Boris Chizh

NMDA receptor antagonists as analgesics: focus on the NR2B subtype

Ifenprodil and a group of related compounds are selective antagonists of NR2B-containing NMDA receptors. These compounds are antinociceptive in a variety of preclinical pain models and have a much lower side-effect profile compared with other NMDA receptor antagonists. It remains unclear whether the improved safety of these compounds is due to their subtype selectivity or to a unique mode of inhibition of the receptor. Human trials have so far confirmed the good tolerability of these subtype-selective NMDA receptor antagonists; however, whether they are as effective as other NMDA receptor antagonists in pain patients remains to be demonstrated.

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 antiallodynic effect of NMDA antagonists in neuropathic pain outlasts the duration of the in vivo NMDA antagonism

Clinical reports have described a long-lasting relief in neuropathic pain patients treated with NMDA receptor antagonists; it is unclear, however, what mediates this effect. In this work, we have used two NMDA antagonists of different class to investigate if the antiallodynic effects in a rat neuropathy model can outlast their in vivo NMDA antagonism. Both the uncompetitive NMDA antagonist ketamine and the glycine(B) antagonist MRZ 2/576 inhibited neuronal responses to iontophoretic NMDA in anaesthetised rats with the time course consistent with their known pharmacokinetics (t(1/2) approximately 10-12min, similar in control and nerve-injured rats). Surprisingly, the antiallodynic effects of the same doses of the NMDA antagonists in the neuropathic pain model were long-lasting (>3h with ketamine, >24h with MRZ 2/576). The effect of ketamine was further prolonged (>24h) when combined with a short-acting opioid, fentanyl, which only produced a short effect ( approximately 40min) when given alone. The duration of centrally mediated side effects of ketamine and MRZ 2/576 was short, similar to the in vivo NMDA antagonism. We speculate that NMDA receptor blockade may down-regulate the central sensitisation triggered by nerve injury, resulting in a long-lasting antiallodynic effect. Development of short-acting NMDA antagonists could represent a strategy for improving their tolerability.

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.

Antiallodynic effects of NMDA glycineB antagonists in neuropathic pain: Possible peripheral mechanisms

NMDA receptors are implicated in central sensitisation underlying chronic pain, and NMDA antagonists have a potential for the treatment of neuropathic pain. Functional NMDA receptors are also present on primary afferents, where they may play a role in pro-nociceptive plasticity. The importance of this mechanism in neuropathic pain remains unclear. In the present work, we have compared in models of chronic pain the effects of NMDA antagonists at the glycine(B) site with different central access. L-701,324 (the centrally active antagonist) and 5,7-dichlorokynurenic acid (5,7-DCK, known to have limited central access) were tested after systemic administration in rats in the formalin test and in two models of neuropathic pain. The ability of these compounds to exert central actions (sedation, ataxia) was tested in the open field locomotion test; central NMDA antagonism in vivo was tested in anaesthetised rats on responses of spinal cord neurones to iontophoretic NMDA. Both L-701,324 (2.15-21.5 mg/kg i.p.) and 5,7-DCK (10-46.4 mg/kg i.v.) dose-dependently inhibited Phase II of formalin-evoked behaviour. Likewise, both compounds reversed cold allodynia in the chronic constriction injury model and tactile allodynia in animals with spinal nerve ligation. However, only L-701,324 was able to inhibit neuronal responses to NMDA in the antihyperalgesic dose range; 5,7-DCK was inactive on NMDA responses up to 46.4 mg/kg i.v. or 68.1 mg/kg i.p. Consistent with the lack of inhibition of central NMDA-evoked activity, 5,7-DCK did not alter spontaneous behaviour in the open field test, whereas it was significantly inhibited by L-701,324. Thus, peripheral NMDA receptors may substantially contribute to the efficacy of NMDA antagonists in neuropathic pain.

Stimulant effect of thyrotropin-releasing hormone and its analog, RGH 2202, on the diaphragm respiratory activity, and their antagonism with morphine: possible involvement of the N-methyl-D-aspartate receptors

Thyrotropin-releasing hormone (TRH) was reported to stimulate respiration and abolish the respiratory depressant effect of morphine-like analgesics. Some TRH analogs which have a diminished hormonal activity may be of interest as potential non-specific opioid antagonists. The mechanism of this effect of TRH and its analogs is still unclear. Thus, in the present work the respiratory stimulant effect of TRH and its analog RGH 2202 was studied in the urethane-anesthetized vagotomized artificially-ventilated rats. The integrated diaphragmatic electromyogram was used to evaluate the effects of the drugs. TRH and RGH 2202 administered either i.v. or directly onto the dorsal medullary surface significantly increased the respiratory activity of the diaphragm. TRH and RGH 2202 also effectively antagonized the diaphragm activity depression caused by morphine. The latency, time course and activity of RGH 2202 turned out to be close to those of TRH. The possible involvement of N-methyl-D-aspartate (NMDA) receptors in the mechanism of action of TRH and RGH 2202 was also investigated. It was shown that the non-competitive NMDA antagonists ketamine and MK-801 and the competitive antagonist D-amino-5-phosphonovalerate after local or i.v. administration prevented or discontinued the diaphragm activity stimulation by TRH and RGH 2202. Moreover, they blocked the antagonistic action of TRH and RGH 2202 on the morphine-induced diaphragm activity depression. Thus, we conclude, that TRH and RGH 2202 cause similar stimulant effects on the respiratory activity of the diaphragm and effectively antagonize its depression by morphine. These effects are likely to be mediated by the NMDA receptors located in the central respiratory structures.

