N‐Methyl‐d‐aspartate receptor modulators block hyperalgesia induced by acute low‐dose morphine

Abstract

1. Following opioid-induced antinociception in mice, hyperalgesic responses may be observed. The present study was designed to evaluate the effect of different N-methyl-d-aspartate (NMDA) receptor modulators (magnesium, dextromethorphan, d-serine) on the development of morphine-induced hyperalgesia in mice. The tail-flick test was used to assess the effects of morphine alone and in combination with the NMDA receptor modulators. 2. Administration of a single low dose (2 mg/kg) of morphine to mice produced antinociception that was followed by hyperalgesia. 3. Administration of magnesium sulphate (5 mg/kg) and d-serine (10 mg/kg) alone produced a transient antinociceptive response, whereas dextromethorphan (10 mg/kg) alone produced a prolonged antinociceptive response that had a relatively delayed onset after 4 h. 4. When coadministered with morphine, the NMDA receptor blockers magnesium (2 mg/kg) and dextromethorphan (2 and 5 mg/kg) and the NMDA receptor agonist d-serine (2, 5 and 10 mg/kg), maintained the duration of the antinociceptive response to morphine and inhibited the development of the hyperalgesic response. Coadministration of dextromethorphan (10 mg/kg) with morphine produced antinociception at 30-120 min and at 4-24 h. 5. The results of the present study suggest that coadministration of low-dose NMDA receptor antagonists, as well as the NMDA receptor agonist d-serine, with morphine can inhibit morphine-induced hyperalgesia.

Anti-hyperalgesic effect of systemic magnesium sulfate in carrageenan-induced inflammatory pain in rats: influence of the nitric oxide pathway

“…Our finding that MS did not modify the mechanical PWT on the contralateral (non-inflamed) paw, provided evidence that MS does not disturb the behavioral assessment of nociceptive sensitivity in rats. This is supported by previous findings that low doses of MS do not induce any adverse effects in rats [7,23,24].…”

Why mu‐opioid agonists have less analgesic efficacy in neuropathic pain?

“…Several studies have demonstrated the involvement of enhanced spinal NMDA activity in the loss of antinociceptive efficacy of morphine in nerve‐injured animals, since NMDA antagonists prevented not only the development of hypersensitivity, but also the loss of antiallodynic efficacy of intrathecal morphine (Bian et al., ; Gupta, Gupta, & Tripathi, ; Mao et al., ; Ossipov et al., 1995b). Patients receiving NMDA antagonists, such as ketamine, alongside opioids have also exhibited recovery of opioid analgesic effect (da Cunha Leal, Clivatti, Garcia, & Sakata, ; Lee, Song, Jeong, & Park, ; Pasero & McCaffery, ).…”

Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin

“…Central pain sensitization, NMDA receptor activity, and spinal dynorphin release have all been implicated as the source of OIH (Daeninck and Bruera, 1999 ; Gardell et al, 2002 ; Koppert and Schmelz, 2007 ; Gupta et al, 2011 ). OIH is comparable to neuropathic pain in both its neuro-inflammatory qualities and central sensitization processes.…”