Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of ethylketazocine (EKC) administered intraperitoneally and the nicotinic ligands (-)- and (+)-nicotine, (-)-cytisine, (-)-lobeline, and (+)-2-methylpiperidine administered into the 4th ventricle on the latency of the thermally evoked withdrawal reflex of the decerebrate rat were investigated. EKC administered intraperitoneally produced both hyperalgesia and analgesia. (-)-Nicotine administered into the 4th ventricle produced a biphasic dose related effect on the latency of the withdrawal reflex; low doses produced a dose related analgesia while higher doses produced hyperalgesia. (-)-Cytisine and (-)-lobeline administered into the 4th ventricle produced biphasic effects. (+)-2-Methylpiperidine administered into the 4th ventricle produced a significant degree of hyperalgesia. Both the analgesic and hyperalgesic effects of (-)-nicotine were antagonized by mecamylamine (1 mg/kg) and naltrexone (5 mg/kg). The hyperalgesic action of (+)-2-methylpiperidine was antagonized by naltrexone but not by mecamylamine. These observations suggest that there are both medullary opioidergic and nicotinic cholinergic mechanisms for modulating both analgesic and hyperalgesic processes and that nicotinic ligands have multiple mechanisms of action in the brain.
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PMID:Opioid and nicotinic medullary hyperalgesic influences in the decerebrated rat. 290 Nov 13

Nicotine produced a distinct reproducible syndrome in the conscious dog when injected intravenously or intracerebroventricularly. Intravenously administered nicotine (40 micrograms/kg/min for 20 minutes) increased cardiac and respiratory rates and produced analgesia, miosis, hypothermia, behavioral restlessness and emesis. When microinjected into the third cerebral ventricle, nicotine (100-200 micrograms) similarly increased cardiac and respiratory rates and pupillary diameter; and produced behavioral restlessness, emesis, erratic analgesia and maintained wakefulness and a desynchronized EEG. Microinjection of nicotine (5-25 micrograms) into the periaqueductal gray failed to alter any of the parameters studied. Intravenous pretreatment with the opioid antagonist naltrexone (2 mg/kg) influenced the action of intravenous nicotine on certain physiological systems. While naltrexone alone produced a significant degree of tachycardia, miosis, and analgesia, it potentiated the tachypnea and antagonized the miotic response evoked by nicotine. Methionine-enkephalin was detected in perfusates obtained from the lateral cerebral ventricles of conscious dogs. Nicotine produced a non-significant decrease in enkephalin levels. These observations suggest that there are interactions between endogenous opioid and nicotinic processes. However, they are complex and may differ from one functional system to another.
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PMID:Interaction between nicotine and endogenous opioid mechanisms in the unanesthetized dog. 717 83

The effects of ethylketazocine, U-50,488, morphine and (-)-nicotine administered both i.p. and into the mid-fourth ventricle of intact rats were investigated using a conventional high intensity tail-flick reflex and one evoked with a lower intensity thermal stimulus. The sensitivity of the low intensity thermally evoked tail avoidance reflex was several times that of a high intensity tail-flick reflex in detecting the analgesic activity of morphine and yielded valid assays and relative potencies between morphine (1), EKC (18.76) and U-50,488 (0.23) when the drugs were administered ip. When the opioid drugs were administered into the fourth ventricle they produced a dose-related shortening of the latency of the low intensity thermally evoked tail avoidance reflex. (-)-Nicotine, when administered into the mid-fourth ventricle, produced analgesia in low doses and hyperalgesia in high doses. Naltrexone and mecamylamine, when administered into the fourth ventricle, produced a dose-related analgesia. Doses of naltrexone and mecamylamine which antagonize maximally hyperalgesic doses of (-)-nicotine and ethylketazocine did not produce analgesia; however, larger doses produced analgesia. These observations suggest that analgesic doses do not involve prototypic kappa opioidergic or nicotinic mechanisms. These data confirm the existence of a medullary hyperalgesic center which may have both mu and kappa opioidergic as well as nicotinic mechanisms. Furthermore, these data indicate that this medullary hyperalgesic mechanism may have spontaneous or evoked tone and provide an explanation for the analgesic action of naltrexone and mecamylamine.
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PMID:Pharmacologic characteristics of a medullary hyperalgesic center. 838 37

