![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEUROPHARMACOLOGY
Department of Pharmacology and Toxicology, Medical Campus, Virginia Commonwealth University, Richmond, Virginia
Received for publication
July 21, 2006
Accepted
October 12, 2006.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
2 nicotinic receptor subunit plays a central role in nicotine-induced spinal antinociception via calcium/calmodulin-dependent calmodulin protein kinase II activation. The antinociceptive effects of i.t. nicotine in the tail-flick test did not significantly differ in wild-type and 
7 knockout (KO) animals but were lost in 2 knockout mice. When calcium/calmodulin-dependent calmodulin protein kinase II activity in the lumbar spinal cord after acute i.t. administration of nicotine was investigated in wild-type and 2 and 7 knockout mice, the increase in calcium/calmodulin-dependent calmodulin protein kinase II activity was not significant reduced in 7 KO mice but was eliminated in the 2 KO mice. In addition, L-type calcium channel blockers nimodipine and verapamil but not the N-methyl-D-aspartate antagonist MK-801 (dizocilpine maleate) blocked the increase in the kinase activity induced by nicotine. Taken together, these results are consistent with the hypothesis that increases in intracellular calcium result in activation of calcium-mediated second messengers in the spinal cord that play an important role in nicotine-induced antinociception as measured in the tail-flick test. Furthermore, our findings indicate that nicotinic stimulation of 2-containing acetylcholine nicotinic receptors in the spinal cord can activate calcium/calmodulin-dependent calmodulin protein kinase II and produce nicotinic analgesia, which may require L-type calcium voltage and gated channels but not the intervention of glutamatergic transmission.
; Aceto et al., 1986). There is strong evidence that the antinociceptive effect of nicotine can occur via activation of nAChRs expressed in a variety of brain loci and spinal cord (Mattila et al., 1968; Aceto et al., 1986; Iwamato, 1991; Iwamoto and Marion, 1993; Khan et al., 1997; Damaj et al., 1998; Scott Bitner et al., 1998). Furthermore, nicotinic agonists have well documented antinociceptive properties when administered i.t. in mice (Damaj et al., 1998). Studies with knockout mice deficient in the 4 and 2 nicotinic acetylcholine receptor subunits suggest an important role of 42 neuronal subtypes in nicotine-induced antinociception in acute pain models such as the hot-plate and tail-flick tests (Marubio et al., 1999). More recently, Cordero-Erausquin et al. (2004), using electrophysiological and molecular approaches, identified spinal 42* and 32* neuronal subtypes as possible targets for nicotinic analgesia. However, the molecular characterization of this nicotinic effect at the spinal cord is still largely unknown. Activation of calcium-dependent signaling mechanisms seems a plausible target. Studies with peripheral and central preparations showed that significant amounts of Ca2+ enter the cell following activation of certain nAChRs such as 2 and 7 subtypes, causing a rise in [Ca2+]i concentration (Fluhler et al., 1992; Mulle et al., 1992; Vijayaraghavan et al., 1992; Barrantes et al., 1994). We recently reported that nicotine increases [Ca2+]i levels in spinal synaptosomes and elevates calcium-dependent calmodulin protein kinase II activity in the spinal cord membrane after acute systemic injection in mice (Damaj, 2000). In addition, calcium/calmodulin-dependent calmodulin protein kinase II inhibitors blocked nicotine's effects in the tail-flick test in a dose-related manner. Collectively, these studies provide strong evidence that nicotinic receptor-mediated antinociception at the spinal level involves a calcium-dependent protein kinase, namely calcium/calmodulin-dependent calmodulin protein kinase II.
