Abstract
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.
Highlights
Tramadol is widely used as an analgesic for the treatment of postoperative, cancer, or chronic neuropathic pain [1, 2]
We evaluated the paw withdrawal response to noxious mechanical stimuli for behavioral analysis in conscious rats to determine the analgesic effects of systemic tramadol (Fig 1)
The present study used an in vivo patch-clamp technique to investigate the effects of the systemic administration of tramadol on substantia gelatinosa (SG) neurons in the spinal dorsal horn
Summary
Tramadol is widely used as an analgesic for the treatment of postoperative, cancer, or chronic neuropathic pain [1, 2]. Its analgesic effects have been reported following its systemic administration in rat acute and chronic pain models [3, 4]. Tramadol itself acts on several ion channels and receptors, including sodium channels, GABAA receptors, NMDA receptors, and nicotinic acetylcholine receptors [8,9,10]. These findings suggest that sensory nociceptive transmission in the spinal cord may be modulated in several different ways
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