The Experts below are selected from a list of 7788 Experts worldwide ranked by ideXlab platform
Palmer Taylor - One of the best experts on this subject based on the ideXlab platform.
-
nociceptive and antinociceptive responses to intrathecally administered Nicotinic Agonists
Neuropharmacology, 1998Co-Authors: Imran M Khan, Hartmut Buerkle, Palmer Taylor, Tony L YakshAbstract:Abstract Activation of spinal Nicotinic receptors evokes a prominent algogenic response. Recently, epibatidine, a potent Nicotinic Agonist, was found to display an antinociceptive response after systemic administration. To examine the spinal component of this action, effects of three Nicotinic Agonists—epibatidine, cytisine and nicotine—were given intrathecally (IT) and their antinociceptive activity was subsequently assessed. All agents elicited dose-dependent algogenic activity, characterized at lower doses by touch-evoked hyperactivity and at higher doses by intermittent vocalization and marked behavioral activity, with the rank order of potency being epibatidine>cytisine>nicotine. In addition, intrathecal epibatidine elicited a short-lasting, dose-dependent thermal antinociception. In contrast, the other Nicotinic Agonists at the highest usable dose failed to produce a significant antinociception. Mecamylamine, a Nicotinic channel blocker, completely abolished the antinociceptive and algogenic responses of epibatidine. The competitive antAgonist, α -lobeline, blocked both the analgesic and algogenic responses, but methyllycaconitine inhibited only the algogenic effects of epibatidine. Dihydro- β -erythroidine, also a competitive antAgonist, had no effect on the initial intense algogenic responses. The analgesic response to epibatidine was neither inhibited by naloxone nor by atropine. 2-Amino-5-phosphopentanoic acid, a competitive N -methyl- d -aspartate receptor antAgonist, did not affect the analgesic response to intrathecal epibatidine or the intense initial algogenic response. Upon repeated administration (30-min interval), epibatidine (1 μg, IT) exhibited marked and rapid desensitization to both the analgesic and algogenic responses which recovered within 8 h. Pretreatment with two consecutive doses of cytisine (5 μg, IT, 30-min apart) inhibited the agitation and analgesic actions of intrathecal epibatidine. Thus, we contend that in addition to the typical nociceptive response elicited by spinal Nicotinic Agonists, intrathecal epibatidine also exhibits a pronounced but short-lasting antinociception. The analgesic and algogenic responses to intrathecal epibatidine may be mediated by distinct subtypes of spinal Nicotinic receptors as suggested by the antAgonist studies.
-
epibatidine binding sites and activity in the spinal cord
Brain Research, 1997Co-Authors: Imran M Khan, Tony L Yaksh, Palmer TaylorAbstract:Epibatidine has been shown to be the most potent Nicotinic Agonist in several neuronal Nicotinic receptor preparations. Similar to other Nicotinic Agonists, intrathecal (-)-epibatidine elicits dose-dependent increases in pressor, heart rate and pain responses in rats, as well as an increase in latency to withdraw from a noxious thermal stimulus. The latter response requires higher doses and is of shorter duration, suggesting interaction with multiple subtypes of spinal Nicotinic receptors. In the present study, we relate the binding properties of (+/-)-[3H]epibatidine in spinal cord membrane preparations to the cardiovascular and behavioral responses. Unlike (-)-[3H]cytisine or (-)-[3H]nicotine, (+/-)-[3H]epibatidine reveals two sites; the ratio of high affinity to low affinity sites is 2:1. The rank ordering of potencies of the Nicotinic Agonists in displacing (+/-)-[3H]epibatidine binding from spinal cord membranes correlates with the potencies in eliciting cardiovascular and behavioral responses upon spinal administration. The Nicotinic receptor antAgonists, alpha-lobeline, dihydro-beta-erythroidine and methyllycaconitine, also displayed similar rank ordering of potencies in displacing (+/-)-[3H]epibatidine, (-)-[3H]cytisine or (-)-[3H]nicotine binding to spinal Nicotinic receptors. Virtually all the Nicotinic analogs exhibited a Hill coefficient of less than one in competing with (+/-)-[3H]epibatidine to spinal cord membranes indicating their interaction with at least two classes of binding sites. Intrathecal (-)-epibatidine, in addition to eliciting an initial and subsequently a sustained pressor and tachycardic response, also exhibited a transient intervening bradycardia which coincided temporally with the duration of the analgesia. Repeated administration of (-)-epibatidine desensitized its responses as well as the cardiovascular and behavioral responses to spinal nicotine and cytisine. Intrathecal alpha-lobeline showed selectivity for blocking the analgesic response, whereas methyllycaconitine exhibited selectivity for the pressor and irritation responses. The NMDA receptor antAgonist, AP-5, inhibited the pressor, tachycardic and irritation responses elicited by intrathecal (-)-epibatidine, confirming a role for spinal excitatory amino acids released by the Nicotinic Agonist.
