Spinal 5-HT7 receptors play an important role in the antinociceptive and antihyperalgesic effects of tramadol and its metabolite, O-Desmethyltramadol, via activation of descending serotonergic pathways.

Abstract

BACKGROUND:

Tramadol is an analgesic drug, and its mechanism of action is believed to be mediated by the mu-opioid receptor. A further action of tramadol has been identified as blocking the reuptake of serotonin (5-HT). One of the most recently identified subtypes of 5-HT receptor is the 5-HT7 receptor. Thus, the authors aimed to examine the potential role of serotonergic descending bulbospinal pathways and spinal 5-HT7 receptors compared with that of the 5-HT2A and 5-HT3 receptors in the antinociceptive and antihyperalgesic effects of tramadol and its major active metabolite O-desmethyltramadol (M1) on phasic and postoperative pain models.

METHODS:

Nociception was assessed by the radiant heat tail-flick and plantar incision test in male Balb-C mice (25-30 g). The serotonergic pathways were lesioned with an intrathecal injection of 5,7-dihydroxytryptamine. The selective 5-HT7, 5-HT2, and 5-HT3 antagonists; SB-269970 and SB-258719; ketanserin and ondansetron were given intrathecally.

RESULTS:

Systemically administered tramadol and M1 produced antinociceptive and antihyperalgesic effects. The antinociceptive effects of both tramadol and M1 were significantly diminished in 5-HT-lesioned mice. Intrathecal injection of SB-269970 (10 microg) and SB-258719 (20 microg) blocked both tramadol- and M1-induced antinociceptive and antihyperalgesic effects. Ketanserin (20 mumicrog) and ondansetron (20 microg) were unable to reverse the antinociceptive and antihyperalgesic effects of tramadol and M1.

CONCLUSIONS:

These findings suggest that the descending serotonergic pathways and spinal 5-HT7 receptors play a crucial role in the antinociceptive and antihyperalgesic effects of tramadol and M1.

• Authors: Omer Yanarates, Ahmet Dogrul, Vedat Yildirim, Altan Sahin, Ali Sizlan, Melik Seyrek, Ozgür Akgül, Orhan Kozak, Ercan Kurt, Ulku Aypar
• Journal: Anesthesiology (Anesthesiology) Vol. 112 Issue 3 Pg. 696-710 (Mar 2010) ISSN: 1528-1175 [Electronic] United States
• PMID: 20179508 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Analgesics, Opioid
• Receptors, Serotonin
• Serotonin Antagonists
• serotonin 7 receptor
• O-demethyltramadol
• Serotonin
• Tramadol

Topics

• Analgesics (pharmacology)
• Analgesics, Opioid (therapeutic use)
• Animals
• Dose-Response Relationship, Drug
• Hot Temperature
• Hyperalgesia (drug therapy)
• Injections, Spinal
• Male
• Mice
• Mice, Inbred BALB C
• Neural Pathways (drug effects)
• Pain (drug therapy, psychology)
• Pain Measurement (drug effects)
• Pain, Postoperative (drug therapy)
• Reaction Time (drug effects)
• Receptors, Serotonin (drug effects)
• Serotonin (physiology)
• Serotonin Antagonists (administration & dosage, pharmacology)
• Spinal Cord (drug effects, metabolism)
• Tramadol (analogs & derivatives, therapeutic use)