The noradrenaline precursor L-threo-3,4-dihydroxyphenylserine exhibits antinociceptive activity via central alpha-adrenoceptors in the mouse.
1. Systemic (s.c. or p.o.) administration of L-threo-3,4-dihydroxyphenylserine (droxidopa, L-threo-DOPS; L-DOPS), a noradrenaline precursor, at a dose-range of 100-800 mg kg-1, produced naloxone-resistant antinociception in a dose-dependent manner in the mouse, as assessed by the tail flick test, kaolin-induced writhing test and formalin-induced nociception test. 2. Antinociception elicited by L-DOPS (400 mg kg-1, s.c.) was not affected by s.c. injection of benserazide, a peripherally preferential L-aromatic amino acid decarboxylase inhibitor, but was suppressed by its intracerebroventricular (i.c.v.) injection. 3. I.c.v. or intrathecal (i.t.) administration of the non-selective alpha-blocker, phentolamine, significantly reduced L-DOPS-induced antinociception. 4. I.c.v. administration of the alpha 1-blocker, prazosin, but not the alpha 2-blocker, yohimbine, abolished the antinociceptive effects of L-DOPS. In contrast, both blockers, when administered i.t., exhibited significant inhibitory effects. 5. These results suggest that systemic L-DOPS produces opioid-independent antinociception, mediated by supraspinal alpha 1-adrenoceptors and by spinal alpha 1- and alpha 2-adrenoceptors and may predict additional therapeutic applications of L-DOPS as an analgesic.
Kawabata
A
A
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Japan.
Kasamatsu
K
K
Umeda
N
N
Takagi
H
H
D000284:Administration, Oral; D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000700:Analgesics / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001545:Benserazide / Q000494:pharmacology; D015103:Droxidopa / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009270:Naloxone / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects
D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D011942:Receptors, Adrenergic, alpha; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D009270:Naloxone; D001545:Benserazide; D015103:Droxidopa