The present study was undertaken to examine and characterize the effect of acute nicotine exposure on the activity of calcium/calmodulin-dependent calmodulin protein kinase II in the spinal cord and investigate whether the regulation of calcium/calmodulin-dependent calmodulin protein kinase II by nicotine occurs directly through nAChRs or indirectly through NMDA receptors or L-type calcium channels. We first investigated the effects of i.t. injection of acute nicotine on calcium/calmodulin-dependent calmodulin protein kinase II activity in the lumbar spinal cord, a region that contains the dorsal horn, which plays an important role in modulating nociceptive transmission. We then determined the time course of changes in calcium/calmodulin-dependent calmodulin protein kinase II activity after nicotine administration. Investigation of the role of major nicotinic subtypes (2 and 7 nAChRs subtypes) in nicotine-induced changes in calcium/calmodulin-dependent calmodulin protein kinase II followed using two approaches for this characterization: classic pharmacological methods (use of nicotinic antagonists) and genetically modified mice (2 and 7 knockout mice). After characterizing the changes in calcium/calmodulin-dependent calmodulin protein kinase II in the spinal cord, we finally investigated the role of L-type calcium channels and NMDA receptors in nicotine-induced calcium/calmodulin-dependent calmodulin protein kinase II activation.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
7 nicotinic receptor (C57BL/6 background) and wild-type littermates were purchased from The Jackson Laboratories (Bar Harbor, ME; B6.129S7-charna7tm1bay, no. 003232). Breeding pairs of mice lacking the 2 nicotinic receptor (C57BL/6 background) and wild-type littermates were shipped from Institut Pasteur (Paris, France). Homozygous 7 and 2 mutant and wild-type controls were obtained from crossing heterozygote mice. Male mice approximately 8 to 12 weeks old (together with age- and sex-matched littermates wild-type controls) were used for the kinase experiments. Animals were housed in an Association for Assessment and Accreditation of Laboratory Animal Care-approved facility in groups of three and had free access to food and water. Animals were housed in an Association for Assessment and Accreditation of Laboratory Animal Care-approved facility, and the study was approved by the Institutional Animal Care and Use Committee of Virginia Commonwealth University.
Drugs. MK-801, verapamil hydrochloride, -bungarotoxin (-BGTX), methyllycaconitine (MLA), and dihydro--erythroidine were purchased from RBI (Natick, MA). Nimodipine was a gift from Miles, Inc. (West Haven, CT), and mecamylamine hydrochloride was a gift from Merck, Sharp and Dohme and Co. (West Point, PA). MLA citrate, dihydro--erythroidine mecamylamine HCl, and verapamil hydrochloride were dissolved in physiological saline (0.9% sodium chloride). Nimodipine was prepared in dimethyl sulfoxide, and its solutions were refrigerated in foil-lined containers. (–)-Nicotine was obtained from Aldrich Chemical Company, Inc. (Milwaukee, WI) and converted to the ditartrate salt as described by Aceto et al. (1979). All doses are expressed as the free base of the drug.
Intrathecal Injections. Intrathecal injections were performed free-hand between the L5 and L6 lumbar space in unanesthetized male mice according to the method of Hylden and Wilcox (1980). The injection was performed using a 30-gauge needle attached to a glass microsyringe. The injection volume in all cases was 5 µl. The accurate placement of the needle was evidenced by a quick "flick" of the mouse's tail. In protocols where two sequential injections were required in an animal, the flicking motion of the tail could be elicited with the subsequent injection.
Antinociceptive Assay. Antinociception was assessed by the tail-flick method of D'Amour and Smith (1941). In brief, mice were lightly restrained whereas a radiant heat source was shone onto the upper portion of the tail. Latency to remove the tail from the heat source was recorded for each animal. A control response (2–4 s) was determined for each mouse before treatment, and test latency was determined after drug administration. To minimize tissue damage, a maximal latency of 10 s was imposed. Antinociceptive response was calculated as percent maximal possible effect (%MPE), where %MPE = [(test – control)/(10 – control)] x 100. The mice were tested 5 min after i.t. injection of nicotine. The mice were tested 5 min after i.t. injection of nicotine. Antagonism studies were carried out by pretreating the mice with either i.t. saline or nicotinic antagonists 5 min before nicotine (20 µg/mouse). The animals were tested 5 min after administration of nicotine. Nimodipine (1 µg/mouse), mecamylamine (20 µg/mouse), -BGTX (2 µg/mouse), and dihydro--erythroidine (20 µg/mouse) doses were based on previously published i.t. administered doses of these antagonists (Damaj et al., 1995; Damaj, 2000). Because of recent reports questioning the receptor selectivity of MLA, the investigation of the role of spinal 7 nicotinic receptors in our behavioral and biochemical studies was carried out using MLA and -BGTX, a selective 7 antagonist with poor blood-brain barrier penetration. The MLA dose (7.5 mg/kg s.c.) was within the range reported to block 7 nicotinic receptors after systemic injection (Turek et al., 1995). The MK-801 (2.5 µg/mouse) dose was based on published studies that determined the most effective i.t. doses for blocking NMDA nociceptive effects (Suh et al., 1995; Suh et al., 2000). Groups of six to eight animals were used for each dose and for each treatment.
