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)

Intrathecal administration of substance P at the lower thoracic spinal level has an antinociceptive effect on reaction time in the tail-flick test; this response is blocked by naloxone i.v. but not by i.v. administration of opiate antagonists which do not cross the blood-brain barrier. As morphine-induced analgesia is blocked by adenosine antagonists, to determine whether this substance P-induced, opioid-mediated antinociception also includes a purine link, the adenosine receptor antagonist, caffeine, was given systemically 10 min prior to substance P administration. In control rats pretreated with saline, substance P (6.5 nmol) produced an increase in reaction time to about 160% of preadministration values at one min after intrathecal injection. The effect could also be observed at 6 min after this injection. Pretreatment with 16 or with 32 mg/kg of caffeine i.p. blocked the response to substance P, and produced a hyperalgesia similar to that reported in studies at the lumbo-sacral spinal level. These results indicate that the adrenal opioid-induced antinociception observed upon intrathecal administration of substance P at the lower thoracic level occurs via an adenosine link. This is the first demonstration of a purine link in the expression of antinociceptive effects of an endogenously released opioid.
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PMID:Adenosine receptor link in an adrenal opioid-induced antinociception in the rat tail-flick test. 137 72

The effect of selective adenosine receptor agonists on nociceptive responses of mice and rats and on morphine analgesia was investigated. All compounds used: phenylisopropyladenosine (R-PIA), adenosine ethylcarboxamide (NECA), cyclohexyladenosine (CHA) and 2-chloroadenosine (2-CADO) exhibited antinociceptive action in mice and rats in the hot-plate (56 degrees C) and tail-immersion (52 degrees C) tests. R-PIA, CHA and NECA potentiated the antinociceptive action of morphine in mice, and R-PIA and NECA--in rats. 2-CADO did not affect the morphine action in the tests.
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PMID:Interaction of adenosine analogs with morphine in analgesic tests. 140 13

Adenosine-mediated analgesia and interactions between opioids and adenosine in the brain have been observed by several researchers. Our investigations were designed to examine opioid-adenosine interactions at spinal sites and possible modulation of opioid-stimulated descending antinociceptive pathways by adenosine in the spinal cord. Methylxanthines administered intrathecally (i.t.) were used as adenosine receptor antagonists to determine possible interactions between opioids and endogenous adenosine. Theophylline administered i.t. dose-dependently antagonized analgesia induced by morphine administered i.t. or i.c.v. as measured by tail-flick and hot-plate assays. Analgesia induced by i.t. injections of 2-chloroadenosine, an adenosine agonist, was also antagonized by theophylline. However, doses of naloxone (i.t.) that antagonized analgesia induced by i.t. injections of morphine had no effect on 2-chloroadenosine (i.t.)-induced analgesia. These data support morphine-stimulated release of adenosine in the spinal cord. Antagonism of morphine (i.c.v.)-induced analgesia by theophylline was mimicked by caffeine and isobutylmethylxanthine. The results could not be explained as a consequence of effects on phosphodiesterease enzymes, drug-induced hyperalgesia or spinal redistribution of i.c.v. administered morphine. Therefore, our studies suggest that endogenous adenosine in the spinal cord is involved in analgesia mediated by opioid-stimulated descending antinociceptive pathways.
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PMID:Spinal adenosine modulates descending antinociceptive pathways stimulated by morphine. 242 75

Spinal analgesia produced by morphine is blocked by methylxanthine adenosine receptor antagonists. In biochemical studies, morphine releases adenosine from spinal cord synaptosomes prepared from the dorsal spinal cord, as well as from the intact spinal cord in vivo. Adenosine release is reduced by intrathecal and neonatal pretreatment with capsaicin but not by intrathecal pretreatment with 6-hydroxydopamine or 5,7-dihydroxytryptamine, indicating that adenosine originates from small-diameter primary afferent neurons but not descending monoaminergic pathways. In this Viewpoint Jana Sawynok and colleagues review the evidence supporting the hypothesis that the spinal analgesic action of morphine is due to the release of adenosine from primary afferent nerve terminals and subsequent activation of A1 and A2 adenosine receptors.
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PMID:Adenosine release may mediate spinal analgesia by morphine. 258 27

