Modulation of excitatory synaptic transmission by nociceptin in superficial dorsal horn neurones of the neonatal rat spinal cord.

1. The modulatory actions of nociceptin/orphanin FQ on excitatory synaptic transmission were studied in superficial dorsal horn neurones in transverse slices from 7 to 14 day old rats. 2. Glutamatergic excitatory postsynaptic currents (e.p.s.cs) were recorded from the somata of the neurones in the whole-cell patch-clamp configuration. E.p.s.cs were evoked by extracellular electrical stimulation (100 microns, 3-10 V) of the ipsilateral dorsal root entry zone by use of a glass electrode. E.p.s.cs with constant short latency (< 2.3 ms) and with no failures upon stimulation were assumed to be monosynaptic. These e.p.s.cs occurred with an average latency of 1.72 +/- 0.098 ms and exhibited a fast decay with a time constant, tau, of 4.8 +/- 0.53 ms (n = 30). 3. Nociceptin reversibly reduced the amplitudes of e.p.s.cs in a concentration-dependent manner in 25 out of 27 cells tested. Average maximum inhibition was 51.6 +/- 5.7% (mean +/- s.e.mean; n = 9), at concentrations > 3 microM. EC30 was 485 +/- 47 nM and the Hill coefficient was 1.29 +/- 0.09. 4. Inhibition of synaptic transmission by nociceptin (10 microM) was insensitive to the non-specific opioid receptor antagonist naloxone (10 microM) indicating that nociceptin did not act via classical opioid receptors. 5. In order to determine the site of action of nociceptin spontaneous miniature e.p.s.cs (m-e.p.s.cs) were recorded. Nociceptin reduced the frequency of m-e.p.s.cs in 6 out of 7 cells but had no effect on their amplitude distribution or on their time course. These findings suggest a pre- rather than a postsynaptic modulatory site of action. This is in line with the finding that current responses elicited by extracellular application of L-glutamate (10 microM) were not affected by nociceptin (10 microM; n = 7). 6. No positive correlation was found between the degree of inhibition by nociceptin (10 microM) and by the mixed delta- and mu-receptor agonist methionine-enkephalin (10 microM). This suggests that both neuropeptides acted on different but perhaps overlapping populations of synaptic connections. 7. Our results indicate that nociceptin inhibits excitatory synaptic transmission in the superficial layers of the rat dorsal horn by acting on presynaptic, presumably ORL1 receptors. This may be an important mechanism for spinal sensory information processing including nociception.