THE RACE TO CONTROL PAIN: MORE PARTICIPANTS, MORE TARGETS

Although the list of targets discussed here is by no means complete, several trends in industrial approaches to developing new analgesics can be highlighted. The chase for a powerful wide-spectrum analgesic mechanism (exemplified by nACh receptors), a potential alternative to opioids, continues. However, it could prove difficult to dissociate acute nociceptive transmission from other normal physiological processes and side-effects are likely to remain a major issue. Quite a different strategy is the development of indication-specific analgesics with a particular efficacy for certain types of pain. This might prove fruitful for chronic pain, where specific pro-nociceptive plasticity occurs in the nociceptive system. Targeting such pathophysiological mechanisms (e.g. ectopic activity of injured peripheral nerves, inflammatory sensitization, abnormally high or tonic central release of glutamate, etc.) will spare normal physiological processes, thus increasing the safety and efficacy of treatment. As this approach seems to gain industrial attention, further targets are likely to be identified and exploited to bring the much-needed improvement in controlling pain.

Modulation of spinal nociception by GluR5 kainate receptor ligands in acute and hyperalgesic states and the role of gabaergic mechanisms

GluR5 receptors modulate spinal nociception, however, their role in nociceptive hypersensitivity remains unclear. Using behavioural and electrophysiological approaches, we have investigated several GluR5 ligands in acute and hyperalgesic states. Furthermore, as the GABAergic system plays a role in GluR5 mediated effects in the brain, we also analysed the interaction between GluR5 agonists and GABA(A) antagonists in the spinal cord. In young rats in vivo, the GluR5 selective agonist ATPA was antinociceptive and antihyperalgesic in a model of inflammatory hyperalgesia (ED(50) approximately 4.6 and approximately 5.2 mg/kg, respectively), whereas the GluR5/GluR6 agonist SYM2081 was only antihyperalgesic. ATPA, but not SYM2081, was also able to inhibit nociceptive motoneurone responses in anaesthetised adult rats after intrathecal administration. In hemisected spinal cords in vitro, SYM2081 was inactive, whereas ATPA and another GluR5 agonist, (S)-5-iodowillardiine, inhibited nociceptive reflexes (EC(50) 1.1+/-0.4 micro M and 0.36+/-0.05 micro M, respectively). Both GluR5 agonists also inhibited motoneurone responses to repetitive dorsal root stimulation and their cumulative depolarisation, a correlate of wind-up. The GABA(A) antagonists bicuculline (10 micro M) and SR95531 (1 micro M) enhanced polysynaptic responses to single stimuli but abolished the cumulative depolarisation. Both bicuculline and SR95531 significantly attenuated the inhibition of nociceptive responses by 1 micro M ATPA (by approximately 50%). We conclude that selective GluR5 kainate receptor activation inhibits spinal nociception and its sensitisation caused by ongoing peripheral nociceptive drive. GABA(A) receptors are involved in tonic inhibition of segmental responses, but contribute to their sensitisation by repetitive primary afferent stimulation. Furthermore, there is a cross-talk between the two systems, presumably due to GluR5-mediated activation of GABAergic inhibitory interneurones in the spinal cord.

Spinal nociceptive processing: NMDA receptors and modulation by neuropeptides

The excitatory amino acids, glutamate and aspartate, have long been recognised as being fundamental to the processing of nociceptive and non-nociceptive information in the spinal cord (for review see [1]). Both of these neurotransmitters are released into the dorsal horn following noxious peripheral stimulation [2]. In the early 1960s it was found that glutamate and aspartate strongly excited spinal neurones [3] and that various analogues of these amino acids were also potently active. Amongst these was NMDA [4]. It was proposed that, based upon the differential potencies of various excitant amino acids on different types of spinal neurones, a specific NMDA sensitive site existed [5, 6]. It was also found that Mg2+ could selectively inhibit responses to NMDA in the spinal cord [7] which has led to the current understanding of the voltage dependent Mg2+ block of the NMDA receptor [8]. Since these early experiments the NMDA receptor has been extensively characterised and molecular cloning techniques have revealed a variety of subunits that have a differential distribution throughout the central nervous system.