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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study determined (1) whether amitriptyline could produce a local antinociceptive action in the formalin test, (2) whether endogenous adenosine was involved in this action, and (3) which other systems might contribute to such an action. Coadministration of amitriptyline 10-100 nmol with 2.5% formalin produced a dose-related reduction in phase 1 (0-12 min) and phase 2 (16-60 min) flinching behaviours, as well as in phase 2 biting/licking time (no phase 1 expression). This action was not seen or only partially expressed at low concentrations of formalin (0.5%, 0.75%). Coadministration of caffeine with amitriptyline partially reversed the antinociceptive action of amitriptyline against both behaviours at 2.5% formalin. At 1.5% formalin, caffeine still produced only a partial reversal of effect; this appeared to be due to a block of adenosine A1 receptors, as it was also seen with the selective adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine. Using antagonists for a number of other systems, no evidence for an involvement of alpha-adrenergic, histamine, excitatory amino acid or opioid receptors in the action of amitriptyline was observed or inferred. A local anaesthetic action for amitriptyline remains a possibility for the residual action. These results indicate that amitriptyline can produce a local peripheral antinociceptive action which is mediated, in part, by an interaction with endogenous adenosine, most likely an inhibition of the cellular uptake of adenosine with a consequent activation of adenosine A1 receptors on sensory nerve terminals. Local application of amitriptyline by cream or gel might prove to be a useful method of drug delivery in inflammatory pain states.
Pain 1999 Mar
PMID:Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine. 1020 17

Caffeine potentiation of ketorolac-induced antinociception in the pain-induced functional impairment model in rats was assessed. Caffeine alone was ineffective, but increased the effect of ketorolac without affecting its pharmacokinetics. Intra-articular administration of adenosine and N6-cyclohexyladenosine (CHA, an adenosine A1 receptor agonist), but not 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680, an adenosine A2A receptor agonist), significantly increased ketorolac antinociception. This effect was not local, as contralateral administration was also effective. Ipsilateral and contralateral administration of adenosine and CHA also increased antinociception by ketorolac-caffeine. Intra-articular 8-Bromo-adenosine cyclic 3',5'-hydrogen phosphate sodium or 8-Bromo-guanosine-3',5'-cyclophosphate sodium (cGMP) given ipsilaterally or contralaterally did not affect ketorolac-induced antinociception. Nevertheless, ipsilateral, but not contralateral, administration of 8-Br-cGMP significantly increased antinociception by ketorolac-caffeine, suggesting a local effect. The results suggest that caffeine potentiation of ketorolac antinociception is mediated, at least partially, by a local increase in cGMP and rule out the participation of adenosine receptor blockade.
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PMID:Effect of coadministration of caffeine and either adenosine agonists or cyclic nucleotides on ketorolac analgesia. 1045 27

The intrathecal (i.t.) administration of the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) reduced pain-related behaviors after peripheral nerve or spinal cord injury in rats. The endogenous ligand adenosine is clinically available and has been tested i.t. as an analgesic. Thus, we set out to investigate whether i.t. adenosine could reduce allodynia in a model of central pain in spinally injured rats. I.t. adenosine did not reduce mechanical and cold allodynia-like behaviors at doses of 10, 100 and 187 nmol, whereas i.t. R-PIA at 10 nmol markedly alleviated allodynia in the same animals. The lack of effect by exogenous adenosine may be due to pharmacokinetic or pharmacodynamic reasons. Alternatively, adenosine may have reduced affinity and selectivity towards the A1-receptors which may be important for the antiallodynic effect.
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PMID:Intrathecal adenosine does not relieve allodynia-like behavior in spinally injured rats. 1057 69

The present study assessed the efficacy and potency of intrathecal (i.t.) administration of the opiate morphine, the gamma-aminobutyric acid-B (GABA(B)) receptor agonist baclofen, the alpha2-adrenoceptor agonist clonidine and the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) on the acute allodynia-like behaviour after photochemically induced spinal cord injury (SCI) in rats. Rats displaying allodynia-like behaviours to brushing, von Frey hairs and cold stimulation 1-2 days after photochemically induced SCI were studied. In a cumulative dose regime, morphine (0.1-10 micrcog), baclofen (0.1-1 microg), clonidine (0.1-10 microg) and R-PIA (0.01-10 nmol) were administered i.t. through an implanted catheter at the lumbar spinal cord. All tested drugs dose-dependently reduced the brushing, von Frey hairs and cold stimulation-induced allodynia-like behaviour. No increase in adverse effects such as motor deficits was found for morphine, clonidine and R-PIA. There was a slight increase in motor impairments at the highest dose of baclofen. For the mechanical allodynia, morphine appeared to be most effective, whereas baclofen, clonidine and R-PIA only provided a partial alleviation. For the cold allodynia, morphine and baclofen were more effective than clonidine and R-PIA. In relieving acute mechanical and cold allodynia-like behaviours in rats 1-2 days after SCI, i.t. morphine and baclofen were superior to clonidine and R-PIA.
Eur J Pain 2001
PMID:Effects of intrathecal morphine, baclofen, clonidine and R-PIA on the acute allodynia-like behaviours after spinal cord ischaemia in rats. 1139 17

