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. 2013 May 17:7:74.
doi: 10.3389/fncel.2013.00074. eCollection 2013.

Response of striosomal opioid signaling to dopamine depletion in 6-hydroxydopamine-lesioned rat model of Parkinson's disease: a potential compensatory role

Hidetaka Koizumi  1 , Ryoma Morigaki, Shinya Okita, Shinji Nagahiro, Ryuji Kaji, Masanori Nakagawa, Satoshi Goto
Affiliations

Response of striosomal opioid signaling to dopamine depletion in 6-hydroxydopamine-lesioned rat model of Parkinson's disease: a potential compensatory role

Hidetaka Koizumi et al. Front Cell Neurosci. .

Abstract

The opioid peptide receptors consist of three major subclasses, namely, μ, δ, and κ (MOR, DOR, and KOR, respectively). They are involved in the regulation of striatal dopamine functions, and increased opioid transmissions are thought to play a compensatory role in altered functions of the basal ganglia in Parkinson's disease (PD). In this study, we used an immunohistochemistry with tyramide signal amplification (TSA) protocols to determine the distributional patterns of opioid receptors in the striosome-matrix systems of the rat striatum. As a most striking feature of striatal opioid anatomy, MORs are highly enriched in the striosomes and subcallosal streak. We also found that DORs are localized in a mosaic pattern in the dorsal striatum (caudate-putamen), with heightened labeling for DOR in the striosomes relative to the matrix compartment. In the 6-hydroxydopamine-lesioned rat model of PD, lesions of the nigrostriatal pathways caused a significant reduction of striatal labeling for both the MOR and DOR in the striosomes, but not in the matrix compartment. Our results suggest that the activities of the striosome and matrix compartments are differentially regulated by the opioid signals involving the MORs and DORs, and that the striosomes may be more responsive to opioid peptides (e.g., enkephalin) than the matrix compartment. Based on a model in which the striosome compartment regulates the striatal activity, we propose a potent compensatory role of striosomal opioid signaling under the conditions of the striatal dopamine depletion that occurs in PD.

Keywords: Parkinson's disease; dopamine; opioid receptors; striatum; striosomes.