(-)-Nicotine, the prototypical agonist for neuronal nicotinic acetylcholine receptors (nAChR) has been shown to bind with high affinity to the rodent and avian alpha 4 beta 2 nAChR subtype. This subtype may represent a primary molecular target for some of the beneficial central nervous system effects i.e., cognitive enhancement, anxiolysis, analgesia, neuroprotection, of (-)-nicotine and related ligands. However, a detailed study of the human alpha 4 beta 2 subunit combination has not yet been reported. In this study, we stably coexpressed the human neuronal alpha 4 and beta 2 nAChR subunits in human embryonic kidney (HEK) 293 cells and studied its pharmacological and regulatory properties. [3H]Cytisine bound to stably transfected cells with high affinity (KD value, 0.2 +/- 0.04 nM) and with a Bmax value of 1359 +/- 91 fmol/mg protein. A good correlation (r = 0.98) was observed between binding affinities in transfected cells and in native neuronal preparations for a series of nAChR ligands. 86Rb+ efflux studies showed that stably transfected cells express functional ion channels that are sensitive to blockade by dihydro-beta-erythroidine. (+/-)-Epibatidine, (-)-nicotine, 1,1-dimethyl-4-phenylpiperazinium, (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT-418), acetylcholine and (-)-cytisine stimulated 86Rb+ efflux with EC50 values of 0.02, 3.9, 2.5, 10, 44 and 38 microM, respectively. Treatment of transfected cells with (-)-nicotine for 7 days led to a significant increase in the density of [3H](-)-cytisine binding sites (EC50 = 0.56 microM) and a significant enhancement in the sensitivity of ACh. Specific binding or (-)-nicotine-evoked cation efflux was not detected in untransfected cells. Analysis of total cellular RNA from transfected, but not untransfected cells, showed the expected fragment sizes corresponding to the human alpha 4 and beta 2 subunit mRNA. These results demonstrate that stable expression of the human alpha 4 beta 2 nAChR subunit combination can give rise to functional ion channels that bind [3H](-)-cytisine with high affinity, exhibit homologous regulation and evoke agonist-induced cation flux with pharmacological properties consistent with native neuronal alpha 4 beta 2 nAChR.
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PMID:Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine alpha 4 beta 2 receptor. 855 45

Neuronal nicotinic acetylcholine receptors (NAChRs) are pentameric ligand-gated ion channel receptors which exist as different functional subunit combinations which apparently subserve different physiological functions as indicated by molecular biological and pharmacological techniques. It is possible to design and synthesize novel compounds that have greater selective affinities and efficacies than nicotine for different NAChRs, which should translate into different behavioral profiles and therapeutic potentials. Examples of NAChR agonists studied are nicotine, SIB-1508Y, SIB-1553A and epibatidine. These compounds have different degrees of selectivity for human recombinant NAChRs, different neurotransmitter release profiles in vitro and in vivo and differential behavioral profiles. Preclinical studies suggest that SIB-1508Y is a candidate for the treatment of the motor and cognitive deficits of Parkinson's disease, whereas SIB-1553A appears to have potential as a candidate for the treatment of Alzheimer's disease. Epibatidine has a strong analgesic profile, however the ratio between pharmacological activity and undesirable effects is so low that it is difficult to envisage the use of this compound therapeutically. Nicotine has a broad profile of pharmacological activity, for instance demonstrating activity in models for cognition and analgesia. As for epibatidine, the adverse effects of nicotine severely limits its therapeutic use in humans. The discovery of subtype-selective NAChR agonists such as SIB-1508Y and SIB-1553A provides a new class of neuropsychopharmacological agents with better therapeutic ratios than nonspecific agents such as nicotine.
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PMID:The potential of subtype-selective neuronal nicotinic acetylcholine receptor agonists as therapeutic agents. 958 43

While the mechanisms underlying nicotinic acetylcholine receptor (nAChR)-mediated analgesia remain unresolved, one process that is almost certainly involved is the recently-described nicotinic enhancement of inhibitory synaptic transmission in the spinal cord dorsal horn. Despite these observations, the prototypical nicotinic analgesic (epibatidine) has not yet been shown to modulate inhibitory transmission in the spinal cord. Furthermore, while nAChRs have been implicated in short-term modulation, no studies have investigated the role of nAChRs in the modulation of long-term synaptic plasticity of inhibitory transmission in dorsal horn. Whole-cell patch clamp recordings from dorsal horn neurons of neonatal rat spinal cord slices were therefore conducted to investigate the short- and long-term effects of nicotinic agonists on GABAergic transmission. GABAergic synaptic transmission was enhanced in 86% of neurons during applications of 1 microM nicotine (mean increased spontaneous GABAergic inhibitory postsynaptic current (sIPSC) frequency was approximately 500% of baseline). Epibatidine (100 nM) induced an increase to an average of approximately 3000% of baseline, and this effect was concentration dependent (EC50=43 nM). Nicotinic enhancement was inhibited by mecamylamine and DHbetaE, suggesting an important role for non-alpha7 nAChRs. Tetrodotoxin (TTX) did not alter the prevalence or magnitude of the effect of nicotine, but the responses had a shorter duration. Nicotine did not alter evoked GABAergic IPSC amplitude, yet the long-term depression (LTD) induced by strong stimulation of inhibitory inputs was reduced when paired with nicotine. These results provide support for a mechanism of nicotinic analgesia dependent on both short and long-term modulation of GABAergic synaptic transmission in the spinal cord dorsal horn.
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PMID:Nicotinic modulation of GABAergic synaptic transmission in the spinal cord dorsal horn. 1564 48

