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.
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.
Yanarates
Omer
O
Department of Anesthesiology and Reanimation, Gulhane Military Academy of Medicine, Ankara, Turkey.
Dogrul
Ahmet
A
Yildirim
Vedat
V
Sahin
Altan
A
Sizlan
Ali
A
Seyrek
Melik
M
Akgül
Ozgür
O
Kozak
Orhan
O
Kurt
Ercan
E
Aypar
Ulku
U
D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009434:Neural Pathways / Q000187:drug effects*; D010146:Pain / Q000188:drug therapy / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D010149:Postoperative Pain / Q000188:drug therapy; D011930:Reaction Time / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D014147:Tramadol / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000700:Analgesics; D000701:Analgesics, Opioid; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor; C080580:O-demethyltramadol; D012701:Serotonin; D014147:Tramadol