ognizant Communication Corporation



Analgesia, Vol. 5, pp. 211-216
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Copyright © 2001 Cognizant Comm. Corp.
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Differential Antinociceptive Effect of Cyclooxygenase Inhibitors in Acetic Acid-Induced Chemonociception in Mice*

Naveen K. Jain,1 S. K. Kulkarni,1 and Amarjit Singh2

1Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160 014, India
2R&D Division, Panacea Biotec Ltd., P.O. Lalru, Chandigarh Road, Punjab-140 501, India

Background: Pain is a common problem, often associated with inflammatory conditions. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used as analgesic agents. NSAIDs inhibit both cyclooxygenase enzymes (COX-1 and COX-2) and are effective in treatment of pain/inflammatory disorders. COX enzyme is expressed in two isoforms. COX-1 is constitutive and responsible for physiological functions and COX-2 is induced by inflammatory stimuli.
Purpose: The aim of the present study is to compare the profile of antinociceptive action of various cyclooxygenase inhibitors (i.e., selective COX-2 inhibitors, preferential COX-2 inhibitors, and nonselective cyclooxygenase inhibitors).
Method: One percent acetic acid-induced chemonociception was used as an animal model of acute nociception in mice.
Results: Nonselective cyclooxygenase (naproxen, ED50 26.52 mg/kg) and preferential COX-2 inhibitor (nimesulide and meloxicam, ED50 6.31 and 1.26 mg/kg, respectively) were found potent antinociceptive agents in comparison to selective COX-2 inhibitors (NS-398, celecoxib, and rofecoxib, ED50 value not achieved over the whole dose range of 5-40 mg/kg).
Conclusion: The present studies suggest that cyclooxygenase-1 inhibition is essential to exert maximum antinociceptive effect in an acute model of nociception in mice. Selective COX-2 inhibitors may be good anti-inflammatory agents but they are relatively less potent antinociceptive agents. This may be due to less involvement of COX-2 enzyme in the pain perception on this animal model.

Key words: Antinociception; Cyclooxygenase-1 enzyme; Cyclooxygenase-2 enzyme; Selective COX-2 inhibitors; Preferential COX-2 inhibitors

Address correspondence and reprint requests to Prof. S. K. Kulkarni, Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160 014, India. Fax: +91- 0172 541409; E-mail: skpu@yahoo.com

*Previous preliminary report: Jain, N. K., Singh, A., Kulkarni, S. K. Analgesic, anti-inflammatory and ulcerogenic activity of a zinc-naproxen complex in mice and rats. Pharm. Pharmacol. Commun. 5:599-602; 1999.

Analgesia, Vol. 5, pp. 217-222
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Copyright © 2001 Cognizant Comm. Corp.
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NMDA Receptor Antagonists Potentiated Antinociceptive Effect of Paracetamol in Writhing Test in Mice

Dominika Labuz,1 Jan Dobrogowski,2 Anna Golec,2 and Barbara Przewlocka1

1Department of Molecular Neuropharmacology, Institute of Pharmacology, Kraków, Poland
2Department of Anaesthesiology and Intensive Care, Collegium Medicum, Jagiellonian University, Kraków, Poland

Background: Antagonists at multiple sites of the NMDA receptor complex attenuate central sensitization and hyperalgesia in animal models of persistent pain. In contrast, very few studies have examined the possible role of NMDA receptors and their antagonists in combination with nonsteroidal antinociceptive drugs (e.g., paracetamol) in pain evoked by noxious stimulation or damage of internal organs.
Purpose: We studied the antinociceptive efficacy of combined treatment with paracetamol and NMDA antagonists in comparison with their effects after individual administration using the writhing test in mice.
Methods: Male Albino-Swiss mice (25-30 g) were injected with 2-phenyl-1,4-benzoquinone (PBQ, 2 mg/kg, IP). Paracetamol, dextromethorphan, ketamine, and memantine were injected IP before PBQ. Ten minutes after PBQ administration, the number of writhing episodes was counted over a 10-min period.
Results: Intraperitoneal administration of paracetamol (10-1000 mg/kg), dextromethorphan (0.1-500 mg/kg), memantine (10-500 mg/kg), and ketamine (10-10000 mg/kg) decreased the number of writhing episodes. After coadministration of a nonactive dose of paracetamol (10 mg/kg) together with a low dose of dextromethorphan (0.1 mg/kg), memantine (10 and 100 mg/kg), and ketamine (10 and 100 mg/kg), further potentiation of the antinociceptive effect in comparison with their effects after individual administration was observed.
Conclusions: We demonstrated the synergistic antinociceptive action of paracetamol and NMDA receptor antagonists. The striking antinociceptive effect of paracetamol and NMDA antagonists was apparent when nonactive doses were given jointly. Higher doses were not as effective in comparison with their effects after individual administration. Therefore, the combined treatment with two drugs at doses much lower than therapeutic doses may be of great value in visceral pain therapy.

