Visualization of opiate receptor upregulation by light microscopy autoradiography.

Abstract

Light microscopy autoradiography has been used to visualize neuroanatomical patterns of brain opiate receptor upregulation in response to chronic naltrexone administration. Slide-mounted brain sections of frozen rat brain were labeled in vitro with dihydro[3H]morphine, a relatively selective ,u opioid ligand. The greatest relative increases in opiate receptor density were observed in the nucleus accumbens, the amygdala, striatal patches, nuclei of the thalamus and hypothalamus, layers I and III of neocortex, substantia nigra compacta, midbrain periaqueductal gray regions, and the parabrachial nuclei of the brainstem. The substantia nigra reticulata, surrounding areas of striatal patches, and the locus ceruleus, were not affected by this drug treatment. These findings demonstrate that chronically administered naltrexone differentially regulates opiate receptors throughout the brain. In particular, three brain systems appear to be target areas of receptor upregulation: (i) the dopamine A9/AlO systems, (ii) the limbic system, and (iii) structures that receive input from afferent sensory pathways. Two possible mechanisms to account for this finding are (i) that the drug does not have uniform effects throughout the brain or (it) that the receptors themselves may be associated with different functional systems. Receptor density changes are paralleled by increases in methionine-enkephalin content in the striatum, nucleus accumbens, periaqueductal gray, and hypothalamic areas of chronic naltrexone-treated rats relative to control rats. Thus opiate receptors and opioid peptides appear to be subject to regulatory mechanisms similar to those that modulate other neurotransmitters and their receptors. These results document in a visual manner brain patterns of opiate receptor upregulation.Opiate narcotic analgesics produce tolerance and dependence in vivo and desensitization in vitro. The observation of these phenomena has raised the question as to whether opiate receptors undergo up-or downregulation in vivo, in response to long-term administration of opiate drugs. Opiate receptor downregulation has been difficult to document. Several groups have reported that chronic administration of narcotic agonists in vivo does not produce any change in either receptor number or affinity (1-7). On the other hand, receptor downregulation has been observed in neurotumor cell lines after long-term exposure to enkephalin (8-10) but not to alkaloid agonists (8). Possible interpretations of the latter findings are (i) that opioid peptides bind differently than do opioid narcotic agonists to the same receptor or (ii) that only a subpopulation of opioid receptors can be so modulated.By contrast, upregulation of brain opiate receptors in vivo after drug-induced denervation (11) or long-term narcotic antagonist administration (12) is well established (7,13,14). Chronic blockade of opiate receptors results in a nearly 2-fold increase in the density of both ,u and 8 receptors (12). The newly synthesized or unmasked receptors are more sensi...

Visualization of multiple opioid-receptor types in rat striatum after specific mesencephalic lesions.

“…4a Left) showed dense patches of receptor labeling in the caudate-putamen overlying the "striosomes." This topographical organization is consonant with the previously reported pattern of ,u receptor labeling in the striatum (15)(16)(17)21). Dense , receptor labeling was also seen in a thin band along the lateral margins of the caudate-putamen and in the dorsomedial one-third of the nucleus accumbens.…”

“…Autoradiographic studies were carried out using tritium-sensitive LKB film as described (17,21,22). Lesioned and control animals were decapitated 15 days after microinjection of 6-hydroxydopamine or vehicle, respectively; brains were rapidly removed, and coronal sections (20 ,um) were prepared as described (23 (23).…”

Neuroanatomical patterns of the mu, delta, and kappa opioid receptors of rat brain as determined by quantitative in vitro autoradiography.

“…The patchy striosomal P-receptor labeling appeared to follow a slight dorsomedialventrolateral gradient, being denser in the ventrolateral caudate-putamen. This topographical organization is consonant with the reported pattern of P-receptor labeling in the striatum (3,6,12). Extremely dense P-receptor labeling was also seen in a thin band along the lateral margins of the caudate-putamen (the "subcallosal streak"), the claustrum, and in the medial aspect of the nucleus accumbens.…”

Naltrexone potentiates 4-aminopyridine seizures in the rat

“…Longlasting receptor blockade by naltrexone increases the density of opiate receptors in different brain regions (Zukin et al, 1982;Tempel et al, 1984). However, very little is known about the effects of bolus administration (Kosten et al, 1986).…”