Orexins in the midline thalamus are involved in the expression of conditioned place aversion to morphine withdrawal

Previous studies have implicated the bed nucleus of the stria terminalis, central nucleus of the amygdala and the shell of the nucleus accumbens (collectively called the extended amygdala) as playing an important role in mediating the aversive emotion associated with opioid withdrawal. The paraventricular nucleus of the thalamus (PVT) provides a very dense input to the extended amygdala, and the PVT is densely innervated by orexin neurons, which appear to be involved in producing some of the physical and emotional effects associated with morphine withdrawal. In the present study, we confirm that the PVT is densely innervated by orexin fibers, whereas the regions of the extended amygdala associated with the effects of morphine withdrawal are poorly innervated. Microinjections of the orexin-1 receptor (OX1R) antagonist SB334867 or the orexin-2 receptor (OX2R) antagonist TCSOX229 at doses of 5.0 or 15.0 μg into the PVT region did not affect the acquisition of the conditioned place aversion (CPA) nor the physical effects produced by naloxone-precipitated morphine withdrawal. In contrast, microinjections of TCSOX229 (15.0 μg) in the PVT region significantly attenuated the expression of naloxone-induced CPA while microinjections of SB334867 at the same dose had no effect. The results from these experiments indicate a role for OX2R in the PVT on the expression of CPA associated with morphine withdrawal. Orexins may mediate the aversive effects of morphine withdrawal by engaging the extended amygdala indirectly through the action of orexins on the PVT.