Key words: Paracetamol; NMDA receptor antagonists; Writhing text; Antinociceptive effect

Address correspondence and reprint requests to Prof. Barbara Przewlocka, Department of Molecular Neuropharmacology, Institute of Pharmacology, 12 Smetna Street, 31-343 Kraków, Poland. Tel: (48-12) 623398; Fax: (48-12) 6374500; E-mail: przebar@if-pan.krakow.pl

Analgesia, Vol. 5, pp. 223-227
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Copyright © 2001 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Nitric Oxide Synthesis in the Brain Mediates Neuropeptide Effects on Pain Sensitivity and Pain-Induced Aggression*

Ludmila Anatolyevna Severyanova,1 Igor Ivanovich Bobyntsev,1 Dmitry Vadimovich Plotnikov,2 and Yury Dmitrievich Lyashev1

1Pathophysiology Department and 2Psychiatry Department, Kursk State Medical University, Kursk, Russia

It is known that certain neuropeptides enhance pain sensitivity and shock-induced aggression. The aim of the present study was to discover the mechanisms of the algesic and aggressogenic effects of the different groups of neuropeptide analogues. Pain sensation and fighting behavior were induced as the response to the gradually increasing inescapable electric stimulation of male rats grouped in pairs in a special chamber. The threshold values of each characteristic of pain and pain-induced behavior were measured. The effects of 20 hypothalamo-pituitary peptide analogues of the different function groups were investigated 15 min after IP injection. To clarify the interaction between a peptide and brain neurotransmitters the modulation of the brain muscarinic receptor activity was induced by the M-agonist and antagonist administration 10 min before the same peptide injection. It was shown that only L-arginine-containing peptides increased pain and fear experience and aggression. Activation of brain muscarinic system due to M-agonist administration induced a similar effect, in contrast to receptor blockade. The phenomenon of pain and behavioral sensitization was found in the case of combined administration of M-receptor agonist and L-arginine-containing peptide. These data demonstrate that L-arginine intervention into the brain plays an important role in increased pain and behavioral response to inescapable painful stimulation. Because L-arginine effect depends on the brain muscarinic system activity, the results of the present study suggest that this effect is mediated by the generation of NO from L-arginine and nitrogenic activation of cyclic GMP formation.

Key words: Pain sensitivity; Pain-induced aggression; Nitric oxide synthesis; Neuropeptide effects

Address correspondence and reprint requests to Ludmila A. Severyanova, Professor, Head of Pathophysiology Department, Kursk State Medical University, K. Marx st. 3, Kursk, 305041, Russia. Tel: 0712-2-56-12, 0712-56-54-58; Fax: 0712-56-54-70, 0712-56-73-99; E-mail: main@ksmu.kursk.ru

*Previous preliminary reports: Severyanova, L A., Plotnikov, D. V. Effect of ACTH fragments on the shock-induced defensive fighting in rats. Sechenov Physiol. J. USSR 72:1614-1618; 1986. Severyanova, L., Bobyntsev, I., Plotnikov, D. Activation of nitric oxide production in the brain as the factor mediating peptide effects on the pain sensitivity and shock-induced aggression. 9th World Congress on Pain, Abstract book, Vienna, 1999:227.

Analgesia, Vol. 5, pp. 229-237
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Copyright © 2001 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Cyclic AMP-Dependent Protein Kinase Contributes to the Excitatory Response to Norepinephrine in Chronically Compressed Rat Dorsal Root Ganglion Neurons*

Hui Xu,1 Sanjue Hu,1 Kaiping Long,2 Hongjun Yang,1 and Junling Xing1

1Institute of Neuroscience and 2Department of Physics, The Fourth Military Medical University, Xi'an, 710032, P.R. China

