Antinociceptive effects of the stereoisomers of nicotine given intrathecally in spinal rats.
TL;DR: The findings show that spinal mechanisms are highly stereoselective toward nicotine, and suggest that primarily nicotinergic andalpha-adrenergic receptors are involved in its central antinociceptive effects.
Abstract: Spinalized rats received an intrathecal injection of either (−)-nicotine or (+)-nicotine in order to study the stereoselectivity of antinociception. Pain threshold was measured using the tail-flick test. Both stereoisomers had antinociceptive effects, but (−)-nicotine was up to 970 times more potent, depending on test conditions. The antinociceptive action of (−)-nicotine was antagonized by mecamylamine and yohimbine but not by naloxone and atropine. The findings show that spinal mechanisms are highly stereoselective toward nicotine, and suggest that primarily nicotinergic andalpha-adrenergic receptors are involved in its central antinociceptive effects.
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TL;DR: In this article, the authors conceptualized the interaction of pain and smoking as a prototypical example of the biopsychosocial model and extrapolated from behavioral, cognitive, affective, biomedical, and social perspectives to propose causal mechanisms that may contribute to the observed comorbidity between these 2 conditions.
Abstract: Tobacco addiction and chronic pain represent 2 highly prevalent and comorbid conditions that engender substantial burdens upon individuals and systems. Interrelations between pain and smoking have been of clinical and empirical interest for decades, and research in this area has increased dramatically over the past 5 years. We conceptualize the interaction of pain and smoking as a prototypical example of the biopsychosocial model. Accordingly, we extrapolated from behavioral, cognitive, affective, biomedical, and social perspectives to propose causal mechanisms that may contribute to the observed comorbidity between these 2 conditions. The extant literature was 1st dichotomized into investigations of either effects of smoking on pain or effects of pain on smoking. We then integrated these findings to present a reciprocal model of pain and smoking that is hypothesized to interact in the manner of a positive feedback loop, resulting in greater pain and increased smoking. Finally, we proposed directions for future research and discussed clinical implications for smokers with comorbid pain disorders. We observed modest evidence that smoking may be a risk factor in the multifactorial etiology of some chronically painful conditions and that pain may come to serve as a potent motivator of smoking. We also found that whereas animal studies yielded consistent support for direct pain-inhibitory effects of nicotine and tobacco, results from human studies were much less consistent. Future research in the emerging area of pain and smoking has the potential to inform theoretical and clinical applications with respect to tobacco smoking, chronic pain, and their comorbid presentation. (PsycINFO Database Record (c) 2011 APA, all rights reserved).
242 citations
TL;DR: In this article, the authors examined current knowledge regarding how acute and chronic exposure to nicotine and cigarette smoke affects chronic pain conditions, and explored the association of cigarette smoking with chronic painful conditions and potential mechanisms to explain this association.
Abstract: Cigarette smoke, which serves as a nicotine delivery vehicle in humans, produces profound changes in physiology. Experimental studies suggest that nicotine has analgesic properties. However, epidemiologic evidence shows that smoking is a risk factor for chronic pain. The complex relationship between smoking and pain not only is of scientific interest, but also has clinical relevance in the practice of anesthesiology and pain medicine. This review will examine current knowledge regarding how acute and chronic exposure to nicotine and cigarette smoke affects acute and chronic painful conditions. It will cover the relevant pharmacology of nicotine and other ligands at the nicotinic acetylcholine receptor as related to pain, explore the association of cigarette smoking with chronic painful conditions and potential mechanisms to explain this association, and examine clinical implications for the care of smokers with pain.
228 citations
Journal Article•
TL;DR: The results of this study suggest that different subtypes of nicotinic receptors may exist in the spinal cord, and a good correlation was found between binding affinity to [3H]-nicotine binding sites and analgesic potency after i.c.t.
Abstract: The objective of this study was to determine which nicotinic receptor subtypes are involved in antinociception and their site of action. For that, the antinociceptive effects of several nicotinic receptor ligands were evaluated in the tail-flick test both after s.c. and intrathecal (i.t.) administration. Nicotine and other nicotine agonists increased tail-flick latencies in a dose-dependent manner after both routes of administration. Epibatidine enantiomers were the most potent agonists examined. Cytisine, a potent nicotinic ligand, failed to elicit antinociception when injected either i.t. or s.c. Despite some similarities in the effects of nicotinic agonists after i.t. and s.c. injections, their rank-order potency was different. In contrast to the s.c. results, the stereoselectivity of nicotine’s effect after i.t. administration was minimal. When various nicotinic antagonists were compared after i.t. and s.c. administration, the results showed that mecamylamine and dihydro-β-erythroidine differ in potency and their degree of antagonism of some of the nicotinic agonists given i.t. These data suggest that different subtypes of nicotinic receptors may exist in the spinal cord. A good correlation was found between binding affinity to [3H]-nicotine binding sites and analgesic potency after i.t. (r = 0.82), suggesting the involvement of α4β2 receptor subunits. In contrast, studies with MLA and α-BGTX suggested a minimal role for α-BGTXsensitive receptors in the antinociceptive effect of nicotinic agonists.
161 citations
TL;DR: These studies suggest that activation of α 7 receptors in the CNS elicits antinociceptive effects in an acute thermal pain model.
146 citations
TL;DR: Anti-nociceptive effects of neuronal nicotinic acetylcholine receptor (NAChR) ligands were evaluated and indicated that a sub-population of NAChR receptors are located pre-synaptically on noradrenergic and/or serotoninergic pathways in the hippocampus, indicating a minimal role for these receptors in the tail-flick response.
