Role of catecholamines and serotonin receptor subtypes in nefopam-induced antinociception.
The non-opiate analgesic nefopam has been shown to inhibit monoamines uptake, but little is known about receptor subtypes effectively involved in its analgesic effect. In vitro binding assays yielded the following measures of affinity (IC(50)): serotonergic 5-HT(2C) (1.4 microM), 5-HT(2A) (5.1 microM), 5-HT(3) (22.3 microM), 5-HT(1B) (41.7 microM), 5-HT(1A) (64.9 microM), adrenergic alpha(1) (15.0 microM) and dopaminergic D(1) (100 microM). Subcutaneous nefopam administration dose-dependently inhibited pain in acetic acid-induced writhing (1-30 mg kg(-1)) and formalin (1-10 mg kg(-1)) tests in the mouse. Pretreatments with adrenergic alpha(1) (prazosin) and alpha(2) (yohimbine), and serotonergic 5-HT(1B) (GR127935) receptor antagonists significantly increased the nefopam ED(50) in the writhing test. The serotonergic 5-HT(2C) (RS102221) and the dopaminergic D(2) (sulpiride) receptor antagonists inhibited nefopam antinociception in the formalin test. However, in both tests, nefopam analgesic activity was not modified by the following receptor antagonists: dopaminergic D(1) (SCH23390), serotonergic 5-HT(1A) (NAN-190, WAY100635), 5-HT(2A) (R96544, ketanserin), 5-HT(3) (tropisetron), and 5-HT(4) (SDZ205557). In conclusion, nefopam analgesic activity could be modulated by the adrenergic alpha(1) and alpha(2) receptors, the dopaminergic D(2) receptors, and the serotonergic 5-HT(1B) and 5-HT(2C) receptor subtypes.
Girard
Philippe
P
Biocodex, Service de Pharmacologie, Zac de Mercières 60200 Compiègne, France.
Coppé
Marie-Claude
MC
Verniers
Danielle
D
Pansart
Yannick
Y
Gillardin
Jean-Marie
JM
D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009340:Nefopam / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects*; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D011985:Receptors, Serotonin / Q000145:classification / Q000378:metabolism*; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology
D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D018712:Analgesics, Non-Narcotic; D015306:Biogenic Monoamines; D002395:Catecholamines; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D011985:Receptors, Serotonin; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D009340:Nefopam; D011224:Prazosin