Genetic factors and the role of the NMDA receptor in pain modulation and the effect of opioids

Pain perception and the response to opioid analgesics are determined by a number of factors, among which genetic variability and the activation of the NMDA-receptor for glutamate play an important role. The effects of two clinically available NMDA-receptor antagonists, ketamine (KET) and dextromethorphan (DEX), were evaluated on an animal model of acute nociception, the hot plate test, and on human experimental acute ischemic pain. Neither KET nor DEX induced antinociception, but potentiated morphine (MO) in the animal model. KET combined with MO had a short-lasting effect, whereas DEX induced a dose-dependent, long lasting potentiation of MO in Sprague-Dawley (SD) rats. In human experimental ischemic pain, continuous intravenous infusion of KET induced significant analgesia, while oral DEX had no effect. Neither of the two drugs had any influence on MO analgesia in humans.

The role of genetic factors in pain modulation and the effects of opioid analgesics was studied in four rat strains: SD, Wistar-Kyoto (WK), Spontaneously Hypertensive (SHR) and Dark-Agouti (DA). Significant differences were found in the nociceptive threshold, the response to morphine, development of tolerance and the effect of DEX on MO antinociception among the animal strains. Genetic differences in the development of peripheral neuropathy following unilateral sciatic nerve ischemia were assessed in SD rats from different vendors (BK-SD and DK-SD), SHR, WK and DA rats. Significant variations were found not only in the pain behaviors, but also in the extent of morphological damage in the sciatic nerve, which was less in DAs compared with the other strains. DK-SD showed a rapid development and consistent hyperalgesia on both the injured and the non-injured side ("mirror pain"-like phenomenon). This substrain was further used for evaluating the effect of methadone, an opioid with NMDA-receptor blocking properties, on this peripheral neuropathy in rats. Methadone in single dose administration showed a comparable effect with MO on pain-like behaviors on the lesioned side, but had a more consistent effect on the contralateral side and it also exerted longer-lasting antinociception in all tests. NMDA-receptor antagonists can induce antinociception/analgesia and potentiate the effect of opioids, but the route of administration and the specific pharmacokinetic profile of each drug are essential factors in order to achieve optimal outcome with reduced adverse effects. Genetic traits have a significant impact on pain-like behaviors, the effects of drugs on acute nociception and in the development of peripheral neuropathy and these factors are important to be taken into account in both pain research and clinical conditions.

List of scientific papers

I. Plesan A, Hedman U, Xu XJ, Wiesenfeld-Hallin Z (1998). Comparison of ketamine and dextromethorphan in potentiating the antinociceptive effect of morphine in rats. Anesth Analg. 86(4):825-829.
https://pubmed.ncbi.nlm.nih.gov/9539609

II. Plesan A, Sollevi A, Segerdahl M. The NMDA-receptor antagonist dextrometorphan lacks analgesic effect in a human experimental ischemic pain model. [Submitted]

III. Hoffmann O, Plesan A, Wiesenfeld-Hallin Z (1998). Genetic differences in morphine sensitivity, tolerance and withdrawal in rats. Brain Res. 806(2):232-237.
https://pubmed.ncbi.nlm.nih.gov/9739144

IV. Plesan A, Hoffmann O, Xu XJ, Wiesenfeld-Hallin Z (1999). Genetic differences in the antinociceptive effect of morphine and its potentiation by dextromethorphan in rats. Neurosci Lett. 263(1):53-56.
https://pubmed.ncbi.nlm.nih.gov/10218909

V. Plesan A, Hao JX, Wiesenfeld-Hallin Z. A comparision between the antinociceptive effect of methadone and morphine in a rat model of peripheral neuropathy. [Submitted]