Calcium/Calmodulin-Dependent Calmodulin Protein Kinase II Phosphorylation Assays. Calcium/calmodulin-dependent calmodulin protein kinase II activity was measured using a modified assay kit (Upstate Biotechnology, Lake Placid, NY). In brief, at different times following experimental treatment, mice were killed by cervical dislocation, and the spinal column was isolated and divided in thoracic, cervical, and lumbar regions. The lumbar segment of spinal cord was removed from the spinal column by gentle flushing with ice-cold, isotonic saline. Lumbar spinal cord tissues were homogenized using a microcentrifuge pestle in a calcium-free buffer that contains 20 mM HEPES, pH 7.4, 2.6 mM EGTA, 80 mM -glycerolphosphate, 20 mM magnesium acetate, 0.1 µM okadaic acid, 0.1 µM calyculin, 0.1 mM dithiothreitol, 50 mM sodium fluoride, 1 mM sodium orthovanadate, and 0.01 mg/ml CLAPS (0.1 mg/ml each pepstatin A, chymostatin, aprotinin, leupeptin, trypsin-chymotrypsin inhibitor). Homogenates were normalized for protein concentration. Samples were centrifuged to separate the membrane and the cytosol-containing kinase. The pellet was resuspended in homogenization buffer plus 1% NP-40 (octylphenoxypolyethoxyethanol) and allowed to incubate on ice 1 h. The tubes were spun again, and supernatant was retained (membrane fraction). Standard phosphorylation reaction solutions contain 15 µg of extract protein, 100 µM calcium/calmodulin-dependent calmodulin protein kinase II -specific substrate peptide (Autocamtide-2), 0.25 µM protein kinase inhibitors (0.25 µM each of protein kinase A and protein kinase C inhibitor peptides), 75 mM magnesium acetate, 500 µM ATP, 20 mM HEPES, 25 mM -glycerolphosphate, 1 mM sodium orthovanadate, 1 mM dithiothreitol, 1 µCi of [32P]ATP, 5 µM CaCl2, and 5 µg of calmodulin for the measurement of calcium-dependent activity. In aliquots used for calcium-independent activity, 5 mM EGTA was added, and CaCl2 and calmodulin were omitted. Standard reactions were performed in triplicate in a shaking water bath at 30°C for 10 min along with background controls lacking substrate. Activity was quantified by spotting half the reaction on phosphocellulose paper squares. Squares were washed in 0.75% phosphoric acid (five times) followed by a brief acetone rinse before analysis by scintillation counting. Calcium/calmodulin-dependent calmodulin protein kinase II activity was expressed in picomoles phosphate per minute per microgram and determined using the following calculations: [(count-specific binding – background) x (correcting factor)]/[(specific radioactivity) x time (10 min)].
|
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
A dose-response relationship was then established for nicotine in mice by measuring both calcium-dependent and -independent calmodulin protein kinase II activity at the time of maximal effect. As shown in Fig. 2, a dose-dependent increase in the membrane kinase activity was seen after acute injection of nicotine. The increase in the kinase activity induced by nicotine was blocked by mecamylamine pretreatment (Table 1). These results are consistent with the notion that calmodulin protein kinase II activation after acute nicotine exposure is a receptor-mediated event.