Allan C. Collins - One of the best experts on this subject based on the ideXlab platform.
-
Increased Sensitivity to Agonist-Induced Seizures, Straub Tail, and Hippocampal Theta Rhythm in Knock-In Mice
2015Co-Authors: Carrying Hypersensitive, Allan C. Collins, Johannes Schwarz, Cesar Labarca, Nicotinic Receptors, Henry A. LesterAbstract:We studied a strain of exon replacement mice (“L9S knock-in”) whose4 Nicotinic receptor subunits have a leucine to serine mutation in the M2 region, 9 position (Labarca et al., 2001); this mutation renders 4-containing receptors hypersensitive to Agonists. Nicotine induced seizures at concentrations (1 mg/kg) approximately eight times lower in L9S than in wild-type (WT) littermates. At these concentrations, L9S but not WT showed increases in EEG amplitude and theta rhythm. L9S mice also showed higher seizure sensitivity to the Nicotinic Agonist epibatidine, but not to the GABAA receptor blocker and proconvulsant bicuculline. Dorsiflexion of the tail (Straub tail) was the most sensitive nicotine effect found in L9S mice (0.1 mg/kg). The L9S mice were hypersensitive to galanthamine- and tacrine-induced seizures and Straub tails. There were no apparent neuroanatomical differences between L9S and WT mice in several brain regions. [ 125I]Epibatidine binding to brain membranes showed that the mutant allele was expressed at 25 % of WT levels, presumably because of the presence of a neomycin selection cassette in a nearby intron. 86Rb efflux experiments on brain synaptosomes showed an increased fraction of function at low Agonist concentrations in L9S mice. These data support the possible involvement of gain-of-function 4 receptors in autosomal dominant nocturnal frontal-lobe epilepsy. Key words: Nicotinic receptor; ADNFLE; seizure; epilepsy; cholinergic; gain of function; knock-in; mous
-
increased sensitivity to Agonist induced seizures straub tail and hippocampal theta rhythm in knock in mice carrying hypersensitive α4 Nicotinic receptors
The Journal of Neuroscience, 2003Co-Authors: Carlos Fonck, Michael J. Marks, Allan C. Collins, Raad Nashmi, Purnima Deshpande, Imad M Damaj, Anett Riedel, Johannes Schwarz, Cesar LabarcaAbstract:We studied a strain of exon replacement mice ("L9'S knock-in") whose alpha4 Nicotinic receptor subunits have a leucine to serine mutation in the M2 region, 9' position (Labarca et al., 2001); this mutation renders alpha4-containing receptors hypersensitive to Agonists. Nicotine induced seizures at concentrations (1 mg/kg) approximately eight times lower in L9'S than in wild-type (WT) littermates. At these concentrations, L9'S but not WT showed increases in EEG amplitude and theta rhythm. L9'S mice also showed higher seizure sensitivity to the Nicotinic Agonist epibatidine, but not to the GABA(A) receptor blocker and proconvulsant bicuculline. Dorsiflexion of the tail (Straub tail) was the most sensitive nicotine effect found in L9'S mice (0.1 mg/kg). The L9'S mice were hypersensitive to galanthamine- and tacrine-induced seizures and Straub tails. There were no apparent neuroanatomical differences between L9'S and WT mice in several brain regions. [(125)I]Epibatidine binding to brain membranes showed that the mutant allele was expressed at approximately 25% of WT levels, presumably because of the presence of a neomycin selection cassette in a nearby intron. (86)Rb efflux experiments on brain synaptosomes showed an increased fraction of function at low Agonist concentrations in L9'S mice. These data support the possible involvement of gain-of-function alpha4 receptors in autosomal dominant nocturnal frontal-lobe epilepsy.
