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

Abstract

1 The modulatory actions of nociceptin/orphanin FQ on excitatory synaptic transmission were studied in super®cial 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 con®guration. E.p.s.cs were evoked by extracellular electrical stimulation (100 ms, 3 ± 10 V) of the ipsilateral dorsal root entry zone by use of a glass electrode. E.p.s.cs with constant short latency (52.3 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, t, 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 43 mM. EC 50 was 485+47 nM and the Hill coecient was 1.29+0.09. 4 Inhibition of synaptic transmission by nociceptin (10 mM) was insensitive to the non-speci®c opioid receptor antagonist naloxone (10 mM) 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 eect on their amplitude distribution or on their time course. These ®ndings suggest a pre-rather than a postsynaptic modulatory site of action. This is in line with the ®nding that current responses elicited by extracellular application of L-glutamate (10 mM) were not aected by nociceptin (10 mM; n=7). 6 No positive correlation was found between the degree of inhibition by nociceptin (10 mM) and by the mixed d-and m-receptor agonist methionine-enkephalin (10 mM). This suggests that both neuropeptides acted on dierent but perhaps overlapping populations of synaptic connections. 7 Our results indicate that nociceptin inhibits excitatory synaptic transmission in the super®cial layers of the rat dorsal horn by acting on presynaptic, presumably ORL 1 receptors. This may be an important mechanism for spinal sensory information processing including nociception.

Activation of Opioid Receptor Like-1 Receptor in the Spinal Cord Produces Sex-Specific Antinociception in the Rat: Estrogen Attenuates Antinociception in the Female, whereas Testosterone Is Required for the Expression of Antinociception in the Male

“…Our finding that OFQ is antinociceptive in males is consistent with the evidence provided in previous electrophysiological and behavioral studies (Stanfa et al, 1996;Xu et al, 1996;Henderson and McKnight, 1997;Lai et al, 1997;Liebel et al, 1997;Meunier, 1997;Harrison and Grandy, 2000) (for review, see Mogil and Pasternak, 2001). Our data, however, as indicated above, indicate that this response of males is not simply attributable to the absence of estrogen but rather relies specifically on the availability of testosterone.…”

Biphasic modulation by galanin of excitatory synaptic transmission in substantia gelatinosa neurons of adult rat spinal cord slices

“…The increase in spontaneous L-glutamate release produced by galanin is an action opposite to that of endogenous neuropeptides, such as endomorphins (Fujita and Kumamoto 2006;Wu et al 2003) and nociceptin (Liebel et al 1997;Luo et al 2002b), and adenosine (Lao et al 2001;Li and Perl 1994), all of which are thought to act as analgesics at the spinal cord level (for review see Fürst 1999). On the other hand, the decrease in evoked L-glutamate release from primary afferent fibers and the outward current (hyperpolarization) produced by galanin are the same as those of norepinephrine (Kawasaki et al 2003;North and Yoshimura 1984), opioids (Fujita and Kumamoto 2006;Kohno et al 1999;Yoshimura and North 1983), nociceptin (Luo et al , 2002b, and adenosine (Lao et al 2004;Liu et al 2004).…”

“…For instance, endogenous analgesics, such as opioids, nociceptin, norepinephrine and adenosine, which exhibit antinociception when administrated intrathecally, hyperpolarize membranes of SG neurons. They also reduce the release of L-glutamate onto SG neurons from nerve terminals, both of which result in reducing the excitability of SG neurons (Fujita and Kumamoto 2006;Kawasaki et al 2003;Kohno et al 1999;Lao et al 2001Lao et al , 2004Li and Perl 1994;Liebel et al 1997;Liu et al 2004;Luo et al 2001Luo et al , 2002bNorth and Yoshimura 1984;Wu et al 2003;Yoshimura and North 1983). The SG neurons receive not only glutamatergic excitatory synaptic transmission but also (GABAergic and glycinergic) inhibitory synaptic transmission (Willis and Coggeshall 1991), the modulation of which may also play a role in regulating nociceptive transmission (Coull et al 2003;Moore et al 2002; for review see Kohno 2007).…”

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

“…In addition, N/OFQ suppresses glutamate ventral root potentials in a concentrationdependent manner (Faber et al, 1996), as well as depresses evoked-excitatory postsynaptic potentials (EPSPs) in the substantial gelatinosa neurons of the spinal cord. Studies have demonstrated that the effects of N/OFQ in the spinal cord are almost all presynaptic because of insensitivity of N/OFQ on mini-EPSC amplitude to tetrodotoxin treatment (Liebel et al, 1997). However, other groups have shown that NOP can exert postsynaptic effects within the spinal cord because of its ability to inhibit glutamatergic and kainic-acid evoked currents (Shu et al, 1998).…”