N-methyl-D-aspartate receptor-mediated modulations of the anti-allodynic effects of 5-HT1B/1D receptor stimulation in a rat model of trigeminal neuropathic pain.
Previous studies showed that triptans and other 5-HT(1B/1D)-receptor agonists attenuate hyper-responsiveness to mechanical stimulation of the face in a rat model of trigeminal neuropathic pain, probably by activating 5-HT(1B/1D)-receptors on primary afferent nociceptive fibers. We now tested whether blockade of post-synaptic receptors for the excitatory amino acid glutamate released by these fibers would increase this action. We thus evaluated whether (±)1-hydroxy-3-aminopyrrolidine-2-one (HA-966), an antagonist at the glycine/D-serine site of N-methyl-D-aspartate (NMDA)-receptors, would potentiate the anti-allodynic action of dihydroergotamine and zolmitriptan in rats with chronic constriction injury to the infraorbital nerve (CCI-ION). Complementary studies were performed with other NMDA-receptor ligands and in rats with chronic constriction injury to the sciatic nerve (CCI-SN) for comparison. Injury was produced by loose ligatures of the nerves. Responsiveness to mechanical stimulation (vibrissae or hindpaw territories) with von Frey filaments was used to evaluate allodynia 2 weeks after nerve ligature. Rats received NMDA-receptor ligands or saline 20 min before dihydroergotamine (25-100 μg/kg, i.v.) or zolmitriptan (25-100 μg/kg, s.c.). HA-966 (2.5mg/kg, s.c.), inactive on its own, enhanced the anti-allodynic effects of dihydroergotamine (eightfold increase) and zolmitriptan (threefold increase) in CCI-ION rats, but these drugs exerted no effects in allodynic CCI-SN rats. NMDA-receptor blockade by memantine (5mg/kg, i.p.) also enhanced, whereas activation at glycine/NMDA site by D-cycloserine (3mg/kg, i.p.) reduced the anti-allodynic properties of zolmitriptan in CCI-ION rats. Combined administration of NMDA-receptor antagonist and 5-HT(1B/1D)-receptor agonist may be a promising approach for alleviating trigeminal neuropathic pain.
INSERM U894, Neuropsychopharmacology, Centre de Psychiatrie et Neurosciences, 91 Boulevard de l'Hôpital, Paris F-75013, France. valerie.kayser@upmc.fr
Valérie
V
Kayser
Alban
A
Latrémolière
Michel
M
Hamon
Sylvie
S
Bourgoin
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D003523:Cycloserine / Q000494:pharmacology; D004087:Dihydroergotamine / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D023303:Oxazolidinones / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012585:Sciatica / Q000188:drug therapy; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D014277:Trigeminal Neuralgia / Q000188:drug therapy*; D014363:Tryptamines / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D018691:Excitatory Amino Acid Antagonists; D023303:Oxazolidinones; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; D058825:Serotonin 5-HT1 Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan; D004087:Dihydroergotamine; D003523:Cycloserine; C001369:1-hydroxy-3-amino-2-pyrrolidone