-
characterization of 125i epibatidine binding and Nicotinic Agonist mediated 86rb efflux in interpeduncular nucleus and inferior colliculus of β2 null mutant mice
Journal of Neurochemistry, 2002Co-Authors: Michael J. Marks, Paul Whiteaker, Sharon R Grady, Michael J Mcintosh, Marina R. Picciotto, Allan C. CollinsAbstract:The beta2 Nicotinic acetylcholine receptor subunit null mutation eliminated most high affinity [(3) H]epibatidine binding in mouse brain, but significant binding remained in accessory olfactory nucleus, medial habenula, inferior colliculus and interpeduncular nucleus. Residual [(125) I]epibatidine binding sites in the inferior colliculus and interpeduncular nucleus were subsequently characterized. Inhibition of [(125) I]epibatidine binding by 12 Agonists and six antAgonists was very similar in these regions. Most acetylcholine-stimulated (86) Rb(+) efflux is eliminated in thalamus and superior colliculus of beta2 null mutants, but significant activity remained in inferior colliculus and interpeduncular nucleus. This residual activity was subsequently characterized. The 12 Nicotinic Agonists tested elicited concentration-dependent (86) Rb(+) efflux. Epibatidine was the most potent Agonist. Cytisine was also potent and efficacious. EC(50) values for quaternary Agonists were relatively high. Cytisine-stimulated (86) Rb(+) efflux was inhibited by six classical Nicotinic antAgonists. Mecamylamine and D-tubocurarine were most potent, while decamethonium was the least potent. Agonists and antAgonists exhibited similar potency in both brain regions. Alpha-bungarotoxin (100 nm) did not significantly inhibit cytisine-stimulated (86) Rb(+) efflux, while the alpha3beta4 selective antAgonist, alphaConotoxinAuIB, inhibited a significant fraction of the response in both brain regions. Thus, beta2 null mutant mice express residual Nicotinic activity with properties resembling those of alpha3beta4*-nAChR.
-
ub 165 a novel Nicotinic Agonist with subtype selectivity implicates the α4β2 subtype in the modulation of dopamine release from rat striatal synaptosomes
The Journal of Neuroscience, 2000Co-Authors: Christopher G V Sharples, Michael J. Marks, Allan C. Collins, Timothy Gallagher, Sergio Kaiser, L Soliakov, Mark S Washburn, Emma Wright, James Spencer, Paul WhiteakerAbstract:Presynaptic Nicotinic acetylcholine receptors (nAChRs) on striatal synaptosomes stimulate dopamine release. Partial inhibition by the α3β2-selective α-conotoxin-MII indicates heterogeneity of presynaptic nAChRs on dopamine terminals. We have used this α-conotoxin and UB-165, a novel hybrid of epibatidine and anatoxin-a, to address the hypothesis that the α-conotoxin-MII-insensitive subtype is composed of α4 and β2 subunits. UB-165 shows intermediate potency, compared with the parent molecules, at α4β2* and α3-containing binding sites, and resembles epibatidine in its high discrimination of these sites over α7-type and muscle binding sites. (±)-Epibatidine, (±)-anatoxin-a, and (±)-UB-165 stimulated [3H]-dopamine release from striatal synaptosomes with EC50 values of 2.4, 134, and 88 nm, and relative efficacies of 1:0.4:0.2, respectively. α-Conotoxin-MII inhibited release evoked by these Agonists by 48, 56, and 88%, respectively, suggesting that (±)-UB-165 is a very poor Agonist at the α-conotoxin-MII-insensitive nAChR subtype. In assays of 86Rb+ efflux from thalamic synaptosomes, a model of an α4β2* nAChR response, (±)-UB-165 was a very weak partial Agonist; the low efficacy of (±)-UB-165 at α4β2 nAChR was confirmed in Xenopus oocytes expressing various combinations of human nAChR subunits. In contrast, (±)-UB-165 and (±)-anatoxin-a were similarly efficacious and similarly sensitive to α-conotoxin-MII in increasing intracellular Ca2+ in SH-SY5Y cells, a functional assay for native α3-containing nAChR. These data support the involvement of α4β2* nAChR in the presynaptic modulation of striatal dopamine release and illustrate the utility of exploiting a novel partial Agonist, together with a selective antAgonist, to dissect the functional roles of nAChR subtypes in the brain.