Adenosine can reduce pain and allodynia in animals and man, probably via spinal adenosine A1 receptors. In the present study, we investigate the distribution of the adenosine A1 receptor in the rat spinal cord dorsal horn using immunohistochemistry, in situ hybridization, radioligand binding, and confocal microscopy. In the lumbar cord dorsal horn, dense immunoreactivity was seen in the inner part of lamina II. This was unaltered by dorsal root section or thoracic cord hemisection. Confocal microscopy of the dorsal horn revealed close anatomical relationships but no or only minor overlap between A1 receptors and immunoreactivity for markers associated with primary afferent central endings: calcitonin gene-related peptide, or isolectin B4, or with neuronal subpopulations: mu-opioid receptor, neuronal nitric oxide synthase, met-enkephalin, parvalbumin, or protein kinase Cgamma, or with glial cells: glial fibrillary acidic protein. A few adenosine A1 receptor positive structures were double-labeled with alpha-amino-3-hydroxy-5-methyl-4-isoaxolepropionic acid glutamate receptor subunits 1 and 2/3. The results indicate that most of the adenosine A1 receptors in the dorsal horn are located in inner lamina II postsynaptic neuronal cell bodies and processes whose functional and neurochemical identity is so far unknown. Many adenosine A1 receptor positive structures are in close contact with isolectin B4 positive C-fiber primary afferents and/or postsynaptic structures containing components of importance for the modulation of nociceptive information.
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PMID:Distribution of antinociceptive adenosine A1 receptors in the spinal cord dorsal horn, and relationship to primary afferents and neuronal subpopulations. 1458 Sep 41

The chronic constriction injury model is a rat model of neuropathic pain based on a unilateral loose ligation of the sciatic nerve. The aim of the present study was to test its sensitivity to various clinically validated and experimental drugs. Mechanical allodynia and thermal hyperalgesia developed within one week post-surgery and were reliably present for at least 7 weeks. Mechanical allodynia was strongly attenuated by morphine (minimal effective dose in brackets: 8 mg/kg, p.o.) and the cannabinoids Delta9-tetrahydrocannabinol (3 mg/kg, p.o.) and (-)-cis-3-[2-hydroxy-4(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940; 0.05 mg/kg, i.p.), and weakly/moderately attenuated by the anticonvulsants gabapentin (50 mg/kg, i.p.) and carbamazepine (32 mg/kg, i.p.), the muscle relaxant baclofen (3 mg/kg, i.p.), and the adenosine kinase inhibitor 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine (ABT-702; 30 mg/kg, i.p.). Thermal hyperalgesia was strongly attenuated by morphine (16 mg/kg, p.o.), Delta9-tetrahydrocannabinol (6 mg/kg, p.o.), CP 55,940 (0.025 mg/kg, i.p.), carbamazepine (32 mg/kg, i.p.) and the antidepressant amitriptyline (32 mg/kg, p.o.), and weakly/moderately attenuated by gabapentin (50 mg/kg, i.p.), the anti-inflammatory cyclooxygenase-2 inhibitor rofecoxib (30 mg/kg, i.p.) and the adenosine A1 receptor positive allosteric modulator 2-amino-4,5,6,7-tetrahydrobenzo(b)thiophen-3-yl 4-chlorophenylmethanone (T62; 30 mg/kg, i.p.). Both symptoms were hardly or not affected by the nonselective N-methyl-d-aspartate receptor antagonists ketamine and dizocilpine, and the N-methyl-d-aspartate receptor NR2B-selective antagonists ifenprodil and R-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenyl-methyl)-1-piperidine propranol (Ro 25-6981). The finding that mechanical allodynia and/or thermal hyperalgesia are attenuated by various established compounds further supports the validity of the chronic constriction injury model for the study of neuropathic pain and its use for the identification of novel treatments.
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PMID:Pharmacological characterization of the chronic constriction injury model of neuropathic pain. 1514 Jun 30

The role of the adenosine A1 receptor in nociception was assessed using mice lacking the A1 receptor (A1R-/-) and in rats. Under normal conditions, the A1R-/- mice exhibited moderate heat hyperalgesia in comparison to the wild-type mice (A1R+/+). The mechanical and cold sensitivity were unchanged. The antinociceptive effect of morphine given intrathecally (i.t.), but not systemically, was reduced in A1R-/- mice and this reduction in the spinal effect of morphine was not associated with a decrease in binding of the mu-opioid ligand DAMGO in the spinal cord. A1R-/- mice also exhibited hypersensitivity to heat, but not mechanical stimuli, after localized inflammation induced by carrageenan. In mice with photochemically induced partial sciatic nerve injury, the neuropathic pain-like behavioral response to heat or cold stimulation were significantly increased in the A1R-/-mice. Peripheral nerve injury did not change the level of adenosine A1 receptor in the dorsal spinal cord in rats and i.t. administration of R-PIA effectively alleviated pain-like behaviors after partial nerve injury in rats and in C57/BL/6 mice. Taken together, these data suggest that the adenosine A1 receptor plays a physiological role in inhibiting nociceptive input at the spinal level in mice. The C-fiber input mediating noxious heat is inhibited more than other inputs. A1 receptors also contribute to the antinociceptive effect of spinal morphine. Selective A1 receptor agonists may be tested clinically as analgesics, particularly under conditions of neuropathic pain.
Pain 2005 Feb
PMID:Increased nociceptive response in mice lacking the adenosine A1 receptor. 1566 49

