1. 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
G H Paalzow J Pharmacol Exp Ther. 1992 Nov;263(2):470-9.
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.
2. Comparison of the methyl ester of L-tyrosine hydrochloride and its methanol monosolvate
Iwona Bryndal, Mariusz Jaremko, Łukasz Jaremko, Tadeusz Lis Acta Crystallogr C. 2006 Mar;62(Pt 3):o111-4. doi: 10.1107/S0108270106002137. Epub 2006 Feb 11.
Solvent-free (2S)-methyl 2-ammonio-3-(4-hydroxyphenyl)propionate chloride, C10H14NO3+.Cl-, (I), and its methanol solvate, C10H14NO3+.Cl-.CH3OH, (II), are obtained from different solvents: crystallization from ethanol or propan-2-ol gives the same solvent-free crystals of (I) in both cases, while crystals of (II) were obtained by crystallization from methanol. The structure of (I) is characterized by the presence of two-dimensional layers linked together by N-H...Cl and O-H...Cl hydrogen bonds and also by C-H...O contacts. Incorporation of the methanol solvent molecule in (II) introduces additional O-H...O hydrogen bonds linking the two-dimensional layers, resulting in the formation of a three-dimensional network.
3. The effects on central dopamine function of chronic L-dopa (methyl ester hydrochloride) treatment of mice
J Tabar, M Hashizume, C J Cook, P M Beart, D M Jackson Pharmacol Biochem Behav. 1989 May;33(1):139-46. doi: 10.1016/0091-3057(89)90443-7.
Mice were treated for 28 days with drinking water containing L-DOPA methyl ester hydrochloride (DME) plus carbidopa, carbidopa alone, or with the vehicle. All mice were then given the vehicle for 1 day and behavioural and biochemical assessments made on the 29th day. On average, mice consumed between 181 and 302 mg/kg of DME (expressed as the base) each day. In behavioural experiments DME- and carbidopa-treated mice were subsensitive to the locomotor stimulating effects of apomorphine, after their pretreatment with reserpine plus alpha-methyl-p-tyrosine to remove endogenous stores of dopamine and to stop its synthesis. Even mice pretreated for only one day with chronic DME or carbidopa displayed some subsensitivity to apomorphine challenge, but the effect was more marked the longer the chronic treatment. Other mice were chronically treated for 28 days with alpha-methylDOPA or vehicle, and these mice when challenged with apomorphine after dopamine depletion (as described above), were also markedly subsensitive to the locomotor activating effects of apomorphine. There were no changes in sensitivity of drug-treated mice to the hypothermic effects of apomorphine, to the stereotypy-inducing effects of apomorphine or d-amphetamine, or to the locomotor activating effects of L-DOPA itself or to bromocriptine. There were, however, some changes in the basal grooming behaviour of both DME- and carbidopa-treated mice, and in their response to SKF38393 challenge. Striatal binding studies with [3H]-spiperone and [3H]-SCH23390 indicated that there were no marked changes in Kd or Bmax of either D-1 or D-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
