Supraspinal vs spinal sites of the antinociceptive action of the subtype-selective NMDA antagonist ifenprodil.

The N-methyl-D-aspartate (NMDA) antagonist ifenprodil and several structurally related compounds are highly selective for the NR2B-containing receptor subtype. This selectivity could provide an explanation for the reported difference of the analgesic and side-effect profile of ifenprodil-like compounds from other NMDA antagonists. In this work, we have queried if the ifenprodil-induced antinociception can be attributed to the block of NMDA receptors in the spinal cord. Ifenprodil and some other NMDA antagonists (MK-801, memantine) were tested in a model of inflammatory pain (Randall-Selitto) in rats. The in vivo NMDA antagonism was assessed in anaesthetised rats on responses of spinal dorsal horn (DH) neurones to iontophoretic NMDA and in the model of single motor unit (SMU) wind-up. Ifenprodil, MK-801 and memantine dose-dependently increased nociceptive thresholds in the Randall-Selitto model. Antinociceptive doses of the channel blockers selectively antagonised NMDA responses of DH neurones and inhibited wind-up. In contrast, antinociceptive doses of ifenprodil did not show any NMDA antagonism in electrophysiological tests. Although ifenprodil did not inhibit the SMU responses to noxious stimuli in spinalised rats, it markedly and dose-dependently inhibited nociceptive SMU responses in sham-spinalised rats. These results argue against the spinal cord being the principal site of antinociceptive action of ifenprodil; supraspinal structures seem to be involved in this effect.

The N-methyl-D-aspartate antagonistic and opioid components of d-methadone antinociception in the rat spinal cord.

The d-enantiomer of the opioid methadone is a weak opioid with low micromolar affinity to the N-methyl-D-aspartate (NMDA) receptor. We have investigated the antinociception and in vivo NMDA antagonism after systemic administration of d-methadone in the rat spinal cord. d-Methadone caused antinociception in the Randall-Selitto model of inflammatory pain and inhibited the responses of hindlimb single motor units to noxious electrical and mechanical stimulation (ED(50) 6.6, 6.8 and 7.2 mg/kg intravenous (i.v.), respectively); the wind-up of these responses was only inhibited at the dose almost completely abolishing the baseline responses. d-Methadone inhibited the activity of spinal dorsal horn neurones evoked by both iontophoretic NMDA and (R, S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA, ED(50) 5.7 and 8.2 mg/kg i.v., respectively). After pre-treatment with naloxone, d-methadone was unable to inhibit nociception in the Randall-Selitto model, the NMDA- or AMPA-evoked neuronal activity or the motoneurone wind-up. Thus, in the antinociceptive dose range, the NMDA antagonism does not appear to contribute to the mechanism of d-methadone antinociception.

Antinociception and (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid antagonism by gabapentin in the rat spinal cord in vivo.

Gabapentin, a novel anticonvulsant and analgesic with an unknown mechanism of action, was tested on spinal dorsal horn neurone activity evoked by iontophoretically applied N-methyl-D-aspartic acid (NMDA) and (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and on nociceptive responses of single motor units (SMU) in anaesthetised rats. Gabapentin (10-215 mg/kg, i.v.) dose-dependently and selectively inhibited AMPA-evoked neuronal responses (ED50 106+/-24 mg/kg); no effect on NMDA-evoked activity was observed. In the same dose-range, gabapentin (10-215 mg/ kg, i.v.) dose-dependently reduced SMU responses to noxious electrical and mechanical stimulation. We conclude that gabapentin acts as an AMPA antagonist in the rat spinal cord, and that this mechanism is likely to substantially contribute to the antinociceptive effect of the drug.

The antinociceptive effects of morphine, desipramine, and serotonin and their combinations after intrathecal injection in the rat.

UNLABELLED: Antinociception can be produced at the spinal level by activation of opioidergic, noradrenergic, and serotonergic systems. We tested the antinociceptive effects of combined activation of all three systems. Antinociception was assessed in the rat tail-flick test, and drugs were administered via an intrathecal catheter. Morphine, the norepinephrine uptake inhibitor desipramine, and serotonin produced antinociception of their own. The combination of subthreshold doses of morphine 1 microg and of desipramine 3 microg produced pronounced antinociception that was antagonized by yohimbine. The combination of subthreshold morphine with serotonin 50 microg or desipramine with serotonin caused only small antinociceptive effects. When morphine combined with desipramine was decreased to a subthreshold dose, we observed pronounced antinociception when a subthreshold dose of serotonin was added. A complex interaction can be supposed by results obtained with antagonists. The activation of all three neurotransmitter systems with small doses of agonists may represent an effective principle for pain control at the spinal level. IMPLICATIONS: Pain sensations are modulated at the spinal level by opioids, noradrenergic drugs, and serotonin. Using a rat model, we showed that the concurrent use of drugs from each of these classes produces good pain control at doses that should avoid the side effects associated with larger doses of each individual drug.