BCTC did not affect motor performance on the rotarod after administration of doses up to 50 mg/kg p.o. These data suggest a role for VR1 in persistent and chronic pain arising from inflammation or nerve injury.The vanilloid receptor type 1 (VR1) is a pivotal molecular integrator of noxious stimuli that is expressed on somatic and autonomic primary afferent neurons. VR1 has been confirmed as a ligand-gated ion channel after its cloning from rat and human tissues, and has been shown to be highly expressed in small-diameter primary afferent neurons (Caterina et al., 1997;Hayes et al., 2000;McIntyre et al., 2001). In vitro studies have shown that, like the native vanilloid receptor, recombinant VR1 can be activated by a variety of chemical as well as physical stimuli. In vitro, VR1 responds to plant-derived compounds, including capsaicin, a pungent component of chili peppers, lipid mediators such as anandamide , the lipoxygenase product 12-(S)-hydroperoxyeicosatetraenoic acid (Hwang et al., 2000), as well as noxious heat (Caterina et al., 1997) and low pH (Tominaga et al., 1998).A potential role for VR1 in nociception has been evident for some time because injection of the VR1 agonist capsaicin induces nocifensive and hyperalgesic behaviors in rodents and pain in humans (Szolcsanyi, 1977;Carpenter and Lynn, 1981;Simone et al., 1987Simone et al., , 1989Gilchrist et al., 1996). Further support for VR1 as a therapeutic target arose from experiments involving capsazepine. Capsazepine is a VR1 antagonist that has been shown to competitively inhibit capsaicin-mediated responses in isolated dorsal root ganglion (DRG) neurons (Bevan et al., 1992a) and tissues from rat (Bevan et al., 1992b;Cholewinski et al., 1993;Maggi et al., 1993;Santicioli et al., 19...

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“…An axon reflex occurs when stimulation of a C fiber ending results in action potentials which, in addition to traveling orthodromically toward the central nervous system, also travel antidromically via collateral branches to effect the release of tachykinins. The release of tachykinins from the peripheral terminals of afferent nerves can be induced by a variety of stimuli including capsaicin (68), bradykinin (69), electrical nerve stimulation (70), cigarette smoke (71), low pH (72), and hypertonic saline (73). The release of tachykinins from the peripheral terminals of C fibers in the airways may result in increased blood flow through the microvascular bed of the airways, increased microvascular permeability, inflammatory cell recruitment, stimulation of airways secretions, and airway smooth muscle contraction (74).…”

Section: Enhanced Release Of Tachykininsmentioning

confidence: 99%

Inflammation-Induced Plasticity of the Afferent Innervation of the Airways

Carr¹,

Undem²

2001

Environmental Health Perspectives

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Inhibition of low pH evoked activation of airway sensory nerves by capsazepine, a novel capsaicin-receptor antagonist

Cited by 80 publications

References 18 publications

N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties

N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties

N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: II. In Vivo Characterization in Rat Models of Inflammatory and Neuropathic Pain

Inflammation-Induced Plasticity of the Afferent Innervation of the Airways

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