N-methyl- d-aspartate receptor-mediated modulations of the anti-allodynic effects of 5-HT 1B/1D receptor stimulation in a rat model of trigeminal neuropathic pain

Abstract

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 (2.5 mg/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 (5 mg/kg, i.p.) also enhanced, whereas activation at glycine/NMDA site by d-cycloserine (3 mg/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.