The main finding of the present investigation is that OFQ/N decreased motor activity after injection into the VTA and, to a lesser extent, after local injection into the nucleus accumbens. However, OFQ/N failed to produce significant motor suppression after injection into the substantia nigra or striatum. The action of intra-VTA OFQ/N on motor activity was attenuated by J-113397, an ORL-1 receptor antagonist. Overall, the present results indicate that activation of the ORL-1 receptor in the VTA and, at least in part, in the nucleus accumbens mediates the inhibitory action of OFQ/N on motor behaviours.
Opioid drugs have been shown to modulate the activity of mesolimbic and nigrostriatal dopaminergic neurons.24,25
Activation of the mu and delta opioid receptors enhances, whereas that of the kappa opioid receptors attenuates, the activity of these pathways,26
possibly because of their differential expression on neuronal components within the cell-body regions and terminal fields of these neurons. Whereas mu and delta opioid receptors are predominantly located on the gamma aminobutyric acid (GABA)-ergic inputs to DA cells in the VTA and substantia nigra,27,28
kappa opioid receptors are believed to be expressed on DA cells themselves.28
The ORL-1 receptor is distributed throughout the brain, particularly in brain regions involved in emotional and motivational behaviours.29
It shows somewhat similar tissue distribution to that of the classical opioid receptors and, thus, its action is somewhat similar to that of dynorphin A (1-17) and other kappa opioid receptor agonists on dopaminergic neurons.12,19
Opioid drugs acting at the mu and delta opioid receptors increase, whereas the kappa opioid receptor agonists decrease, extracellular DA.26,30
OFQ/N has been shown to decrease extracellular DA in the nucleus accumbens after intracerebroventricular administration12
and therefore resembles more closely the action of kappa opioid receptor agonists on this system.24
However, kappa opioid receptor agonists are believed to exert their effects on DA release via a direct action on DA terminals in the nucleus accumbens and striatum.3
In contrast, our previous findings suggested a predominantly VTA site of action for OFQ/N.13,14,19,31
Thus, the inhibitory effect of OFQ/N could be the result of direct activation of the ORL-1 receptors expressed on the dopaminergic neurons in the VTA.20,21,32
The present study was designed to determine where along the mesoaccumbens and nigrostriatal dopaminergic pathways OFQ/N acts to suppress motor activity. Our present behavioural data corroborate previous microdialysis data14
by showing that OFQ/N was most potent in inhibiting locomotor activity when administered into the VTA. The observation that OFQ/N failed to produce motor suppression in the presence of J-113397, an ORL-1 receptor antagonist,22
strongly suggests that the motor-suppressant action of OFQ/N is mediated through activation of the ORL-1 receptor. Thus, the decreased motor activity reported following intracerebroventricular OFQ/N administration2,13,18
results, at least in part, from an action of OFQ/N on dopaminergic neurons in the VTA. Further support for this comes from our recent observation that OFQ/N attenuates the motor stimulation and the increase in extracellular DA induced by cocaine in the nucleus accumbens in rats.13
Given that the nigrostriatal dopaminergic neurons play a modulatory role on motor behaviour and that the ORL-1 receptor is expressed in this brain region,20,21
our failure to observe long-lasting motor suppression after intranigral OFQ/N was somewhat surprising. Currently, it is not known what effect, if any, intranigral OFQ/N exerts on extracellular DA in the striatum, but our present data suggest that OFQ/N may have a somewhat selective action on the mesoaccumbens versus the nigrostriatal dopaminergic pathway. Consistent with this notion, we observed that direct injection of OFQ/N into the nucleus accumbens, but not the striatum, also suppressed motor activity. A previous report by Di Giannuario and Pieretti15
further supports this notion by showing that intracerebroventricular OFQ/N administration selectively decreases morphine-induced increases in extracellular DA in the nucleus accumbens but not in the striatum.
Intra-VTA OFQ/N injection has been shown to increase extracellular GABA in this brain region, an effect associated with a decrease in extracellular DA in the nucleus accumbens.14
Thus, the action of OFQ/N on dopaminergic as well as nondopaminergic neurons in the VTA could contribute to a greater motor suppression observed after intra-VTA OFQ/N administration. However, evidence is lacking to show that such a mechanism does not occur in the substantia nigra. An alternative explanation could, therefore, be that the density of ORL-1 receptors may be different in these brain regions. Unfortunately, earlier studies have aimed at localization rather than quantification of the ORL-1 receptor.20,21
Because the mesoaccumbens and nigrostriatal neurons are thought to mediate different aspects of motor behaviours, it may be possible that the measure of motor activity (distance travelled) is mediated by activation of the mesoaccumbens dopaminergic neurons. This may explain why the action of OFQ/N was more pronounced after intra-VTA or intra-accumbal, as compared with intranigral or intrastriatal, administration.
In summary, OFQ/N decreased motor activity after administration into the VTA and to a lesser extent after injection into the nucleus accumbens and substantia nigra. OFQ/N, however, failed to produce any significant effect after direct injection into the striatum. Although the current data cannot rule out the involvement of additional motor brain regions and/or modulation of other neurotransmitter systems in the motor-suppressant action of OFQ/N, our results suggest that OFQ/N attenuated motor activity via activation of the ORL-1 receptor primarily along the mesoaccumbens axis. Given the fact that hyperactivity of the mesoaccumbens axis is implicated in schizophrenia33,34,35
and development of drug dependency,36,37
agonists of the ORL-1 receptor may have potential therapeutic value in this regard.