Imran M Khan - One of the best experts on this subject based on the ideXlab platform.
-
nociceptive and antinociceptive responses to intrathecally administered Nicotinic Agonists
Neuropharmacology, 1998Co-Authors: Imran M Khan, Hartmut Buerkle, Palmer Taylor, Tony L YakshAbstract:Abstract Activation of spinal Nicotinic receptors evokes a prominent algogenic response. Recently, epibatidine, a potent Nicotinic Agonist, was found to display an antinociceptive response after systemic administration. To examine the spinal component of this action, effects of three Nicotinic Agonists—epibatidine, cytisine and nicotine—were given intrathecally (IT) and their antinociceptive activity was subsequently assessed. All agents elicited dose-dependent algogenic activity, characterized at lower doses by touch-evoked hyperactivity and at higher doses by intermittent vocalization and marked behavioral activity, with the rank order of potency being epibatidine>cytisine>nicotine. In addition, intrathecal epibatidine elicited a short-lasting, dose-dependent thermal antinociception. In contrast, the other Nicotinic Agonists at the highest usable dose failed to produce a significant antinociception. Mecamylamine, a Nicotinic channel blocker, completely abolished the antinociceptive and algogenic responses of epibatidine. The competitive antAgonist, α -lobeline, blocked both the analgesic and algogenic responses, but methyllycaconitine inhibited only the algogenic effects of epibatidine. Dihydro- β -erythroidine, also a competitive antAgonist, had no effect on the initial intense algogenic responses. The analgesic response to epibatidine was neither inhibited by naloxone nor by atropine. 2-Amino-5-phosphopentanoic acid, a competitive N -methyl- d -aspartate receptor antAgonist, did not affect the analgesic response to intrathecal epibatidine or the intense initial algogenic response. Upon repeated administration (30-min interval), epibatidine (1 μg, IT) exhibited marked and rapid desensitization to both the analgesic and algogenic responses which recovered within 8 h. Pretreatment with two consecutive doses of cytisine (5 μg, IT, 30-min apart) inhibited the agitation and analgesic actions of intrathecal epibatidine. Thus, we contend that in addition to the typical nociceptive response elicited by spinal Nicotinic Agonists, intrathecal epibatidine also exhibits a pronounced but short-lasting antinociception. The analgesic and algogenic responses to intrathecal epibatidine may be mediated by distinct subtypes of spinal Nicotinic receptors as suggested by the antAgonist studies.
-
mechanism of action of chromogranin a on catecholamine release molecular modeling of the catestatin region reveals a β strand loop β strand structure secured by hydrophobic interactions and predictive of activity
Regulatory Peptides, 1998Co-Authors: I Tsigelny, L Taupenot, Imran M Khan, N E Preece, Daniel T OconnorAbstract:Abstract A novel fragment of chromogranin A, known as `catestatin' (bovine chromogranin A 344–364 ), inhibits catecholamine release from chromaffin cells and noradrenergic neurons by acting as a non-competitive Nicotinic cholinergic antAgonist, and may therefore constitute an endogenous autocrine feedback regulator of sympathoadrenal activity. To characterize how this activity depends on the peptide's structure, we searched for common 3-dimensional motifs for this primary structure or its homologs. Catestatin's primary structure bore significant (29–35.5% identity, general alignment score 44–57) sequence homology to fragment sequences within three homologs of known 3-dimensional structures, based on solved X-ray crystals: 8FAB, 1PKM, and 2IG2. Each of these sequences exists in nature as a β-strand/loop/β-strand structure, stabilized by hydrophobic interactions between the β-strands. The catestatin structure was stable during molecular dynamics simulations. The catestatin loop contains three Arg residues, whose electropositive side chains form the terminus of the structure, and give rise to substantial uncompensated charge asymmetry in the molecule. A hydrophobic moment plot revealed that catestatin is the only segment of chromogranin A predicted to contain amphiphilic β-strand. Circular dichroism in the far ultraviolet showed substantial (63%) β-sheet structure, especially in a hydrophobic environment. Alanine-substitution mutants of catestatin established a crucial role for the three central arginine residues in the loop (Arg 351 , Arg 353 , and Arg 358 ), though not for two arginine residues in the strand region toward the amino-terminus. [ 125 I]Catestatin bound to Torpedo membranes at a site other than the Nicotinic Agonist binding site. When the catestatin structure was `docked' with the extracellular domain of the Torpedo Nicotinic cholinergic receptor, it interacted principally with the β and δ subunits, in a relatively hydrophobic region of the cation pore extracellular orifice, and the complex of ligand and receptor largely occluded the cation pore, providing a structural basis for the non-competitive Nicotinic cholinergic antAgonist properties of the peptide. We conclude that a homology model of catestatin correctly predicts actual features of the peptide, both physical and biological. The model suggests particular spatial and charge features of the peptide which may serve as starting points in the development of non-peptide mimetics of this endogenous Nicotinic cholinergic antAgonist.
