Effects of tramadol on substantia gelatinosa neurons in the rat spinal cord: an in vivo patch-clamp analysis.
Tramadol is thought to modulate synaptic transmissions in the spinal dorsal horn mainly by activating µ-opioid receptors and by inhibiting the reuptake of monoamines in the CNS. However, the precise mode of modulation remains unclear. We used an in vivo patch clamp technique in urethane-anesthetized rats to determine the antinociceptive mechanism of tramadol. In vivo whole-cell recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) and spontaneous excitatory postsynaptic currents (sEPSCs) were made from substantia gelatinosa (SG) neurons (lamina II) at holding potentials of 0 mV and -70 mV, respectively. The effects of intravenous administration (0.5, 5, 15 mg/kg) of tramadol were evaluated. The effects of superfusion of tramadol on the surface of the spinal cord and of a tramadol metabolite (M1) were further analyzed. Intravenous administration of tramadol at doses >5 mg/kg decreased the sEPSCs and increased the sIPSCs in SG neurons. These effects were not observed following naloxone pretreatment. Tramadol superfusion at a clinically relevant concentration (10 µM) had no effect, but when administered at a very high concentration (100 µM), tramadol decreased sEPSCs, produced outward currents, and enhanced sIPSCs. The effects of M1 (1, 5 mg/kg intravenously) on sEPSCs and sIPSCs were similar to those of tramadol at a corresponding dose (5, 15 mg/kg). The present study demonstrated that systemically administered tramadol indirectly inhibited glutamatergic transmission, and enhanced GABAergic and glycinergic transmissions in SG neurons. These effects were mediated primarily by the activation of μ-opioid receptors. M1 may play a key role in the antinociceptive mechanisms of tramadol.
Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Hiroyuki
H
Yamasaki
Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Yusuke
Y
Funai
Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Tomoharu
T
Funao
Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Takashi
T
Mori
Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Kiyonobu
K
Nishikawa
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods*; D017207:Rats, Sprague-Dawley; D013376:Substantia Gelatinosa / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects; D014147:Tramadol / Q000031:analogs & derivatives / Q000494:pharmacology*
D000700:Analgesics; C080580:O-demethyltramadol; D014147:Tramadol