|
|
Nicotine-Induced Antinociception in 2 and 7 Knockout Mice after i.t. Injection. The antinociceptive effects of i.t. nicotine in the tail-flick test are shown in Fig. 3. The control latency response to painful stimuli did not significantly differ in wild-type and knockout animals indicating that the endogenous activation of the 2 and 7 nAChR subunit is not essential in the perception of acute thermal nociception (data not shown). Nicotine given at a dose of 20 µg/mouse showed a 87 ± 7%MPE in wild-type and 90 ± 5%MPE in –/–7 mice. In contrast, –/–2 mice did not exhibit a significant antinociceptive response to nicotine (Fig. 3).
|
2 and 7 Knockout Mice and after i.t. Injection of Nicotine. The activity of calcium/calmodulin-dependent calmodulin protein kinase II in the spinal cord after acute i.t. administration of nicotine in mice was investigated in wild-type and 2 and 7 knockout mice. Animals received either saline or nicotine (20 µg/mouse i.t.) and were sacrificed 15 min after injection. Spinal cord tissues were dissected, and the calcium-dependent and -independent activity of calcium/calmodulin-dependent calmodulin protein kinase II in the membrane was measured. As shown in Fig. 4, A and B, a significant increase in both dependent and independent kinase activity was seen after acute injection of nicotine in wild-type mice. This increase in calcium/calmodulin-dependent calmodulin protein kinase II activity was not significantly reduced in 7 KO mice but was eliminated in the 2 KO mice. The increase in the kinase activity induced by nicotine was blocked by mecamylamine and dihydro--erythroidine, but not MLA and -BGTX pretreatment (Table 1). By themselves, nicotinic antagonists did not cause any significant change in calcium/calmodulin-dependent calmodulin protein kinase II activity at the indicated doses and times (data not shown).
|
Effects of Calcium Channel Blockers and an NMDA Antagonist on the Nicotine-Induced Increase in Spinal Calcium/Calmodulin-Dependent Calmodulin Protein Kinase II Activity in Mice. To further investigate the regulation of calcium/calmodulin-dependent calmodulin protein kinase II activation by nicotine, various L-type calcium channels inhibitors and an NMDA antagonist were evaluated for their ability to alter the increase in spinal calcium/calmodulin-dependent calmodulin protein kinase II activity induced by nicotine. Nimodipine and verapamil, L-type calcium channels inhibitors, given i.t. inhibited the increase in both dependent and independent calcium/calmodulin-dependent calmodulin protein kinase II activity (Fig. 5). In contrast, the NMDA antagonist MK-801 failed to statistically reduce calcium/calmodulin-dependent calmodulin protein kinase II activation. By themselves, these antagonists did not cause any significant change in calcium/calmodulin-dependent calmodulin protein kinase II (data not shown).
|
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
). In addition, selective calcium/calmodulin-dependent calmodulin protein kinase II inhibitors in the spinal cord blocked nicotine-induced antinociception in the tail-flick test. These results suggested that spinally located calcium/calmodulin-dependent calmodulin protein kinase II might be involved in the modulation of nicotine-induced antinociception. In the present study, we found that spinally injected nicotine directly activates calcium/calmodulin-dependent calmodulin protein kinase II in the lumbar spinal cord section, a region that contains the dorsal horn, which plays an important role in modulating nociceptive transmission. The difference in kinetics for the increase in Ca2+-dependent compared with Ca2+-independent activity shows a delay in the increase in the autonomous activity of the enzyme. This delay may reflect the "switch" from the activated to the autonomous form. It is possible also that nicotine induced a shift of autonomous calmodulin protein kinase II to the membrane. However, no significant decrease in the activity of the enzyme in the cytosolic fraction was observed as well as in the total amount of the enzyme (data not shown).
