In vivo pharmacology of SDZ 249-665, a novel, non-pungent capsaicin analogue

Urbán, László; Campbell, Elizabeth A.; Panesar, Moh; Patel, Sadhana; Chaudhry, N. K.; Kane, S.A.; Buchheit, Karl-Heinz; Sandells, Barrie; James, Iain F.

doi:10.1016/s0304-3959(00)00349-3

Cited by 71 publications

(47 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For example, the half-maximal concentrations (EC 50 ) of capsaicin for activating native capsaicin- sensitive currents is ϳ0.68 -1.1 M (Liu and Simon, 1996;Oh et al, 1996;Koplas et al, 1997;Liu et al, 1997;Jung et al, 1999). In contrast, EC 50 values for activating TRPV1 expressed in mammalian cell lines are 0.1-0.25 M, much lower than those for native capsaicin-sensitive currents in sensory neurons (Tominaga et al, 1998(Tominaga et al, , 2001Mohapatra and Nau, 2003 Wood et al, 1988;Cholewinski et al, 1993;Urban et al, 2000), whereas those in HEK-TRPV1 or CHO-TRPV1 cells are 0.016 -0.098 M (Gavva et al, 2004;Toth et al, 2004). The difference in potency stems from variation possibly raised by different experimental procedures performed in different laboratories.…”

Section: Discussionmentioning

confidence: 98%

TRPV1 Recapitulates Native Capsaicin Receptor in Sensory Neurons in Association with Fas-Associated Factor 1

et al. 2006

View full text Add to dashboard Cite

TRPV1, a cloned capsaicin receptor, is a molecular sensor for detecting adverse stimuli and a key element for inflammatory nociception and represents biophysical properties of native channel. However, there seems to be a marked difference between TRPV1 and native capsaicin receptors in the pharmacological response profiles to vanilloids or acid. One plausible explanation for this overt discrepancy is the presence of regulatory proteins associated with TRPV1. Here, we identify Fas-associated factor 1 (FAF1) as a regulatory factor, which is coexpressed with and binds to TRPV1 in sensory neurons. When expressed heterologously, FAF1 reduces the responses of TRPV1 to capsaicin, acid, and heat, to the pharmacological level of native capsaicin receptor in sensory neurons. Furthermore, silencing FAF1 by RNA interference augments capsaicin-sensitive current in native sensory neurons. We therefore conclude that FAF1 forms an integral component of the vanilloid receptor complex and that it constitutively modulates the sensitivity of TRPV1 to various noxious stimuli in sensory neurons.

show abstract

Section: Discussionmentioning

confidence: 98%

TRPV1 Recapitulates Native Capsaicin Receptor in Sensory Neurons in Association with Fas-Associated Factor 1

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Anandamide was originally isolated from porcine brain as the first endogenous cannabinoid (Devane et al, 1992), and its biosynthesis has subsequently been demonstrated in neurons (Di Marzo et al, 1994), macrophages (Di Marzo et al, 1996), and recently in lung (Calignano et al, 2000). In contrast to capsaicin, anandamide and the synthetic vanilloids and analgesic agents olvanil and SDZ 249 -665 do not induce airway obstruction in vivo (Wrigglesworth et al, 1996;Stengel et al, 1998;Calignano et al, 2000;Urban et al, 2000). Consistent with these observations, recent studies suggest that anandamide is a weak constrictor of isolated airways compared with capsaicin Tucker et al, 2001).…”

mentioning

confidence: 81%

Mechanisms Underlying Tissue Selectivity of Anandamide and Other Vanilloid Receptor Agonists

et al. 2002

View full text Add to dashboard Cite

Anandamide acts as a full vanilloid receptor agonist in many bioassay systems, but it is a weak activator of primary afferents in the airways. To address this discrepancy, we compared the effect of different vanilloid receptor agonists in isolated airways and mesenteric arteries of guinea pig using preparations containing different phenotypes of the capsaicin-sensitive sensory nerve. We found that anandamide is a powerful vasodilator of mesenteric arteries but a weak constrictor of main bronchi. These effects of anandamide are mediated by vanilloid receptors on primary afferents and do not involve cannabinoid receptors. Anandamide also contracts isolated lung strips, an effect caused by the hydrolysis of anandamide and subsequent formation of cyclooxygenase products. Although capsaicin is equally potent in bronchi and mesenteric arteries, anandamide, resiniferatoxin, and particularly olvanil are significantly less potent in bronchi. Competition experiments with the vanilloid receptor antagonist capsazepine did not provide evidence of vanilloid receptor heterogeneity. Arachidonoyl-5-methoxytryptamine (VDM13), an inhibitor of the anandamide membrane transporter, attenuates responses to olvanil and anandamide, but not capsaicin and resiniferatoxin, in mesenteric arteries. VDM13 did not affect responses to these agonists in bronchi, suggesting that the anandamide membrane transporter is absent in this phenotype of the sensory nerve. Computer simulations using an operational model of agonism were consistent, with differences in intrinsic efficacy and receptor content being responsible for the remaining differences in agonist potency between the tissues. This study describes differences between vanilloid receptor agonists regarding tissue selectivity and provides a conceptual framework for developing tissue-selective vanilloid receptor agonists devoid of bronchoconstrictor activity.