-
epibatidine binding sites and activity in the spinal cord
Brain Research, 1997Co-Authors: Imran M Khan, Tony L Yaksh, Palmer TaylorAbstract:Epibatidine has been shown to be the most potent Nicotinic Agonist in several neuronal Nicotinic receptor preparations. Similar to other Nicotinic Agonists, intrathecal (-)-epibatidine elicits dose-dependent increases in pressor, heart rate and pain responses in rats, as well as an increase in latency to withdraw from a noxious thermal stimulus. The latter response requires higher doses and is of shorter duration, suggesting interaction with multiple subtypes of spinal Nicotinic receptors. In the present study, we relate the binding properties of (+/-)-[3H]epibatidine in spinal cord membrane preparations to the cardiovascular and behavioral responses. Unlike (-)-[3H]cytisine or (-)-[3H]nicotine, (+/-)-[3H]epibatidine reveals two sites; the ratio of high affinity to low affinity sites is 2:1. The rank ordering of potencies of the Nicotinic Agonists in displacing (+/-)-[3H]epibatidine binding from spinal cord membranes correlates with the potencies in eliciting cardiovascular and behavioral responses upon spinal administration. The Nicotinic receptor antAgonists, alpha-lobeline, dihydro-beta-erythroidine and methyllycaconitine, also displayed similar rank ordering of potencies in displacing (+/-)-[3H]epibatidine, (-)-[3H]cytisine or (-)-[3H]nicotine binding to spinal Nicotinic receptors. Virtually all the Nicotinic analogs exhibited a Hill coefficient of less than one in competing with (+/-)-[3H]epibatidine to spinal cord membranes indicating their interaction with at least two classes of binding sites. Intrathecal (-)-epibatidine, in addition to eliciting an initial and subsequently a sustained pressor and tachycardic response, also exhibited a transient intervening bradycardia which coincided temporally with the duration of the analgesia. Repeated administration of (-)-epibatidine desensitized its responses as well as the cardiovascular and behavioral responses to spinal nicotine and cytisine. Intrathecal alpha-lobeline showed selectivity for blocking the analgesic response, whereas methyllycaconitine exhibited selectivity for the pressor and irritation responses. The NMDA receptor antAgonist, AP-5, inhibited the pressor, tachycardic and irritation responses elicited by intrathecal (-)-epibatidine, confirming a role for spinal excitatory amino acids released by the Nicotinic Agonist.
Roger L Papke - One of the best experts on this subject based on the ideXlab platform.