The increase in calcium/calmodulin-dependent calmodulin protein kinase II activity was blocked by mecamylamine, a nonselective nicotinic antagonist, suggesting the involvement of spinal nAChRs in this effect. It is interesting to note that the increase in calcium/calmodulin-dependent calmodulin protein kinase II activity in the spinal cord was sustained until at least 60 to 120 min after a single injection of nicotine (Fig. 1). This sustained activation could potentially have important pharmacological and molecular consequences since calcium/calmodulin-dependent calmodulin protein kinase II is a key element in neuronal plasticity and in calcium-dependent neurotransmitter release. In addition, this extended time course is consistent with an initiation of neuronal plasticity in some supraspinal regions of the brain as reported in the VTA after an acute exposure to nicotine (Mansvelder and McGehee, 2002; Mansvelder et al., 2003).
Although the behavioral results in our study confirm a previously reported role for 2 subunits in nicotine-induced antinociception, our data suggest a calcium-dependent kinase molecular mechanism mediating the activation of the 2-containing receptor subtype. We now propose that calcium/calmodulin-dependent calmodulin protein kinase II activation in the spinal cord mediates nicotine's antinociceptive effects through the activation of 2- but not 7-containing nAChRs. Although calcium/calmodulin-dependent calmodulin protein kinase II has long been reported as a calcium-dependent kinase in memory and learning, more recently, this kinase was reported to have important roles in nociceptive signaling (Willis, 2001).
Radioligand binding and molecular studies have revealed the existence and location of multiple neuronal nicotinic receptor subtypes in brain as well as in the spinal cord. Molecular biology studies confirmed the existence of multiple nAChRs in the spinal cord. Indeed, Wada et al. (1989) conducted a very extensive analysis of 2, 3, 4, and 2 mRNA localization in the brain. Although a small portion of this study was directed to the spinal cord, transcripts for these subunits were detected in the spinal cord. In another study, no signal was detected for 4 mRNA in the spinal cord (Dineley-Miller and Patrick, 1992). However, it has been difficult to determine which subtypes of nAChRs mediate the various effects of nicotine in the spinal cord. Recently, Cordero-Erausquin et al. (2004) identified a 2-containing nAChRs, 462* subtype as major contributors for nicotine's effects on spinal inhibitory neurons. In the same study, the authors reported that the spinal excitatory neurons expressed an 7-containing nAChRs. On the other hand, it has been suggested that 7 nicotinic receptor subtypes may mediate a pronociceptive action at the level of the spinal cord (Khan et al., 1997). This nociceptive effect was blocked by MK-801, suggesting the involvement of spinal NMDA receptors. Interestingly, MK-801 failed to block nicotine's antinociceptive effects and calcium/calmodulin-dependent calmodulin protein kinase II activation as reported in our studies. Taken together, these results are consistent with the involvement of spinal calcium/calmodulin-dependent calmodulin protein kinase II in nicotine-induced antinociception via 2-containing nAChRs.
It is known that transduction changes can be set in motion by calcium influx through activation of ligand-gated ion channels such as NMDA receptors together with contributions from LCC and release from internal calcium stores. Indeed, sustained L-type calcium channels activation triggers calcium release from internal stores. In a recent report, neither L- nor N-type channels were shown to be required for nicotinic regulation of CREB phosphorylation in ciliary ganglion neurons (Chang and Berg, 2001). Instead, calcium influx through nAChRs themselves, together with calcium-induced calcium release from internal stores, sustained CREB phosphorylation levels in the ganglionic neurons. In contrast, stimulation of 7 nAChRs subtypes in rat cultured hippocampal neurons was reported to activate CREB through both glutamatergic and nonglutamatergic components and does not, however, require activation of LCC (Hu et al., 2002). Our findings in this present case show that nicotinic stimulation of 2-containing nAChRs in the spinal cord can activate calcium/calmodulin-dependent calmodulin protein kinase II and produce nicotinic analgesia, which may require L-type calcium voltage-gated channels but not the intervention of glutamatergic transmission. It also possible that the LCC antagonists inhibit directly 2-containing nAChR since earlier reports suggest that these antagonists could block neuronal nAChR present on chromaffin cells (Donnelly-Roberts et al., 1995).
