Abstract
Background: μ-opioid receptor knockout (MOP-KO) mice display baseline hyperalgesia. We have recently identified changes in tissue volume in the periaqueductal gray matter (PAG) using magnetic resonance imaging voxel-based morphometry. Changes in the structure and connectivity of this region might account for some behavior phenotypes in MOP-KO mice, including hyperalgesia.Methods: Adult male MOP-KO and wild-type (WT) mice were studied. Immunohistochemistry was performed to detect microglia, astrocytes, and neurons in the PAG using specific markers: ionized calcium-binding adaptor molecule 1 (Iba-1) for microglia, glial fibrillary acidic protein (GFAP) for astrocytes, and the neuronal nuclei antigen (NeuN; product of the Rbfox3 gene) for neurons, respectively. Cell counting was performed in the four parallel longitudinal columns of the PAG (dorsomedial, dorsolateral, lateral, and ventrolateral) at three different locations from bregma (−3.5, −4.0, and −4.5 mm).Results: The quantitative analysis showed larger numbers of well-distributed Iba1-IR cells (microglia), NeuN-IR cells (neurons), and GFAP-IR areas (astrocytes) at all the anatomically distinct regions examined, namely, the dorsomedial (DM) PAG, dorsolateral (DL) PAG, lateral (L) PAG, and ventrolateral (VL) PAG, in MOP-KO mice than in control mice.Conclusions: The cellular changes in the PAG identified in this paper may underlie aspects of the behavioral alterations produced by MOP receptor deletion, and suggest that alterations in the cellular structure of the PAG may contribute to hyperalgesic states.
Highlights
Studies in knockout (KO) mice have demonstrated that μopioid (MOP) receptors play crucial roles in several physiological functions, including nociception, stress responses, tolerance, reward learning, and immune function (1–5)
The aim of this study was to determine the contribution of changes in the numbers of different neural cell types to the volume changes in the periaqueductal gray matter (PAG) of MOP-KO mice
Immunohistochemical analysis revealed that enlarged brain size was accompanied by an increase in the number of microglia and neurons, and area of astrocyte immunoreactivity, in all of the anatomically distinct regions of the PAG that were examined
Summary
Studies in knockout (KO) mice have demonstrated that μopioid (MOP) receptors play crucial roles in several physiological functions, including nociception, stress responses, tolerance, reward learning, and immune function (1–5). These effects of MOP deletion have been generally thought to result from elimination of MOP signaling (6), as would be expected from elimination of opiate reinforcement in MOP-KO mice (7, 8), effects on drug reinforcement extend to abused drugs acting through diverse mechanisms [(9–11), see summary in Hall et al (12)]. MOP receptor gene alters the widespread brain functional connectome and remodels the reward/aversion circuit (22) Such connectivity remodeling may account for brain morphology alterations
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