Modulation by adenosine of Adelta and C primary-afferent glutamatergic transmission in adult rat substantia gelatinosa neurons.

The present study examined the actions of adenosine on monosynaptic Adelta and C primary-afferent excitatory postsynaptic currents (EPSCs) recorded from substantia gelatinosa (SG) neurons of an adult rat spinal cord slice. In 67% of the neurons examined, adenosine reversibly decreased the amplitude of the Adelta-fiber EPSC, while in 13% of the neurons the amplitude was reduced or unaffected, which was followed by its increase persisting for several minutes after adenosine washout. The remaining neurons did not exhibit a change in the amplitude. The reduction in Adelta-fiber EPSC amplitude by adenosine was dose-dependent with an effective concentration for half-inhibition (EC50) value of 217 microM. When examined by using a paired-pulse stimulus, a ratio of the second to first Adelta-fiber EPSC amplitude under the reduction was larger than that of EPSC amplitude in the control, suggesting a presynaptic action of adenosine. In 69% of the neurons tested, the C-fiber EPSC was reversibly decreased in amplitude by adenosine (100 microM) by an extent comparable to that of Adelta-fiber EPSC; the remaining neurons were without adenosine actions. Similar inhibitory actions of adenosine were also seen in neurons where both Adelta-fiber and C-fiber EPSCs were elicited. Similar reduction in the Adelta-fiber or C-fiber EPSC amplitude was induced by an A1 adenosine-receptor agonist, N6-cyclopentyladenosine (1 microM), and the adenosine-induced reduction was not observed in the presence of an A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (1 microM). An A2a agonist, CGS 21680 (1 microM), did not significantly affect the Adelta-fiber EPSC amplitude. It is concluded that adenosine presynaptically inhibits monosynaptic Adelta-fiber and C-fiber transmission by a similar extent through the activation of the A1 receptor in many but not all SG neurons; this could contribute to at least a part of antinociception by intrathecally administered adenosine analogues and probably by endogenous adenosine.

Neurokinin release produced by capsaicin acting on the central terminals and axons of primary afferents: relationship with N-methyl-D-aspartate and GABA(B) receptors.

Capsaicin stimulates neurokinin release in the spinal cord when applied both centrally and peripherally. To determine whether these two actions have different mechanisms, we measured neurokinin 1 receptor (NK1R) internalization in rat spinal cord slices elicited by incubating the whole slice or just the dorsal root with capsaicin. NK1R internalization produced by incubating the slices with capsaicin was abolished by the NK1R antagonist RP-67580, by the vanilloid receptor 1 (VR1) antagonist capsazepine, and by eliminating Ca(2+) from the medium, but was not affected by the Na(+) channel blocker lidocaine. Therefore, the internalization was due to neurokinin release mediated by Ca(2+) entry through VR1 receptors, but did not require the firing of action potentials. Incubating the root with capsaicin produced NK1R internalization in the ipsilateral dorsal horn that was abolished when capsazepine or lidocaine was included in, or when Ca(2+) was omitted from, the medium surrounding the root. Therefore, the internalization was mediated by Ca(2+) entry in the axons through VR1, and required firing of action potentials. The efficacy of capsaicin when applied to the root (36+/-3%) was lower than when applied to the slice (91+/-3%), but its potency was the same (0.49 microM and 0.37 microM, respectively). We also investigated whether presynaptic N-methyl-D-aspartate (NMDA) and GABA(B) receptors modulate these two actions of capsaicin. Neither the NMDA receptor blocker MK-801 nor the GABA(B) agonist baclofen decreased NK1R internalization produced by 1 microM capsaicin applied to the slices, but they inhibited the internalization produced by 0.3 microM capsaicin applied to the slices or 1 microM capsaicin applied to the root. Therefore, capsaicin can produce neurokinin release from primary afferents 1) by a direct action on their central terminals and 2) by increasing the firing of action potentials on their axons. The first effect largely bypasses other modulatory mechanism, but the second does not.