The fact that LCC blockers inhibited the nicotinic effects further suggests that calcium influx through 2-containing nAChRs in the spinal cord is not sufficient to trigger enough calcium/calmodulin-dependent calmodulin protein kinase II activation for behavioral expression as measured in the tail-flick, an acute pain model. It is possible that these signaling cascades may play a critical role in mediating nicotine-induced long-lasting changes in brain neurochemistry and, therefore, may be involved in the development of nicotine tolerance and/or dependence.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: nAChR, acetylcholine nicotinic receptor; NMDA, N-methyl-D-aspartate; MK-801, dizocilpine maleate; -BGTX, -bungarotoxin; MLA, methyllycaconitine; %MPE, % maximal possible effect; LCC, L-type calcium channel; CREB, cAMP response element-binding protein.
Address correspondence to: Dr. M. Imad Damaj, Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980613, Richmond, VA 23298-0613. E-mail: mdamaj{at}vcu.edu
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Aceto MD, Bagley RS, Dewey WL, Fu T-C, and Martin BR (1986) The spinal cord as a major site for the antinociceptive action of nicotine in the rat. Neuropharmacology 25: 1031–1036.[CrossRef][Medline]
Aceto MD, Martin BR, Uwaydah IM, May EL, Harris LS, Izazola-Conde C, Dewey WL, and Vincek WC (1979) Optically pure (+)-nicotine from (±)-nicotine and biological comparisons with (–)-nicotine. J Med Chem 22: 174–177.[CrossRef][Medline]
Barrantes GE, Westwick J, and Wonnacott S (1994) Nicotinic acetylcholine receptors in primary cultures of hippocampal neurons: pharmacology and Ca2+ permeability. Biochem Soc Trans 22: 294S–195S.[Medline]
Chang KT and Berg DK (2001) Voltage-gated channels block nicotinic regulation of CREB phosphorylation and gene expression in neurons. Neuron 32: 855–865.[CrossRef][Medline]
Cordero-Erausquin M, Pons P, Faure P, and Changeux J-C (2004) Nicotine differentially activates inhibitory and excitatory neurons in the dorsal spinal cord. Pain 109: 308–318.[CrossRef][Medline]
Damaj MI (2000) The involvement of spinal calcium/calmodulin-protein kinase II in nicotine-induced antinociception in mice. Eur J Pharmacol 404: 103–110.[CrossRef][Medline]
Damaj MI, Fei-Yin M, Dukat M, Glassco W, Glennon RA, and Martin BR (1998) Antinociceptive responses to nicotinic acetylcholine receptor ligands after systemic and intrathecal administration in mice. J Pharmacol Exp Ther 284: 1058–1065.
Damaj MI, Welch SP, and Martin BR (1995) In vivo pharmacological effects of dihydro-beta-erythroidine, a nicotinic antagonist, in mice. Psychopharmacology 117: 67–73.[CrossRef][Medline]
D'Amour FE and Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72: 74–79.
Dineley-Miller K and Patrick J (1992) Gene transcripts for the nicotinic acetylcholine receptor subunit, Beta4, are distributed in multiple areas of the rat central nervous system. Mol Brain Res 16: 339–344.[Medline]
Donnelly-Roberts DL, Arneric SP, and Sullivan JP (1995) Functional modulation of human "ganglionic-like" neuronal nicotinic acetylcholine receptors (nAChRs) by L-type calcium channel antagonists. Biochem Biophys Res Commun 15: 657–662.
Fluhler E, Lippiello P, and Fernandes K (1992) Localization and function of high-affinity nicotine receptors on cultured cortical neurons from rat brain, in The Biology of Nicotine: Current Research Issues (Lippiello PM, Collins AC, Gray JA, and Robinson JH eds) pp 23–38, Raven Press, New York.
Hu M, Liu QS, Chang KT, and Berg DK (2002) Nicotinic regulation of CREB activation in hippocampal neurons by glutamatergic and nonglutamatergic pathways. Mol Cell Neurosci 21: 616–625.[CrossRef][Medline]
Hylden JL and Wilcox GL (1980) Intrathecal morphine in mice: A new technique. Eur J Pharmacol 67: 313–316.[CrossRef][Medline]
Iwamato ET (1991) Characterization of the antinociception induced by nicotine in the pedunculus tegmental nucleus and the nucleus raphe magnus. J Pharmacol Exp Ther 257: 120–133.
