Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems
OBJECTIVE: In pain management, alternative medications are necessary due to the development of tolerance to traditional opioid analgesics. Literature data suggest that N-methyl-D-aspartate (NMDA) receptor antagonizing drugs can induce antinociception, and can reduce the opioid requirement. Ketamine...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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AVES
2019-07-01
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| Series: | Psychiatry and Clinical Psychopharmacology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/24750573.2019.1605665 |
| _version_ | 1797920782319353856 |
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| author | Meral Erdinc Emre Uyar Ilker Kelle Hasan Akkoc |
| author_facet | Meral Erdinc Emre Uyar Ilker Kelle Hasan Akkoc |
| author_sort | Meral Erdinc |
| collection | DOAJ |
| description | OBJECTIVE: In pain management, alternative medications are necessary due to the development of tolerance to traditional opioid analgesics. Literature data suggest that N-methyl-D-aspartate (NMDA) receptor antagonizing drugs can induce antinociception, and can reduce the opioid requirement. Ketamine is a non-competitive NMDA receptor antagonist drug and has well-known antinociceptive properties. The drug acts not only on NMDA receptors but also has effects on the monoaminergic system and non-NMDA glutamatergic receptors which have vital roles in the regulation of pain. This study was conducted to investigate the serotonergic and glutamatergic involvement in low-dose ketamine (20 mg/kg) analgesia in mice. METHOD: The effects of serotonin were suppressed with two different ways; either the serotonin was depleted with p-chlorophenylalanine (pCPA, 150 mg/kg/d; 4 days) or the serotonin receptors were blocked with methiothepin (0.1 mg/kg), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors were antagonized with GYKI-52466 (20 mg/kg). Fluoxetine (20 mg/kg; 7 days) was used to increase the serotoninergic activity. We used a hotplate (HP) test to measure pain reaction latencies. Furthermore, we tested sustained analgesic effects of ketamine for six consecutive times (1-hour break between each test). RESULTS: In our experiment, ketamine treatment increased pain reaction latencies, yet it failed to increase the latencies when combined with antiserotonergic drugs, e.g. pCPA and methiothepin. The latencies were increased with AMPA receptor blockade, yet ketamine did not increase the analgesic effect of the AMPA receptor antagonist, i.e. GYKI-52466. In consecutive tests, ketamine was effective for 5 h, and the peak effect was seen at the 3rd-hour test. CONCLUSION: Our data suggest that the activity of the serotonergic system and AMPA receptors are necessary for ketamine to produce antinociceptive effects. In pain management, ketamine can offer an alternative option to traditional analgesics and may be useful to reduce opioid tolerance. |
| first_indexed | 2024-04-10T14:07:31Z |
| format | Article |
| id | doaj.art-317176f68b9f4ab6bffe07f86977a712 |
| institution | Directory Open Access Journal |
| issn | 2475-0581 |
| language | English |
| last_indexed | 2024-04-10T14:07:31Z |
| publishDate | 2019-07-01 |
| publisher | AVES |
| record_format | Article |
| series | Psychiatry and Clinical Psychopharmacology |
| spelling | doaj.art-317176f68b9f4ab6bffe07f86977a7122023-02-15T16:09:56ZengAVESPsychiatry and Clinical Psychopharmacology2475-05812019-07-0129325225610.1080/24750573.2019.16056651605665Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systemsMeral Erdinc0Emre Uyar1Ilker Kelle2Hasan Akkoc3Dicle UniversityDicle UniversityDicle UniversityDicle UniversityOBJECTIVE: In pain management, alternative medications are necessary due to the development of tolerance to traditional opioid analgesics. Literature data suggest that N-methyl-D-aspartate (NMDA) receptor antagonizing drugs can induce antinociception, and can reduce the opioid requirement. Ketamine is a non-competitive NMDA receptor antagonist drug and has well-known antinociceptive properties. The drug acts not only on NMDA receptors but also has effects on the monoaminergic system and non-NMDA glutamatergic receptors which have vital roles in the regulation of pain. This study was conducted to investigate the serotonergic and glutamatergic involvement in low-dose ketamine (20 mg/kg) analgesia in mice. METHOD: The effects of serotonin were suppressed with two different ways; either the serotonin was depleted with p-chlorophenylalanine (pCPA, 150 mg/kg/d; 4 days) or the serotonin receptors were blocked with methiothepin (0.1 mg/kg), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors were antagonized with GYKI-52466 (20 mg/kg). Fluoxetine (20 mg/kg; 7 days) was used to increase the serotoninergic activity. We used a hotplate (HP) test to measure pain reaction latencies. Furthermore, we tested sustained analgesic effects of ketamine for six consecutive times (1-hour break between each test). RESULTS: In our experiment, ketamine treatment increased pain reaction latencies, yet it failed to increase the latencies when combined with antiserotonergic drugs, e.g. pCPA and methiothepin. The latencies were increased with AMPA receptor blockade, yet ketamine did not increase the analgesic effect of the AMPA receptor antagonist, i.e. GYKI-52466. In consecutive tests, ketamine was effective for 5 h, and the peak effect was seen at the 3rd-hour test. CONCLUSION: Our data suggest that the activity of the serotonergic system and AMPA receptors are necessary for ketamine to produce antinociceptive effects. In pain management, ketamine can offer an alternative option to traditional analgesics and may be useful to reduce opioid tolerance.http://dx.doi.org/10.1080/24750573.2019.1605665ketamineantinociceptionopioid toleranceserotonergic systemglutamatergic system |
| spellingShingle | Meral Erdinc Emre Uyar Ilker Kelle Hasan Akkoc Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems Psychiatry and Clinical Psychopharmacology ketamine antinociception opioid tolerance serotonergic system glutamatergic system |
| title | Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems |
| title_full | Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems |
| title_fullStr | Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems |
| title_full_unstemmed | Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems |
| title_short | Anti-nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems |
| title_sort | anti nociceptive effects of low dose ketamine in mice may be mediated by the serotonergic systems |
| topic | ketamine antinociception opioid tolerance serotonergic system glutamatergic system |
| url | http://dx.doi.org/10.1080/24750573.2019.1605665 |
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