-
modulation of inhibitory synaptic activity by a non α4β2 non α7 subtype of Nicotinic receptors in the substantia gelatinosa of adult rat spinal cord
Pain, 2003Co-Authors: Daisuke Takeda, Terumasa Nakatsuka, Roger L PapkeAbstract:The GABA/glycine-mediated inhibitory activity in the substantia gelatinosa (SG) of the spinal cord is critical in the control of nociceptive transmission. We examined whether and how SG inhibitory activity might be regulated by neuronal Nicotinic receptors (nAChRs). Patchclamp recordings were performed in SG neurons of spinal slice preparations from adult rats. We provided electrophysiological evidence that inhibitory presynaptic terminals in the SG expressed nAChRs and their activation resulted in large increases in the frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in over 90% SG neurons tested. The enhancement of inhibitory activity was mediated by increases in the release of GABA/glycine, and direct Ca 21 entry through SG presynaptic nAChRs appeared to be involved. Miniature IPSC frequency could be enhanced by the nAChR Agonists nicotine or cytisine. Nicotine could still elicit large increases in mIPSC frequency in the presence of the a4b2 nAChR antAgonist dihydro-beta-erythroidine (5 mM) and the a7 nAChR-selective antAgonist methyllycaconitine (40 nM). However, nicotine did not produce a significant enhancement of mIPSC frequency in the presence of the broad spectrum nAChR antAgonist mecamylamine (5 mM). Nicotinic Agonist-evoked whole-cell currents from SG neurons and the antAgonist profiles also indicated the presence of a subtype of nAChRs, which were different from the major central nervous system nAChR subtypes, i.e. a4b2* or a7 nAChRs. Together, our results suggest that a subtype of nAChR, possibly a3b4* nAChR or a new nAChR type, is highly expressed at the inhibitory presynaptic terminals in SG of adult rats and play a role in the control of inhibitory activity in SG. q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
-
characterization of a series of anabaseine derived compounds reveals that the 3 4 dimethylaminocinnamylidine derivative is a selective Agonist at neuronal Nicotinic alpha 7 125i alpha bungarotoxin receptor subtypes
Molecular Pharmacology, 1995Co-Authors: C M De Fiebre, William R Kem, Edwin M Meyer, J C Henry, S I Muraskin, Roger L PapkeAbstract:Investigation of the naturally occurring, Nicotinic Agonist anabaseine and novel derivatives has shown that these compounds have cytoprotective and memory-enhancing effects. The hypothesis that these arise at least in part through actions on brain Nicotinic receptors was evaluated by examining the ability of these compounds to displace the binding of Nicotinic ligands and to affect the function of the alpha 4 beta 2 and alpha 7 receptor subtypes expressed in Xenopus oocytes. The derivative 3-(4)-dimethylaminocinnamylidine anabaseine (DMAC) was found to be a selective alpha 7 receptor Agonist; it was more potent than nicotine, acetylcholine, anabaseine, and other derivatives at activating the alpha 7 receptor subtype, while displaying little Agonist activity at alpha 4 beta 2 and other receptor subtypes. Compared with anabaseine and the other derivatives, DMAC was the most potent at displacing 125I-alpha-bungarotoxin binding (putative alpha 7) and the least potent at displacing [3H]cytisine binding (putative alpha 4 beta 2) to brain membranes. Independently of Agonist activities, all of the novel compounds displayed secondary inhibitory activity at both receptor subtypes. At the alpha 4 beta 2 receptor subtype, inhibition by the 3-(2,4)-dimethoxybenzylidene derivative was enhanced by coapplication of acetylcholine, suggesting a noncompetitive form of inhibition. Anabaseine and nicotine prolonged the time course of activation of alpha 4 beta 2 receptors, compared with acetylcholine, suggesting sequential channel-blocking activity. As selective Agonists, anabaseine derivatives such as DMAC may be useful for elucidating the function of alpha 7 Nicotinic receptors, including their potential role(s) in the cytoprotective and memory-enhancing effects of Nicotinic agents.
Tony L Yaksh - One of the best experts on this subject based on the ideXlab platform.