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Figures

Figure 1
Figure 1
Characterization of antibodies against opioid receptors. (A) Rat striatal extracts (10 μg of protein) treated with Endo-β-N-acetyl-glucosaminidase F1 (100 milliunits/ml) (see Materials and Methods) were subjected to trans-immunoblots using the antibodies against MOR, DOR, and KOR. Arrows indicate immunoreactive protein bands. MW, molecular weight; PS, protein staining. (B–D) Single-label TSA immunostaining of the upper cervical spinal cord by using the antibodies against MOR (B), DOR (C), or KOR (D). Arrows indicate the superficial layers of the dorsal horn of the spinal cord. (E) No specific immunoreactivity was found in the spinal cord processed for the TSA protocols in the absence of the primary antibodies. Scale bar = 500 μm.
Figure 2
Figure 2
Distributional patterns of MOR, DOR, and KOR in the striosome-matrix systems of the rat striatum. Single-label TSA immunostaining of the striatum using the antibody against MOR (A), DOR (B) or KOR (C). Asterisks indicate examples of the striosomes, and arrows do the subcallosal streak. Scale bars = 500 μm.
Figure 3
Figure 3
Striatal patches identified by DOR-immunostaining in the rat striatum. The frontal sections from anterior to posterior of the striatum labeled for DOR (A–C) and their color-converted images (D–F). CP, caudate-putamen; NAc, nucleus accumbens; GP; globus pallidus. Scale bars = 500 μm.
Figure 4
Figure 4
Compartmental and cellular localization of DORs in the rat striatum. (A,B) Representative images of striatal sections double-stained for MOR (A) and DOR (B). Asterisks indicate a corresponding striosome, and arrows do the subcallosal streak. (C–E) Photomicrographs of the striosomes (arrows) double-stained for MOR (C) and DOR (D), with merged image (E). DOR labeling is more highly concentrated in the striosomes than in the matrix, although both the compartments contain many cells labeled for DOR. (F) A high-power photomicrograph of striosomal cells stained for DORs (arrows). Scale bar: (A,B), 500 μm; (C–E), 100 μm; (F), 10 μm.
Figure 5
Figure 5
Rat model with unilateral 6-OHDA lesions of the nigrostriatal pathways. (A,B) A representative image of the forebrain sections immunostained for TH. Severe loss of TH-immunoreactive afferents is found in the lesioned striatum (Lesion) compared to the non-lesioned striatum (Non-Lesion). Its color-converted image is shown in (B). The intensity of the labeling is shown in a standard pseudocolor scale from blue (lowest labeling) to white (highest labeling) through green, yellow, and red. (C) Optical density measurements of striatal TH labeling in the lesioned striatum (Lesion) (n = 25) compared to the non-lesioned striatum (Non-Lesion) (n = 25). Values are means ± S.E.M. *P < 0.001 (Mann–Whitney U-test), Non-Lesion vs. Lesion. (D,E) A representative image of the forebrain sections stained for Met-enkephalin (MEnk). An increase in striatal Met-enkephalin labeling is found on the lesioned side (Lesion) compared to the non-lesioned side (Non-Lesion). Its color-converted image is shown in (E). The intensity of the labeling is shown in a standard pseudocolor scale. (F) Optical density measurements of striatal Met-enkephalin labeling in the lesioned striatum (Lesion) (n = 25) compared to the non-lesioned striatum (Non-Lesion) (n = 25). Values are means ± S.E.M. *P < 0.01 (Mann–Whitney U-test), Non-Lesion vs. Lesion.
Figure 6
Figure 6
Loss of striosomal labeling for MOR and DOR in rats with unilateral 6-OHDA lesions of nigrostriatal pathways. (A) A representative image of the forebrain sections stained for MOR. (B) Optical density measurements of MOR labeling in the striosomes and matrix compartment in the dorsolateral portions of the non-lesioned (Non-Lesion) and lesioned (Lesion) striatum. Data are mean ± S.E.M. (bars) values (n = 25). *P < 0.005 (Mann–Whitney U-test), Non-Lesion vs. Lesion. N.D. indicates no statistically significant difference (P > 0.05, Mann–Whitney U-test) between Non-Lesion and Lesion. (C) A representative image of the forebrain sections stained for DOR. (D) Optical density measurements of DOR labeling in the striosomes and matrix compartment in the dorsal striatum of the non-lesioned (Non-Lesion) and lesioned (Lesion) striatum. Data are mean ± S.E.M. (bars) values (n = 25). *P < 0.01 (Mann–Whitney U-test), Non-Lesion vs. Lesion. N.D. indicates no statistically significant difference (P > 0.05, Mann–Whitney U–test) between Non-Lesion and Lesion. (E) A representative image of the forebrain sections immunostained for KOR. No apparent difference in striatal KOR-labeling is found between the non-lesioned (Non-Lesion) and lesioned (Lesion) sides. (F) Optical density measurements of KOR labeling in the striosomes and matrix compartment in the dorsal striatum of the non-lesioned (Non-Lesion) and lesioned (Lesion) striatum. Data are mean ± S.E.M. (bars) values (n = 25). N.D. indicates no statistically significant difference (P > 0.05, Mann–Whitney U-test) between Non-Lesion and Lesion. Scale bars = 500 μm.
Figure 7
Figure 7
Light microscopic localization of MOR, DOR, and KOR in the dorsal striatum and its alterations following dopamine depletion. (A–F) Representative microscopic images of the striatal sections stained for MOR (A and B), DOR (C and D), and KOR (E and F) on the non-lesioned (A,C, and E) and lesioned (B, D, and F) sides. Scale bar = 200 μm. (G) Summary of patterned loss of striatal labeling for MOR, DOR, and KOR under the conditions of dopamine depletion. In normal controls, a heightened labeling for MORs or DORs is found in the striosomes (S). Striatal dopamine depletion causes marked reduction of MOR- and DOR-labeling in the striosomes, but not in the matrix compartment (M). Neuronal cell bodies labeled for DOR or KOR are indicated by small dots.
Figure 8
Figure 8
Neural circuits based on the striosome compartment. (A) Model of the striosome-SNc pathways. SNc, substantia nigra pars compacta; DA-cells, dopamine-producing cells; VPI, ventral pallidum intermediate; LHb, lateral habenula. (B) Model of the intercompartmental communication via striatal interneurons. D1, dopamine D1 receptor; D2, dopamine D2 receptor; GPe, globus pallidus externa; STN, subthalamic nucleus; GPi, globus pallidus internus; SNr, substantia nigra pars reticulata; PV, parvalbumin; Ach, acetylcholine; NOS, nitric oxide synthase.
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