(-)-N6-(R-phenylisopropyl)-adenosine (PIA) was shown to possess analgesic activity in both the tail flick and acetic acid writhing assays. The analgesic actions of PIA were antagonized by caffeine in a dose-dependent manner. An apparent pA2 analysis in vivo suggested that the antagonism by caffeine was not competitive. Subanalgesic doses of PIA potentiated morphine-induced analgesia, tolerance and dependence. Caffeine antagonized these effects of morphine. PIA attenuated while caffeine exacerbated opiate withdrawal. While a low dose of caffeine antagonized PIA effects on withdrawal, a low dose of PIA did not antagonize the effects of caffeine. These results indicate that PIA can facilitate, and caffeine can antagonize the actions of morphine and that caffeine may be exerting some of its actions independent of adenosine receptor antagonism.
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PMID:Effects of (-)-N6-(R-phenylisopropyl)-adenosine (PIA) and caffeine on nociception and morphine-induced analgesia, tolerance and dependence in mice. 299 93

Chronic administration of caffeine to mice (1 mg/ml in drinking water X 14 d) led to a downward shift in the dose-response curve for the locomotor effects of caffeine. Caffeine was also less effective as an antagonist against (-)-(N6-phenylisopropyl)-adenosine (PIA)-induced analgesia in the tail flick assay in these animals. The dose-response curves of PIA for both analgesia and locomotor depression were shifted to the left in animals chronically administered caffeine. In mice chronically administered PIA (1 mg/kg/d X 14 d), the dose-response curves of PIA for both analgesia and locomotor depression were shifted to the right. The dose-response curve for the locomotor effects of caffeine was shifted to the left, and caffeine exhibited greater antagonist activity against the analgesic action of PIA in these animals. There was no change in the Kd or Bmax values of either 3H-PIA or 3H-diethylphenylxanthine (DPX, a potent adenosine receptor antagonist) in mice chronically administered PIA. The Bmax values for both 3H-PIA and 3H-DPX were significantly increased, while the Kd values were not changed in mice chronically administered caffeine. There was no detectable change in the brain levels of either PIA or caffeine in animals chronically treated with either drug. The results demonstrate that chronic administration of caffeine increases the sensitivity of mice to the actions of PIA and vice versa, providing supportive evidence for the interaction of these drugs at the same receptor, which is probably an adenosine receptor.
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PMID:Cross-tolerance studies between caffeine and (-)-N6-(phenylisopropyl)-adenosine (PIA) in mice. 300 86

When injected intrathecally in mice in a volume of 5 microliter, adenosine had no effect on tail-flick or hot-plate reaction latencies at dosages up to 1 mM concentration. There were no other behavioral effects observed either. Injecting 1 mM of the adenosine receptor agonist, 5'-N-ethylcarboxamide adenosine (NECA) caused both motor paralysis of the hind-legs with a duration of approximately 4 h and simultaneous antinociception. A slight weakness of the hindlegs, but a profound antinociceptive effect, was observed after the 100 microM dose only. After 10 microM, there was no effect on motor behavior but still a prolongation of the tail-flick and hot-plate reaction latencies. Pretreatment with the adenosine receptor antagonist theophylline attenuated the antinociceptive effect of NECA. Activation of spinal adenosine receptors thus appears to selectively elicit analgesia.
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PMID:Antinociceptive effects in mice after intrathecal injection of 5'-N-ethylcarboxamide adenosine. 609 41