Nicotine is reported to have analgesic properties. Patients with chronic pain who smoke could therefore, be expected to require less analgesia than non-smokers because of the possible synergism of the two substances. One hundred healthy patients were studied who had non-radicular low back pain for greater than three months. Each patient failed conservative therapies, which consisted of muscle relaxants, physical therapy and/or NSAIDS. Our study population consisted of two groups of 50 patients. Each group included: I, cigarette smokers; and II, non-smokers. Each patient received 0-40 mg/24hrs of hydrocodone as needed for pain relief for the duration of this four week study. Numeric pain intensity scores (0-10), mean total hydrocodone dosing, and quantitative blood nicotine and hydrocodone levels were assessed at the beginning and end of this study. Patients kept daily diaries and recorded pain scores and self hydrocodone dosing upon awakening, in the afternoon, and at bed time. Parametric and nonparametric statistical analysis was performed using the appropriate test with p < or = 0.05 necessary to reject the null hypothesis There were no differences in demographics between the two groups. Smokers had higher end of study pain scores and required more hydrocodone than non-smokers but had significantly lower serum levels of hydrocodone than non-smokers. The results of this study suggest that cigarette smoking adversely affects serum hydrocodone levels. Prescribing physicians should be aware that in some cigarette smokers, serum hydrocodone levels might not be detectible.
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PMID:Effect of cigarette smoking on serum hydrocodone levels in chronic pain patients. 1766 88

Delta9-tetrahydrocannabinol is the active component in cannabis and has long been associated with pain relief. This effect is believed to be mediated through central and peripheral CB1 and peripheral CB2 receptors. We have explored the possible antinociceptive effect of a CB2 receptor agonist, JWH133, using the formalin test in mice. The drug was administered by the intracerebroventricular and intraperitoneal routes. Although no antinociceptive effect was observed after intracerebroventricular administration of JWH133, when the drug was administered by the intraperitoneal route, it produced an analgesic effect. The influence of nicotinic cholinergic receptor modulators, nicotine and mecamylamine, on antinociceptive effect of JWH133 was also studied. Nicotine increased and mecamylamine decreased the antinociceptive effect of JWH133. It is concluded that JWH133-induced analgesia is influenced by nicotinic cholinergic receptor activity.
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PMID:Influence of nicotinic receptor modulators on CB2 cannabinoid receptor agonist (JWH133)-induced antinociception in mice. 1791 54

The present study was designed to investigate the role of spinal neuronal nicotinic acetylcholine receptors in the analgesic effects of isoflurane. After having established the mice model of analgesia by intraperitoneally injecting (i.p.) appropriate doses of isoflurane, nicotine, a neuronal nicotinic acetylcholine receptor agonist was intrathecally injected. The effects of isoflurane and nicotine on paw licking times and formalin-induced c-fos expression in the spinal cord dorsal horn were examined. Our correlative studies have shown that isoflurane can decrease the paw licking times and simultaneously suppress c-fos expression after injection of formalin in the mice. Nicotine can partially antagonize the effects induced by isoflurane above. Spinal neuronal nicotinic acetylcholine receptors may be important targets for the analgesic effects of isoflurane in formalin pain.
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PMID:Effects of intrathecal injection of nicotine on the analgesic effects of isoflurane in a model of inflammatory pain. 1938 46

Neuronal nicotinic acetylcholinic receptors (nAChR) are promising targets for the development of novel analgesics. Nicotine and other nAChR-agonists produce profound analgesia in rodent models of acute and persistent pain. However, significant side-effects are of concern. Nornicotine (N-desmethyl-nicotine) appears to activate different nAChR subtypes, has a better pharmacokinetic profile, and produces less toxicity than nicotine. Little is known about its analgesic properties. In the present study, the S(-)- and R(+)-enantiomers of nornicotine were characterized with regard to analgesia and side-effects profile. Efficacy was demonstrated in rat models of pain where central sensitization is involved: i.e. the chronic constriction nerve injury model of peripheral neuropathy and the formalin model of tonic inflammatory pain. The desirable (analgesic) properties resided predominantly in the S(-)- rather than the R(+)-enantiomer. In contrast, undesirable effects (motor in-coordination, reduced locomotor activity, ataxia) were more pronounced with the R(+)-enantiomer. This is an interesting finding, which may suggest separation of toxicity from analgesia by utilization of S(-)-enantiomer of nornicotine. Maximum analgesic effectiveness without significant side-effects was achieved when S(-)-nornicotine (sub-analgesic dose) was combined with a low-dose of the micro-opioid, morphine. These preclinical data suggest that S(-)-nornicotine may be of value, either alone or in combination with an opioid, for treatment of a broad-spectrum of pain (i.e. nociceptive, neuropathic, and mixed pain).
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PMID:The analgesic and toxic effects of nornicotine enantiomers alone and in interaction with morphine in rodent models of acute and persistent pain. 1980 Sep 11


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