title: Noradrenaline but not dopamine involved in NMDA receptor-mediated hyperalgesia induced by theophylline in awake rats.
abstract: Theophylline dose-dependently decreased a supraspinally integrated nociceptive threshold in awake rats. This hyperalgesia was antagonized by pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801, suggesting involvement of NMDA receptors. Depletion of endogenous catecholamines with reserpine or alpha-methyl-DL-p-tyrosine and inhibition of noradrenaline synthesis with FLA 63 reduced the theophylline-induced hyperalgesia, whereas blockade of dopamine D2 receptors by pimozide, haloperidol (2 mg/kg) or (-)-sulpiride, of dopamine D1 receptors by SCH 23390, or of dopamine autoreceptors by a low dose of haloperidol (25 micrograms/kg), had no effect. By contrast, the alpha 1-adrenoceptor-blocking agent phenoxybenzamine abolished the hyperreactivity induced by theophylline, whereas the alpha 1-adrenoceptor antagonist prazosin and the beta-adrenoceptor antagonist (+/-)-propranolol were without effect. Furthermore, the alpha 2-adrenoceptor agonist clonidine (50 micrograms/kg) considerably decreased the hyperalgesia caused by theophylline. The adenosine A1/A2 receptor agonist N-ethyl-carboxamide adenosine (NECA) produced dose-dependent antinociception on the threshold for vocalization. Moreover, NECA (25 micrograms/kg) antagonized the hyperalgesia induced by different doses of theophylline, indicating that the effect is susceptible to purinergic modulation. It is suggested that theophylline-induced hyperreactivity to nociception is attributed to increased activity in NMDA and noradrenaline neurotransmission, possibly secondary to adenosine antagonism. Elevated intracellular levels of cyclic AMP might, however, also be involved in theophylline-produced hyperexcitability.
authors.affiliation: Department of Biopharmaceutics and Pharmacokinetics, Uppsala University, Sweden.
authors.forename: G H
authors.initials: GH
authors.lastname: Paalzow
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D005406:Bis(4-Methyl-1-Homopiperazinylthiocarbonyl)disulfide / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D009638:Norepinephrine / Q000502:physiology*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012110:Reserpine / Q000494:pharmacology; D013469:Sulpiride / Q000494:pharmacology; D013806:Theophylline / Q000008:administration & dosage / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D019805:alpha-Methyltyrosine
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018492:Dopamine Antagonists; D008781:Methyltyrosines; D016194:Receptors, N-Methyl-D-Aspartate; D005406:Bis(4-Methyl-1-Homopiperazinylthiocarbonyl)disulfide; D019830:Adenosine-5'-(N-ethylcarboxamide); D019805:alpha-Methyltyrosine; D016291:Dizocilpine Maleate; D013469:Sulpiride; D012110:Reserpine; D013806:Theophylline; D014446:Tyrosine 3-Monooxygenase; D000241:Adenosine; D004298:Dopamine; D009638:Norepinephrine