L-dopa induces opposing effects on pain in intact rats: (-)-sulpiride, SCH 23390 or alpha-methyl-DL-p-tyrosine methylester hydrochloride reveals profound hyperalgesia in large antinociceptive doses.
The present study shows that during the time course of the action of single doses, L-dopa induces multiphasic opposing effects on pain, recorded as vocalization during the presentation of electrical stimulation applied to the tail of normal rats. This indicates that two or more functional systems contribute to produce the net response. A small dose (15 mg/kg) of L-dopa facilitates pain slightly, whereas larger doses (100-200 mg/kg) can produce an antinociceptive effect following an initial hyperalgesia. Moreover, profound hyperalgesia is revealed by either dopamine (DA) D1 and D2 receptor blockade by means of SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H- 3-benzazepine hydrochloride] or (-)-sulpiride, respectively, as well as after a reduction of the presynaptic synthesis of catecholamines after pretreatment of the animals with the tyrosine hydroxylase inhibitor alpha-methyl-DL-p-tyrosine (alpha-MPT). The enhancement of L-dopa's hyperalgesic effect after SCH 23390 treatment is maximal already at the onset of the effects, whereas (-)-sulpiride or alpha-methyl-DL-p-tyrosine precipitates the hyperalgesia after a certain temporal delay during defined phases of the time course of the effects of large L-dopa doses. The D1 receptor agonist (+)-SKF 38393 potentiates both the hyperalgesic and antinociceptive effects of 100 mg/kg of L-dopa. It is suggested that L-dopa's net effect on pain is modulated from concentration-dependent, opposing effector systems involving both DA stimulatory and inhibitory receptor mechanisms. At high dosing, activation of D2 receptors enhancing DA functional activity produces an antinociceptive response that normally outweighs the hyperalgesia, but this effect becomes dissociable with inhibition of central DA activity.
Paalzow
G H
GH
Department of Biopharmaceutics and Pharmacokinetics, Uppsala University, Sweden.
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002395:Catecholamines / Q000096:biosynthesis; D004347:Drug Interactions; D004558:Electric Stimulation; D006930:Hyperalgesia / Q000139:chemically induced*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D013469:Sulpiride / Q000494:pharmacology*; D013997:Time Factors; D014828:Vocalization, Animal
D000700:Analgesics; D001552:Benzazepines; D002395:Catecholamines; D008781:Methyltyrosines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C022260:alpha-methyltyrosine methyl ester; D007980:Levodopa; D013469:Sulpiride