Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)-epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain

Kesingland, Adam; Gentry, Clive; Panesar, Moh; Bowes, M; Vernier, Jean‐Michel; Cube, Rowena V.; Walker, Katharine; Urbán, László

doi:10.1016/s0304-3959(00)00233-5

Cited by 73 publications

(38 citation statements)

References 5 publications

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“…The functional activity of ABT-594 at the human muscle type of nicotinic receptor was quite unexpected since this compound has been shown to have a 180,000-fold specificity for recombinantly expressed human α4β2 compared to Torpedo α1β1γδ receptors (Donnelly et al 1998). The functional activation of the neuromuscular receptor by ABT-594 is reflected in in vivo experiments where it has been demonstrated that higher doses of ABT-594 disrupt performance in the rotarod test, although the separation between motor and anti-hyperalgesic effects is clearer compared to epibatidine (Kesingland et al 2000). GTS21 and AAR17779 have been described as specific α7 receptor agonists (De Fiebre et al 1995;Levin et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Study of the calcium dynamics of the human α4β2, α3β4 and α1β1γδ nicotinic acetylcholine receptors

Michelmore

Croskery

Nozulak

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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In this study three major subtypes of nicotinic acetylcholine receptors were characterized pharmacologically using the calcium influx through the ion channel as a robust functional assay system. Human alpha3beta4 receptors and alpha4beta2 receptors were cloned and stably expressed in HEK293 cells. [(125)I]epibatidine saturation binding yielded a B(max) of 4420+/-840 fmol/mg protein for the alpha4beta2 receptor ( n=4) and 518+/-15 fmol/mg protein for the alpha3beta4 receptor ( n=4). As a source for muscle type of nicotinic receptor, the TE671 cell line was used which expresses endogenously the human fetal alpha1beta1gammadelta subtype of nicotinic receptor. Stimulation of these nicotinic receptor subtypes in the different cell lines led to calcium transients that peaked 5-10 s after agonist application and declined thereafter. Eleven agonists were tested in this study and their efficacy and potency at the three nicotinic receptor subtypes were determined (epibatidine, ABT594, anatoxin, ABT418, nicotine, DMPP, cytisine, ABT089, choline, GTS21, AAR17779). This pharmacological characterization of agonist-induced elevation of intracellular free Ca(2+) revealed a distinct rank order of agonist potency for each receptor subtype. Epibatidine showed at all three subtypes the highest potency and was a full agonist. The agonist-elicited response could be blocked by co-incubation of different antagonists from which mecamylamine did not display a strong subtype specificity. These data illustrate that the assessment of calcium transients upon receptor stimulation is a powerful tool for rapid examination of the functional properties of nicotinic receptors.

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Section: Discussionmentioning

confidence: 99%

Study of the calcium dynamics of the human α4β2, α3β4 and α1β1γδ nicotinic acetylcholine receptors

Michelmore

Croskery

Nozulak

et al. 2002

Naunyn-Schmiedeberg's Archives of Pharmacology

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“…The α4β2 subtype-selective ligands were the first to be developed. ABT-594, which is a structural analogue of epibatidine, was shown to be a potent full agonist for the α4β2 nAChRs with a strong analgesic effect [158, 163, 164]. In various animal models of pain, the analgesic activity of ABT-594 was inhibited by the administration of the general antagonist mecamylamine [162, 165].…”

Section: Painmentioning

confidence: 99%

Nicotinic ACh receptors as therapeutic targets in CNS disorders

Dineley

Pandya

Yakel

2015

Trends in Pharmacological Sciences

396

345

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The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor channels (nAChRs). These receptors are widely distributed throughout the central nervous system, being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. In the mammalian brain, nine different subunits have been found thus far, which assemble into pentameric complexes with much subunit diversity; however the α7 and α4β2 subtypes predominate in the CNS. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders. Here we will briefly discuss the functional makeup and expression of the nAChRs in the mammalian brain, and their role as targets in neurodegenerative diseases (in particular Alzheimer’s disease), neurodevelopmental disorders (in particular autism and schizophrenia), and neuropathic pain.

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“…In addition to its clear nociceptive role, nicotinics may be able to confer a degree of analgesia (Carstens et al 2001;Kesingland et al 2000;Reuter et al 2003). These influences might arise from modulation of peptide release (Bannon et al 1998a,b;Donnelly-Roberts et al 1998), cross desensitization (Sudo et al 2002), tachphylaxis (Dessirier et al 2000;Jinks and Carstens 1999), or direct interaction with voltage-dependent channels (Liu et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Nicotinic AChR in Subclassified Capsaicin-Sensitive and -Insensitive Nociceptors of the Rat DRG

Rau¹,

Johnson²,

Cooper³

2005

Journal of Neurophysiology

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Nociceptive cells of the dorsal root ganglion (DRG) were subclassified, in vitro, according to patterns of voltage-activated currents. The distribution and form of nicotinic ACh receptors (nAChRs) were determined. nAChRs were present on both capsaicin-sensitive and -insensitive nociceptors but were not universally present in unmyelinated nociceptors. In contrast, all A delta nociceptors (types 4, 6, and 9) expressed slowly decaying nAChR. Three major forms of nicotinic currents were identified. Specific agonists and antagonists were used to demonstrate the presence of alpha7 in two classes of capsaicin-sensitive, unmyelinated nociceptors (types 2 and 8). In type 2 cells, alpha7-mediated currents were found in isolation. Whereas alpha7 was co-expressed with other nAChR in type 8 cells. These were the only classes in which alpha7 was identified. Other nociceptive classes expressed slowly decaying currents with beta4 pharmacology. Based on concentration response curves formed by nicotinic agonists [ACh, nicotine, dimethyl phenyl piperazinium (DMPP), cytisine] evidence emerged of two distinct nAChR differentially expressed in type 4 (alpha3beta4) and types 5 and 8 (alpha3beta4 alpha5). Although identification could not be made with absolute certainty, patterns of potency (type 4: DMPP > cytisine > nicotine = ACh; type 5 and type 8: DMPP = cytisine > nicotine = ACh) and efficacy provided strong support for the presence of two distinct channels based on an alpha3beta4 platform. Studies conducted on one nonnociceptive class (type 3) failed to reveal any nAChR. After multiple injections of Di-I (1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) into the hairy skin of the hindlimb, we identified cell types 2, 4, 6, 8, and 9 as skin nociceptors that expressed nicotinic receptors. We conclude that at least three nicotinic AChR are diversely distributed into discrete subclasses of nociceptors that innervate hairy skin.

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Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)-epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain

Cited by 73 publications

References 5 publications

Study of the calcium dynamics of the human α4β2, α3β4 and α1β1γδ nicotinic acetylcholine receptors

Study of the calcium dynamics of the human α4β2, α3β4 and α1β1γδ nicotinic acetylcholine receptors

Nicotinic ACh receptors as therapeutic targets in CNS disorders

Nicotinic AChR in Subclassified Capsaicin-Sensitive and -Insensitive Nociceptors of the Rat DRG

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