show abstract

“…In some animals, capsaicin was subcutaneously administered in three divided doses (50 and 25 mg/kg on the first day and 50 mg/kg on the second day) over a 2-day period to desensitize the majority of C-fiber afferents that are sensitive to capsaicin 5 days before cystometry (47). C-fiber desensitization was confirmed by negative response to an eye wipe test before the experiments (53).…”

Section: Methodsmentioning

confidence: 99%

Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 α-subunit in rats with cystitis

Hayashi

Takimoto²,

Chancellor³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Hayashi Y, Takimoto K, Chancellor MB, Erickson KA, Erickson VL, Kirimoto T, Nakano K, de Groat WC, Yoshimura N. Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 ␣-subunit in rats with cystitis. Am J Physiol Regul Integr Comp Physiol 296: R1661-R1670, 2009. First published March 11, 2009 doi:10.1152/ajpregu.91054.2008.-Hyperexcitability of C-fiber bladder afferent pathways has been proposed to contribute to urinary frequency and bladder pain in chronic bladder inflammation including interstitial cystitis. However, the detailed mechanisms inducing afferent hyperexcitability after bladder inflammation are not fully understood. Thus, we investigated changes in the properties of bladder afferent neurons in rats with bladder inflammation induced by intravesical application of hydrochloric acid. Eight days after the treatment, bladder function and bladder sensation were analyzed using cystometry and an electrodiagnostic device of sensory function (Neurometer), respectively. Whole cell patch-clamp recordings and immunohistochemical staining were also performed in dissociated bladder afferent neurons identified by a retrograde tracing dye, Fast Blue, injected into the bladder wall. Cystitis rats showed urinary frequency that was inhibited by pretreatment with capsaicin and bladder hyperalgesia mediated by C-fibers. Capsaicin-sensitive bladder afferent neurons from sham rats exhibited high thresholds for spike activation and a phasic firing pattern, whereas those from cystitis rats showed lower thresholds for spike activation and a tonic firing pattern. Transient A-type K ϩ current density in capsaicinsensitive bladder afferent neurons was significantly smaller in cystitis rats than in sham rats, although sustained delayed-rectifier K ϩ current density was not altered after cystitis. The expression of voltage-gated K ϩ Kv1.4 ␣-subunits, which can form A-type K ϩ channels, was reduced in bladder afferent neurons from cystitis rats. These data suggest that bladder inflammation increases bladder afferent neuron excitability by decreasing expression of Kv1.4 ␣-subunits. Similar changes in capsaicin-sensitive C-fiber afferent terminals may contribute to bladder hyperactivity and hyperalgesia due to acid-induced bladder inflammation. urinary bladder; hyperalgesia; inflammation; C-fiber afferent; potassium channel IT HAS BEEN DEMONSTRATED THAT afferent pathways innervating the urinary bladder consist of myelinated A␦-fibers and unmyelinated C-fibers and that hyperexcitability of C-fibers in bladder afferent pathways contributes to bladder overactivity and/or bladder pain under pathological conditions such as painful bladder syndrome/interstitial cystitis (PBS/IC) (60, 61).Voltage-gated K ϩ (Kv) currents are major determinants of neuronal excitability. Kv currents in sensory neurons are divided into two major categories; i.e., sustained delayed rectifier-type K ϩ (K DR ) and transient A-type K ϩ (K A ) currents (19,21,30,57). K A currents in sensory neurons ...

show abstract

In vivo pharmacology of SDZ 249-665, a novel, non-pungent capsaicin analogue

Cited by 71 publications

References 25 publications

TRPV1 Recapitulates Native Capsaicin Receptor in Sensory Neurons in Association with Fas-Associated Factor 1

TRPV1 Recapitulates Native Capsaicin Receptor in Sensory Neurons in Association with Fas-Associated Factor 1

Mechanisms Underlying Tissue Selectivity of Anandamide and Other Vanilloid Receptor Agonists

Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 α-subunit in rats with cystitis

Contact Info

Product

Resources

About