mu-Opioid receptor agonists, e.g. morphine, produce analgesia that can be potentiated by restraint stress. Adenosine receptor agonists, e.g. 5'-N-ethylcarboxamidoadenosine (NECA), also produce analgesia. To determine if adenosine-induced analgesia is also potentiated by stress, dose- and time-effect curves for NECA (0.01-0.1 mg/kg s.c.) were generated in adult male Sprague-Dawley rats either unrestrained or restrained in Plexiglas cylinders, using the tail-flick assay. Morphine (1.0-5.6 mg/kg s.c.) was also tested for comparison. Both compounds produced dose-dependent increases in tail-flick latencies. This effect of both drugs was potentiated in restrained rats. The opioid receptor antagonist, naltrexone (1.0 mg/kg s.c.) blocked completely the effect of morphine in both groups and attenuated the stress-induced potentiation of NECA-induced analgesia. The adenosine receptor antagonist, caffeine (10.0 mg/kg s.c.), blocked the analgesic effect of NECA but not that of morphine. These results indicate that adenosine-mediated analgesia is potentiated by restraint stress and suggest a role for endogenous opioids in the mediation of stress-induced potentiation of analgesia.
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PMID:Restraint stress potentiates analgesia induced by 5'-N-ethylcarboxamidoadenosine: comparison with morphine. 822 92

The present study examined the spinal antinociceptive effects of adenosine analogs and inhibitors of adenosine kinase and adenosine deaminase in the carrageenan-induced thermal hyperalgesia model in the rat. The possible enhancement of the antinociceptive effects of adenosine kinase inhibitors by an adenosine deaminase inhibitor also was investigated. Unilateral hindpaw inflammation was induced by an intraplantar injection of lambda carrageenan (2 mg/100 microl), which consistently produced significant paw swelling and thermal hyperalgesia. Drugs were administered intrathecally, either by acute percutaneous lumbar puncture (individual agents and combinations) or via an intrathecal catheter surgically implanted 7-10 days prior to drug testing (antagonist experiments). N6-cyclohexyladenosine (CHA; adenosine A1 receptor agonist; 0.01-1 nmol), 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenos ine (CGS21680; adenosine A2A receptor agonist; 0.1-10 nmol), 5'-amino-5'-deoxyadenosine (NH2dAdo; adenosine kinase inhibitor: 10-300 nmol), and 5-iodotubercidin (ITU; adenosine kinase inhibitor; 0.1-100 nmol) produced, to varying extents, dose-dependent antinociception. No analgesia was seen following injection of 2'-deoxycoformycin (dCF; an adenosine deaminase inhibitor; 100-300 nmol). Reversal of drug effects by caffeine (non-selective adenosine A1/A2 receptor antagonist; 515 nmol) confirmed the involvement of the adenosine receptor, while antagonism by 8-cyclopentyl-1,3-dimethylxanthine (CPT; adenosine A1 receptor antagonist; 242 nmol), but not 3,7-dimethyl-1-propargylxanthine (DMPX; adenosine A2A receptor antagonist; 242 nmol), evidenced an adenosine A1 receptor mediated spinal antinociception by NH2dAdo. dCF (100 nmol), which was inactive by itself, enhanced the effects of 10 nmol and 30 nmol NH2dAdo. Enhancement of the antinociceptive effect of ITU by dCF was less pronounced. None of the antinociceptive drug regimens had any effect on paw swelling. These results demonstrate that both directly and indirectly acting adenosine agents, when administered spinally, produce antinociception through activation of spinal adenosine A1 receptors in an inflammatory model of thermal hyperalgesia. The spinal antinociceptive effects of selected adenosine kinase inhibitors can be significantly augmented when administered simultaneously with an adenosine deaminase inhibitor.
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PMID:Antinociception by adenosine analogs and inhibitors of adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat. 952 Feb 38

Adenosine is a modulator that has a pervasive and generally inhibitory effect on neuronal activity. Tonic activation of adenosine receptors by adenosine that is normally present in the extracellular space in brain tissue leads to inhibitory effects that appear to be mediated by both adenosine A1 and A2A receptors. Relief from this tonic inhibition by receptor antagonists such as caffeine accounts for the excitatory actions of these agents. Characterization of the effects of adenosine receptor agonists and antagonists has led to numerous hypotheses concerning the role of this nucleoside. Previous work has established a role for adenosine in a diverse array of neural phenomena, which include regulation of sleep and the level of arousal, neuroprotection, regulation of seizure susceptibility, locomotor effects, analgesia, mediation of the effects of ethanol, and chronic drug use.
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PMID:The role and regulation of adenosine in the central nervous system. 1128 4


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