94 citations
References
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01 Mar 1948
TL;DR: The method provides means for the rapid test of parallelism of two curves and easy computation of relative potency with its confidence limits and its accuracy is commensurate with the nature of dose-per cent effect data.
Abstract: 1. A rapid graphic method for approximating the Median Effective Dose and the Slope of dose-per cent effect curves is presented. Confidence limits of both of these parameters for 19/20 probability are given by the method. In addition, confidence limits for any other probability or for a dose other than the Median Effective Dose are readily estimated. 2. The data are used throughout the method in their original form without transformation to logarithms and probits. 3. An effective means for plotting and using 0 and 100 per cent effects is provided. 4. The calculations have been simplified by means of nomographs to the extent that a slide rule is a convenience but not a necessity. 5. A simple means is provided for detecting a poorly fitted line or significantly heterogeneous data, In the former case, the line may be refitted; in the latter, the confidence limits are corrected for the degree of heterogeneity. 6. The method provides means for the rapid test of parallelism of two curves and easy computation of relative potency with its confidence limits. 7. Although the method is rapid (10-15 minutes), its accuracy is commensurate with the nature of dose-per cent effect data.
7,221 citations
Journal Article•
TL;DR: In this article, a rapid graphic method for approximating the median effective dose and the slope of dose-per-cent effect curves is presented, and confidence limits of both of these parameters for 19/20 probability are given by the method.
Abstract: 1. A rapid graphic method for approximating the Median Effective Dose and the Slope of dose-per cent effect curves is presented. Confidence limits of both of these parameters for 19/20 probability are given by the method. In addition, confidence limits for any other probability or for a dose other than the Median Effective Dose are readily estimated. 2. The data are used throughout the method in their original form without transformation to logarithms and probits. 3. An effective means for plotting and using 0 and 100 per cent effects is provided. 4. The calculations have been simplified by means of nomographs to the extent that a slide rule is a convenience but not a necessity. 5. A simple means is provided for detecting a poorly fitted line or significantly heterogeneous data, In the former case, the line may be refitted; in the latter, the confidence limits are corrected for the degree of heterogeneity. 6. The method provides means for the rapid test of parallelism of two curves and easy computation of relative potency with its confidence limits. 7. Although the method is rapid (10-15 minutes), its accuracy is commensurate with the nature of dose-per cent effect data.
7,217 citations
Journal Article•
TL;DR: A simple, rapid method for determining the pain threshold in the rat was applied to the determination of analgesic properties of several substances, including cobra venom, where no analgesic property in the latter could be demonstrated.
Abstract: 1. A simple, rapid method for determining the pain threshold in the rat is described. 2. The individual variation, under a variety of conditions, was found to be surprisingly small. 3. The method was applied to the determination of analgesic properties of several substances, including cobra venom. No analgesic property in the latter could be demonstrated. 4. A comparative assay of five opiates gave results in good agreement with clinical experience.
3,373 citations
"Antinociceptive effects of the ster..." refers methods in this paper
...Tail-flick test The nociceptive threshold was measured by the tail-flick method (D'Amour and Smith, 1941)....
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Journal Article•
TL;DR: The data implicate several different mechanisms in the antinociceptive action of nicotine, which appeared to be central in both rats and mice inasmuch as mecamylamine antagonized completely but hexamethonium (5 mg/kg) antagonized partially.
Abstract: Nicotine was found to be potent in producing antinociception in mice and rats as measured by tail-flick latency but its action was of short duration. Nicotine's ED50 values (confidence limits) were 0.7 (0.4-1.1) and 2.0 (1.2-3.4) mg/kg in rats and mice, respectively, at the time of maximum effect. Brain levels of nicotine reached a maximum at 10 min, whereas antinociception was maximal within 2 min in rats. However, there was a good correlation between the time courses of antinociception and brain levels of nicotine in mice with both attaining maximal levels at 5 min. It was found that tachyphylaxis developed to the antinociception in rats within 10 min and lasted for up to 14 h, but tachyphylaxis did not develop to nicotine-induced antinociception in mice. The effect of nicotine appeared to be central in both rats and mice inasmuch as mecamylamine antagonized completely but hexamethonium (5 mg/kg) antagonized partially. Nicotine-induced antinociception was not blocked in either rats or mice by atropine in doses up to 10 mg/kg. Naloxone did not block nicotine in rats but did antagonize the antinociception in mice. In addition, yohimbine, a selective alpha-2 antagonist, blocked the antinociception in both species. These data implicate several different mechanisms in the antinociceptive action of nicotine.
195 citations
"Antinociceptive effects of the ster..." refers background in this paper
...In the third, the effects of receptor antagonists [mecamylamine (1 mg/kg), yohimbine (5 mg/kg), naloxone (10 mg/kg) and atropine (10 mg/kg)] (Tripathi et al., 1982) on antinociceptive actions of (-)-nicotine (-)ditartrate (43 nmol/rat) were studied....
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TL;DR: The present results support the suggestion that nicotine may selectively reduce sensitivity to certain classes of pain stimuli, perhaps through a central releasing action on acetylcholine.
Abstract: Nicotine (0.16–0.50 mg/kg, SC) was found to exert a potent antinociceptive action on thermal stimuli as measured by the tail-flick test. This antinociceptive action of nicotine could be blocked by centrally active nicotinic or muscarinic blockers implicating both classes of cholinergic receptors in this effect. Quaternary blockers, however, failed to prevent nicotine-induced antinociception. This finding, together with the ability of small doses of nicotine (25 μg) to induce potent antinociceptive effects when administered centrally, suggests a central site of action for the antinociceptive action of nicotine. The present results also support the suggestion that nicotine may selectively reduce sensitivity to certain classes of pain stimuli, perhaps through a central releasing action on acetylcholine.
183 citations