Iwamoto ET and Marion L (1993) Adrenergic, serotonergic and cholinergic components of nicotinic antinociception in rats. J Pharmacol Exp Ther 265: 777–789.
Khan IM, Yaksh TL, and Taylor P (1997) Epibatidine binding sites and activity in the spinal cord. Brain Res 753: 269–282.[CrossRef][Medline]
Mansvelder HD, De Rover M, McGehee DS, and Brussaard AB (2003) Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction. Eur J Pharmacol 480: 117–123.[CrossRef][Medline]
Mansvelder HD and McGehee DS (2002) Cellular and synaptic mechanisms of nicotine addiction. J Neurobiol 53: 606–617.[CrossRef][Medline]
Marubio LM, Arroyo-Jimenez MM, Cordero-Erausquin M, Léna C, LeNovère N, de Kerchove d'Exaerde A, Huchet M, Damaj MI, and Changeux J-P (1999) Reduced antinociception in mice lacking neuronal nicotinic receptor subunits. Nature (Lond) 398: 805–810.[CrossRef][Medline]
Mattila MJ, Ahtee L, and Saarnivaara L (1968) The analgesic and sedative effects of nicotine in white mice, rabbits and golden hamsters. Ann Med Exp Fenn 46: 78–84.
Mulle C, Choquet D, Korn H, and Changeux J-P (1992) Calcium influx through nicotinic receptor in rat central neurons: its relevance to cellular regulation. Neuron 8: 135–143.[CrossRef][Medline]
Scott Bitner RL, Curzon P, Arneric SP, Bannon AW, and Decker MW (1998) Role of the nucleus raphe magnus in antinociception produced by ABT-594: immediate early gene responses possibly linked to neuronal nicotinic acetylcholine receptors on serotonergic neurons. J Neurosci 18: 5426–5432.
Suh HW, Choi YS, Yoo JS, Song DK, Kim YH, and Tseng LF (1995) Non-NMDA receptor antagonist attenuates antinociception induced by morphine but not beta-endorphin, D-Pen2-D-Pen5-enkephalin, and U50,488H administered intracerebroventricularly in mice. Neuropeptides 28: 125–129.[CrossRef][Medline]
Suh HW, Song DK, Huh SO, Lee KC, and Kim YH (2000) Differential potentiative effects of GABA receptor agonists in the production of antinociception induced by morphine and beta-endorphin administered intrathecally in the mouse. Life Sci 66: PL61–PL69.[CrossRef][Medline]
Turek JW, Kang CH, Campbell JE, Arneric SP, and Sullivan JP (1995) A sensitive technique for the detection of the alpha 7 neuronal nicotinic acetylcholine receptor antagonist, methyllycaconitine, in rat plasma and brain. J Neurosci Methods 61: 113–118.[CrossRef][Medline]
Vijayaraghavan S, Pugh PC, Zhang Z-W, Rathouz MM, and Berg DK (1992) Nicotinic receptors that bind -bungarotoxin on neurons raise intracellular free Ca2+. Neuron 8: 353–362.[CrossRef][Medline]
Wada E, Wada K, Boulter J, Deneris E, Heinemann S, Patrick J, and Swanson L (1989) Distribution of alpha2, alpha3, alpha4, and beta2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridization histochemical study in the rat. J Comp Neurol 284: 314–335.[CrossRef][Medline]
Willis WD (2001) Role of neurotransmitters in sensitization of pain responses. Ann NY Acad Sci 933: 142–156.[Medline]
This article has been cited by other articles:
|
|
 |
|
  G. Sharma, M. Grybko, and S. Vijayaraghavan Action Potential-Independent and Nicotinic Receptor-Mediated Concerted Release of Multiple Quanta at Hippocampal CA3-Mossy Fiber Synapses J. Neurosci., March 5, 2008; 28(10): 2563 - 2575. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