-
nociceptive and antinociceptive responses to intrathecally administered Nicotinic Agonists
Neuropharmacology, 1998Co-Authors: Imran M Khan, Hartmut Buerkle, Palmer Taylor, Tony L YakshAbstract:Abstract Activation of spinal Nicotinic receptors evokes a prominent algogenic response. Recently, epibatidine, a potent Nicotinic Agonist, was found to display an antinociceptive response after systemic administration. To examine the spinal component of this action, effects of three Nicotinic Agonists—epibatidine, cytisine and nicotine—were given intrathecally (IT) and their antinociceptive activity was subsequently assessed. All agents elicited dose-dependent algogenic activity, characterized at lower doses by touch-evoked hyperactivity and at higher doses by intermittent vocalization and marked behavioral activity, with the rank order of potency being epibatidine>cytisine>nicotine. In addition, intrathecal epibatidine elicited a short-lasting, dose-dependent thermal antinociception. In contrast, the other Nicotinic Agonists at the highest usable dose failed to produce a significant antinociception. Mecamylamine, a Nicotinic channel blocker, completely abolished the antinociceptive and algogenic responses of epibatidine. The competitive antAgonist, α -lobeline, blocked both the analgesic and algogenic responses, but methyllycaconitine inhibited only the algogenic effects of epibatidine. Dihydro- β -erythroidine, also a competitive antAgonist, had no effect on the initial intense algogenic responses. The analgesic response to epibatidine was neither inhibited by naloxone nor by atropine. 2-Amino-5-phosphopentanoic acid, a competitive N -methyl- d -aspartate receptor antAgonist, did not affect the analgesic response to intrathecal epibatidine or the intense initial algogenic response. Upon repeated administration (30-min interval), epibatidine (1 μg, IT) exhibited marked and rapid desensitization to both the analgesic and algogenic responses which recovered within 8 h. Pretreatment with two consecutive doses of cytisine (5 μg, IT, 30-min apart) inhibited the agitation and analgesic actions of intrathecal epibatidine. Thus, we contend that in addition to the typical nociceptive response elicited by spinal Nicotinic Agonists, intrathecal epibatidine also exhibits a pronounced but short-lasting antinociception. The analgesic and algogenic responses to intrathecal epibatidine may be mediated by distinct subtypes of spinal Nicotinic receptors as suggested by the antAgonist studies.
-
epibatidine binding sites and activity in the spinal cord
Brain Research, 1997Co-Authors: Imran M Khan, Tony L Yaksh, Palmer TaylorAbstract:Epibatidine has been shown to be the most potent Nicotinic Agonist in several neuronal Nicotinic receptor preparations. Similar to other Nicotinic Agonists, intrathecal (-)-epibatidine elicits dose-dependent increases in pressor, heart rate and pain responses in rats, as well as an increase in latency to withdraw from a noxious thermal stimulus. The latter response requires higher doses and is of shorter duration, suggesting interaction with multiple subtypes of spinal Nicotinic receptors. In the present study, we relate the binding properties of (+/-)-[3H]epibatidine in spinal cord membrane preparations to the cardiovascular and behavioral responses. Unlike (-)-[3H]cytisine or (-)-[3H]nicotine, (+/-)-[3H]epibatidine reveals two sites; the ratio of high affinity to low affinity sites is 2:1. The rank ordering of potencies of the Nicotinic Agonists in displacing (+/-)-[3H]epibatidine binding from spinal cord membranes correlates with the potencies in eliciting cardiovascular and behavioral responses upon spinal administration. The Nicotinic receptor antAgonists, alpha-lobeline, dihydro-beta-erythroidine and methyllycaconitine, also displayed similar rank ordering of potencies in displacing (+/-)-[3H]epibatidine, (-)-[3H]cytisine or (-)-[3H]nicotine binding to spinal Nicotinic receptors. Virtually all the Nicotinic analogs exhibited a Hill coefficient of less than one in competing with (+/-)-[3H]epibatidine to spinal cord membranes indicating their interaction with at least two classes of binding sites. Intrathecal (-)-epibatidine, in addition to eliciting an initial and subsequently a sustained pressor and tachycardic response, also exhibited a transient intervening bradycardia which coincided temporally with the duration of the analgesia. Repeated administration of (-)-epibatidine desensitized its responses as well as the cardiovascular and behavioral responses to spinal nicotine and cytisine. Intrathecal alpha-lobeline showed selectivity for blocking the analgesic response, whereas methyllycaconitine exhibited selectivity for the pressor and irritation responses. The NMDA receptor antAgonist, AP-5, inhibited the pressor, tachycardic and irritation responses elicited by intrathecal (-)-epibatidine, confirming a role for spinal excitatory amino acids released by the Nicotinic Agonist.