The objective of this investigation was to characterise the pharmacokinetic-pharmacodynamic correlation of adenosine A1 receptor partial agonists in the chronic constriction injury model of neuropathic pain. Following intravenous administration of 8-methylamino-N6-cyclopentyl-adenosine (MCPA; 10 mg/kg) and 2'deoxyribose-N6-cyclopentyl-adenosine (2'dCPA; 20 mg/kg), the time course of the effect on the mechanical paw pressure threshold was determined in conjunction with plasma concentrations. Population pharmacokinetic/pharmacodynamic analysis was applied to derive individual concentration-effect relationships. A composite model consisting of an E(max) model for the anti-hyperalgesic effect in combination with a linear model for the anti-nociceptive effect accurately described the concentration-effect relationship. For both compounds, a full anti-hyperalgesic effect was observed. The values of the EC50 for the anti-hyperalgesic effect were (mean+/-S.D.): 3170+/-1460 and 2660+/-1200 ng/ml for MCPA and 2'dCPA versus 178+/-51 ng/ml for the reference full agonist 5'deoxyribose-N6-cyclopentyl-adenosine (5'dCPA). The values of the slope for the anti-nociceptive effect were 1.9+/-0.30 and 1.2+/-0.20 g.microl/ng, respectively, versus 55+/-8 g microl/ng for 5'dCPA. Adenosine A1 receptor partial agonists behave as full agonists with regard to the anti-hyperalgesic effect in neuropathic pain, but the anti-nociceptive effect is diminished.
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PMID:Pharmacokinetic/pharmacodynamic modelling of the anti-hyperalgesic and anti-nociceptive effect of adenosine A1 receptor partial agonists in neuropathic pain. 1591 Jul 99

This review summarizes clinical application of adenosine and adenosine 5'-triphosphate (ATP) in pain conditions. Investigations have been performed in patients with acute perioperative pain or chronic neuropathic pain treated with intravenous adenosine or ATP, or intrathecal adenosine. Characteristic central adenosine A1 receptor-mediated pain-relieving effects have been observed after intravenous adenosine infusion in human inflammation/sensitization pain models and in patients with chronic neuropathic pain. Adenosine compounds, in low doses, can reduce allodynia/hyperalgesia more consistently than spontaneous pain, suggesting that these compounds affect neuronal pathophysiological mechanisms involved in central sensitization. Such pain-relieving effects, which are mostly mediated via central adenosine A1 receptor activation, have a slow onset and long duration of action, lasting usually for hours or days and occasionally for months. With acute perioperative pain, treatment with a low-dose infusion of adenosine compounds and the A1 receptor-mediated central antisensitization mechanisms may play only a minor part in the total perioperative pain experience. By administering sufficient doses of adenosine compounds during surgery, however, significant and long-lasting perioperative pain relief can be achieved via central A1 receptor-mediated antinociceptive/analgesic actions as well as via peripheral A2a or A3 receptor-mediated antiinflammatory actions. Thus, adenosine compounds have significant potential for alleviating various types of pain.
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PMID:Clinical application of adenosine and ATP for pain control. 1603 51

In recent studies performed in our laboratory we have shown that acute administration of (-)-linalool, the natural occurring enantiomer in essential oils, possesses anti-inflammatory, antihyperalgesic and antinociceptive effects in different animal models. The antihyperalgesic and antinociceptive effects of (-)-linalool have been ascribed to its capacity in stimulating the opioidergic, cholinergic and dopaminergic systems, as well as to its interaction with K+ channels, or to its local anaesthetic activity and/or to the negative modulation of glutamate transmission. Activation of A1 or A2A receptors has been shown to induce antinociceptive effects, and the possible involvement of adenosine in (-)-linalool antinociceptive effect, has not been elucidated yet. Therefore, in the present study, we have investigated the effects of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a selective adenosine A1 receptor antagonist and the effects of 3,7-dimethyl-1-propargilxanthine (DMPX), a selective adenosine A2A receptor antagonist on the antinociception of (-)-linalool in mice, measured in the hot-plate test. Both DPCPX (0.1 mg/kg; i.p.) and DMPX (0.1 mg/kg; i.p.) pre-treatment significantly depressed the antinociceptive effect of (-)-linalool at the highest doses tested. These findings demonstrated that the effect of (-)-linalool on pain responses is, at least partially, mediated by the activity of adenosine A1 and A2A receptors.
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PMID:Involvement of adenosine A1 and A2A receptors in (-)-linalool-induced antinociception. 1634 51


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