Neuronal inhibitory effects of methadone are predominantly opioid receptor mediated in the rat spinal cord in vivo
Abstract
This study aims to assess whether the antinociceptive actions of methadone are mediated solely through opioid mechanisms, or whether its reported affinity for NMDA receptors has physiological relevance in vivo. Methadone is a μ‐opioid receptor agonist reported to relieve pain unresponsive to other opioids. It is a racemic mixture comprising d ‐ and l ‐optical isomers; the d ‐isomer has a lower affinity for opioid receptors, and both also exhibit NMDA receptor binding, likely to indicate antagonist activity. d ‐Methadone is antinociceptive in behavioural studies via non‐opioid mechanisms, which could include functional NMDA receptor‐blocking activity. Here we investigate the ability of d ‐ and dl ‐methadone to inhibit noxious and innocuous electrically‐evoked responses of dorsal horn neurones in the anaesthetized rat. Racemic methadone (5, 25, 50, 250 μg) applied spinally, dose‐relatedly inhibited the C‐fibre evoked response, input and wind‐up of the neurones, with a profile resembling that of morphine. d‐Methadone (5, 25, 50, 250, 500 μg) was also inhibitory, although less potent by a factor of between 13 and 48 depending on the neuronal measure; its profile of inhibition resembled that of the racemic mixture rather than an NMDA receptor antagonist. Both compounds had minimal effects on Aβ‐fibre‐evoked activity. The inhibitory effects of both d ‐ and dl ‐methadone on noxious‐evoked activity were naloxone reversible. The naloxone reversibility of d ‐methadone inhibitions is best interpreted as indicative of a purely opioid mechanism of action. However, the ability of naloxone to reverse the effects of d ‐methadone may also reflect a degree of synergy between weak NMDA antagonist and opioid agonist activity. Copyright 2000 European Federation of Chapters of the International Association for the Study of Pain
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Methadone is a long-acting μ-opioid receptor agonist and an NMDA-receptor antagonist with a half-life of 27 ± 12 hours that is effective in treating pain and opioid addiction.
“Methadone is a long-acting μ-opioid receptor agonist and an NMDA-receptor antagonist with a half-life of 27 ± 12 hours that is effective in treating pain and opioid addiction.15–17”
From A Preliminary Study Comparing Methadone and Buprenorphine in Patients with Chronic Pain and Coexistent Opioid Addiction (2013) · cites this paper as [15]
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- Authors
- Carpenter, K. J., Chapman, V., & Dickenson, A. H.
- Affiliations
- University College London (GB)
- Corresponding author
- Chapman, Victoria
- Venue
- European Journal of Pain
- Publisher
- Wiley
- Published
- 2000-03
- Volume
- 4
- Issue
- 1
- Pages
- 19-26
- ISSN
- 1090-3801 (ISSN-L)
- 1532-2149
- OpenAlex
- W2024033804
- Cited by
- 39
- References
- 24
- Citations by year
- 2025: 1 · 2024: 3 · 2020: 1 · 2019: 2 · 2017: 2 · 2016: 1 · 2014: 1 · 2013: 4
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Pain (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- European Commission
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Keywords
- methadone, NMDA receptor antagonism, antinociception, dorsal horn neurons, wind-up, naloxone reversibility, mu-opioid receptor agonists, analgesia
- MeSH terms
- Analgesics, Opioid, Animals, Electrophysiology, Male, Methadone, Naloxone, Narcotic Antagonists, Nerve Fibers, Nerve Fibers, Myelinated, Neurons, Receptors, Opioid, Spinal Cord, Stereoisomerism, Rats, Sprague-Dawley, Rats
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