Chronic compression of the dorsal root ganglion (DRG) in the rat, which closely mimics intervertebral foraminal stenosis in humans, produces mechanical and thermal hyperalgesia as shown by behavioral signs. The present study was undertaken to further investigate the sensitivity to norepinephrine (NE) and its underlying intracellular mechanism in sensory neurons with a new model of chronic DRG compression. Extracellular recordings of the spontaneous activity (SA) of single fibers were made from teased dorsal root myelinated fibers originating from A-type DRG neurons in vitro. Responsiveness to exogenously applied NE (10 mM) was observed in 74 of 84 spontaneously active neurons from injured DRGs, but not in any neurons from uninjured DRGs. The excitatory effect of NE was partly blocked by the a1- and a2-adrenoceptor antagonists, yohimbine (10 mM) and prazosin (5 mM), respectively. Moreover, a specific inhibitor of cAMP-dependent protein kinase (PKA) Rp-cAMPS (50-250 mM), an inhibitor of PKA catalytic subunit H-89 (10 mM), and an adenylate cyclase inhibitor SQ22,536 (1 mM) markedly decreased the excitatory effect of NE on the SA of injured DRG neurons. The results demonstrate that there exists obvious adrenosensitivity in chronically compressed DRG neurons, and suggest that PKA contributes to the excitatory response to NE in the injured DRG A-neurons.

Key words: cAMP-dependent protein kinase; Spontaneous activity; Adrenosensitivity; Dorsal root ganglion

Address correspondence and reprint requests to Sanjue Hu, Institute of Neuroscience, The Fourth Military Medical University, Xi'an 710032, P.R. China. Fax: 86 29 3246270; E-mail: sjhu@fmmu.edu.cn

*Preliminary results of this study have been reported in an abstract form (Xu et al., 1999).

Analgesia, Vol. 5, pp. 239-247
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Copyright © 2001 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Effects of Nicotine and Epibatidine on Thermal Nociception and Prostaglandin E2-Induced Thermal Hypersensitivity in Rhesus Monkeys

Michael R. Brandt* and S. Stevens Negus

Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hospital, Belmont, MA 02178-9106

Purpose. It has been suggested that nicotinic acetylcholine receptor agonists may produce clinically useful analgesic effects. To further evaluate this hypothesis, the present study compared the effects of the nicotinic agonists nicotine and epibatidine with the effects of the mu-opioid agonist morphine on schedule-controlled responding, thermal nociception, and thermal hypersensitivity in rhesus monkeys.
Results. In the assay of schedule-controlled responding, nicotine (0.1-3.2 mg/kg), epibatidine (0.00032-0.0032 mg/kg), and morphine (0.32-10.0 mg/kg) dose-dependently decreased response rates maintained under a fixed ratio 30 schedule of food presentation. High doses of nicotine and epibatidine also produced sedation in all monkeys and vomiting in some monkeys. In the assay of thermal nociception, neither nicotine (0.32-5.6 mg/kg) nor epibatidine (0.00032-0.0032 mg/kg) substantially altered tail-withdrawal latencies from 50°C water. In contrast, morphine (0.32-10.0 mg/kg) produced dose-dependent and maximal antinociceptive effects at doses similar to those that also decreased rates of schedule-controlled responding. Thermal hypersensitivity was induced by administration of prostaglandin E2 (PGE2; 0.0158 mg) into the tail, which decreased tail-withdrawal latencies from 18 s to less than 3 s in 46°C water. Nicotine (1.0-5.6 mg/kg) and epibatidine (0.00032-0.0032 mg/kg) reversed thermal hypersensitivity in one of three and two of three monkeys, respectively, and these effects were only observed at high doses that also produced sedation and vomiting. Morphine (0.1-1.0 mg/kg) dose-dependently reversed thermal hypersensitivity in all three monkeys at doses approximately five- to ninefold lower than those that decreased rates of schedule-controlled responding or produced thermal nociception.
Conclusions. These findings suggest that up to doses that produce adverse behavioral effects, nicotine and epibatidine produce only weak and inconsistent antinociceptive effects in rhesus monkeys.

Key words: Nicotine; Epibatidine; Morphine; Monkey; Schedule-controlled responding; Prostaglandin E2; Antinociception; Thermal hypersensitivity

Address correspondence and reprint requests to S. Stevens Negus, Ph.D., Harvard Medical School-McLean Hospital, Alcohol and Drug Abuse Research Center, 115 Mill Street, Belmont, MA 02178-9106. Tel: (617) 855-3324; Fax: (617) 855-2606; E-mail: negus@mclean.org

*Current address: Wyeth-Ayerst Research, Wyeth Neuroscience, CN-8000, Princeton, NJ 08543-8000.