Spinal sensory transmission is under descending biphasic modulation, and descending facilitation is believed to contribute to chronic pain. Descending modulation from the brainstem rostral ventromedial medulla (RVM) has been the most studied, whereas little is known about direct corticospinal modulation. Here, we found that stimulation in the anterior cingulate cortex (ACC) potentiated spinal excitatory synaptic transmission and this modulation is independent of the RVM. Peripheral nerve injury enhanced the spinal synaptic transmission and occluded the ACC-spinal cord facilitation. Inhibition of ACC reduced the enhanced spinal synaptic transmission caused by nerve injury. Finally, using optogenetics, we showed that selective activation of ACC-spinal cord projecting neurons caused behavioral pain sensitization, while inhibiting the projection induced analgesic effects. Our results provide strong evidence that ACC stimulation facilitates spinal sensory excitatory transmission by a RVM-independent manner, and that such top-down facilitation may contribute to the process of chronic neuropathic pain.

Presynaptic ATP P2X receptors have been proposed to play a role in modulating glutamate release from the first sensory synapse in the spinal cord. Using spinal cord slice preparations and patch-clamp recordings from dorsal horn neurons in lamina V of the rat spinal cord, we showed that the activation of P2X receptors by ␣,␤-methylene-ATP (␣␤m-ATP) resulted in a large increase in the frequency of spontaneous EPSCs (sEPSCs) and miniature EPSCs (mEPSCs). The increases in mEPSC frequency by ␣␤m-ATP were not blocked by the Ca 2ϩ channel blocker, 30 M La 3ϩ , but were abolished in a bath solution when Ca 2ϩ was omitted. The increases in mEPSC frequency by ␣␤m-ATP were blocked completely by the P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2Ј,4Ј-disulfonic acid (PPADS) at 10 M. Furthermore, the EPSCs evoked by dorsal root stimulation were potentiated by ␣␤m-ATP as well as by the ecto-ATPase inhibitor ARL67156 and were depressed in the presence of P2 receptor antagonists PPADS (10 M) and suramin (5 M). The effects of these compounds on the evoked EPSCs were associated with the changes in glutamate release probability of primary afferent central terminals. Our results indicate that ␣␤m-ATP-sensitive P2X receptors play a significant role in modulating excitatory sensory synaptic transmission in the spinal cord, and the potential role of endogenous ATP is suggested.

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TRPA1 is expressed in primary sensory neurons and hair cells, and it is proposed to be activated by cold stimuli, mechanical stimuli, or pungent ingredients. However, its role in regulating synaptic transmission has never been documented yet. In the present study, we examined whether activation of the TRPA1 channels affects synaptic transmission in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. A chief ingredient of mustard oil, allyl isothiocyanate (AITC), superfused for 2 min markedly increased the frequency and amplitude of spontaneous EPSCs (sEPSCs), which was accompanied by an inward current. Similar actions were produced by cinnamaldehyde and allicin. The AITC-induced increases in sEPSC frequency and amplitude were resistant to tetrodotoxin (TTX) and La 3ϩ , whereas being significantly reduced in extent in a Ca 2ϩ -free bath solution. In the presence of glutamate receptor antagonists CNQX and AP5, AITC did not generate any synaptic activities. The AITC-induced increases in sEPSC frequency and amplitude were reduced by ruthenium red, whereas being unaffected by capsazepine. AITC also increased the frequency and amplitude of spontaneous inhibitory postsynaptic currents; this AITC action was abolished in the presence of TTX or glutamate receptor antagonists. These results indicate that TRPA1 appears to be localized not only at presynaptic terminals on SG neurons to enhance glutamate release, but also in terminals of primary afferents innervating onto spinal inhibitory interneurons, which make synapses with SG neurons. This central modulation of sensory signals may be associated with physiological and pathological pain sensations.

Background and purpose: Although tramadol is known to exhibit a local anaesthetic effect, how tramadol exerts this effect is not understood fully. Experimental approach: The effects of tramadol and its metabolite mono-O-demethyl-tramadol (M1) on compound action potentials (CAPs) were examined by applying the air-gap method to frog sciatic nerves, and the results were compared with those of other local anaesthetics, lidocaine and ropivacaine. Key results: Tramadol reduced the peak amplitude of the CAP in a dose-dependent manner (IC 50 ¼ 2.3 mM). On the other hand, M1 (1-2 mM), which exhibits a higher affinity for m-opioid receptors than tramadol, did not affect CAPs. These effects of tramadol were resistant to the non-selective opioid receptor antagonist naloxone and the m-opioid receptor agonist, DAMGO, did not affect CAPs. This tramadol action was not affected by a combination of the noradrenaline uptake inhibitor, desipramine, and the 5-hydroxytryptamine uptake inhibitor, fluoxetine. Lidocaine and ropivacaine also concentrationdependently reduced CAP peak amplitudes with IC 50 values of 0.74 and 0.34 mM, respectively. Conclusions and implications: These results indicate that tramadol reduces the peak amplitude of CAP in peripheral nerve fibres with a potency which is less than those of lidocaine and ropivacaine, whereas M1 has much less effect on CAPs. This action of tramadol was not produced by activation of m-opioid receptors nor by inhibition of noradrenaline and 5-hydroxytryptamine uptake. It is suggested that the methyl group present in tramadol but not in M1 may play an important role in producing nerve conduction block.