Tramadol inhibits glutamatergic excitatory synaptic transmission in rat spinal dorsal horn neurons by activating μ-opioid receptors without monoamine uptake inhibition

Abstract

A clinically-used analgesic tramadol reportedly not only activates μ-opioid receptors but also exhibits various actions including monoamine uptake inhibition in the CNS. Both opioids and monoamines such as norepinephrine (NE) and serotonin (5-HT) are known to modulate excitatory synaptic transmission in substantia gelatinosa (SG; lamina II) neurons of the spinal cord. In order to know which of μ-opioid, NE and 5-HT receptor activation is mainly involved in the antinociceptive action of tramadol, we examined the effects of a metabolite of tramadol, mono-O-demethyl-tramadol (M1; 1 mM), NE and 5-HT on glutamatergic excitatory transmission by applying the whole-cell patch-clamp technique to SG neurons of adult rat spinal cord slices. M1 produced an outward current mediated by μ-opioid receptors at -70 mV in about 40% of SG neurons examined; NE (20 μM) produced an outward current in a SG neuron which did not respond to M1. M1 persistently decreased the frequency of spontaneous EPSC by activating μ-opioid receptors whereas NE (20 μM) did not affect sEPSC frequency and 5-HT (40 μM) decreased sEPSC frequency, which was followed by its increase. It is concluded that M1 inhibits glutamatergic excitatory transmission in a manner different from those of NE and 5-HT. μ-Opioid receptor activation but not monoamine uptake inhibition could contribute to the antinociceptive action of tramadol at the spinal cord level. [J Physiol Sci. 2008;58 Suppl:S133]