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Opioid Antagonist (Naltrexone) Modulation of Cerebellar Development: Histological and Morphometric Studies

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Opioid Antagonist (Naltrexone) Modulation of Cerebellar Development: Histological and Morphometric Studies The Journal of Neuroscience May 1986 6(5): 1424-1432 Opioid Antagonist (Naltrexone) Modulation of Cerebellar Development: Histological and Morphometric Studies Ian S. Zagon and Patricia J. McLaughlin Department of Anatomy, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania 17033 The role of endogenous opioid systems in preweaning cerebellar (Zagon and McLaughlin, 1983a+ 1984,1985a-c). These effects development was explored in rats utilizing naltrexone, a potent are stereospecific (Zagon and McLaughlin, 1985c), with the du- opioid antagonist. Sprague-Dawley rats were given daily sub- ration of opioid receptor blockade determining the outcome of cutaneous injections of either 1 or 50 mg/kg naltrexone to in- developmental events (Zagon and McLaughlin, 1984). Thus, voke a temporary or complete blockade, respectively, of opioid continuous blockade of opioid receptors each day enhances receptors throughout the first 3 weeks of postnatal life; animals growth; temporary opioid receptor blockade each day inhibits injected with sterile water served as controls. At weaning (day growth. These results indicate that endogenous opioid systems 21), macroscopic, morphometric, and histological determina- (i.e., endogenous opioids and opioid receptors) subserve an im- tions were conducted. In general, 50 mg/kg naltrexone had a portant function in developmental and tumor biology: regula- stimulatory action on cerebellar development, whereas 1 mg/kg tion of growth (Zagon and McLaughlin, 1983a, b, 1984). Ad- naltrexone had an inhibitory influence. Both sexes were affected ditional information concerning endogenous opioids and growth comparably. Limits to naltrexone’s ability to modulate cerebel- has recently come from studies (Zagon et al., 1985) showing lar ontogeny were noted, with more latitude existing toward that enkephalin immunoreactivity was present in germinative growth enhancement than impairment. The temporal course of cells of the postnatally developing rat cerebellum but not in ontogeny was generally unaltered in naltrexone-treated rats. adult neural cells. These findings indicate further the impor- Rather, only events that transpired over this period were dra- tance, and special relationships, of endogenous opioid systems matically affected. The most notable effects in 1 mg/kg naltrex- to development. one rats were marked decreases in cerebellar area1 dimensions, It is known that preweaning rats receiving daily injections of the content of internal granule neurons, and cellular and tissue 50 mg/kg naltrexone, which block the opioid receptor for 24 hr differentiation. Characteristics of the 50 mg/kg naltrexone group each day, were found to have an increase in body, brain, and included increases in cerebellar area1 dimensions, neural cell organ weights (Zagon and McLaughlin, 1983b, c, 1984, 1985b) number, content, and size, and structural changes consistent with and an acceleration in the appearance of physical characteristics acceleration in growth and differentiation. Naltrexone influ- and maturation of spontaneous motor and sensorimotor be- enced both neurons and glia, but only neural cells still being haviors (Zagon and McLaughlin, 1983q 1985a). Daily admin- generated during the first 21 d after birth were altered in regard istration of 1 mg/kg naltrexone, a dosage that only blocked the to quantity. Previous evidence has shown the presence of peak opioid receptor for 4-6 hr each day, had the opposite action on levels of endogenous opioids and opioid receptors in the cere- development. Little is known about the morphological effects bellum during the first weeks of life, as well as demonstrating involved in opioid antagonist modulation of neurobiological the presence of enkephalin immunoreactivity on germinative development. Zagon and McLaughlin (1983b) have demon- cerebellar cells during postnatal neurogenesis but not in adult strated that macroscopic dimensions of the brain and cerebel- counterparts. Our results show that endogenous opioid systems lum of 2 1-d-old offspring (sexes combined) chronically exposed are natural trophic factors in cerebellar growth and serve to to 50 mg/kg naltrexone were markedly increased from control document the critical importance of endogenous opioid-opioid levels; notable increases in cerebral and cerebellar areas, as well receptor interaction in nervous system development. as content of some neural cells in the cerebellum were also recorded. The untoward action of exogenous opioid agonists such as her- The purpose of this investigation was to establish more fully oin, methadone, and morphine on somatic and neurobiological the role of endogenous opioid systems in regulating preweaning development of humans and laboratory animals is well docu- cerebellar development by perturbing the interaction of endog- mented (Slotkin et al., 1980; Smith et al., 1977; Wilson, 1975; enous opioids and opioid receptors with an opioid antagonist also see Zagon et al., 1982, 1984). In laboratory studies, these (i.e., naltrexone). The rat cerebellum presents an opportune re- growth-altering effects have been demonstrated to be stereo- gion in which to explore neuromorphogenic processes. In the specific and blocked by concomitant administration of opioid rat, macroneurons such as the Purkinje cells proliferate pre- antagonists (McLaughlin and Zagon, 1984; Smith et al., 1977). natally, whereas the ontogeny of microneurons (e.g., internal Investigations in our laboratory have documented that opioid granule cells) is largely confined to the first 3 postnatal weeks antagonists also influence normal growth, as well as neoplasia (Altman, 1972). Indeed, between birth and day 2 1, cell number increases from about 6 to 94 million (Zagon and McLaughlin, 1979). Thus, in this study, macroscopic, histological, and mor- phometric analyses of 2 1 -d-old rats subjected to temporary (1 Received July 17, 1985; revised Nov. 22, 1985; accepted Nov. 22, 1985. mg/kg naltrexone) or continuous (50 mg/kg naltrexone) receptor This work was supported in part by NIH Grants NS-20500 and NS-20623. A blockade throughout the preweaning period were performed in preliminary report was presented at the Vth Meeting of the International Society for Developmental Neurobiology, Chieti, Italy, June, 1984. order to evaluate cerebellar size, cell concentration and distri- Correspondence should be addressed to Dr. Zagon at the above address. bution, and cellular differentiation. Males and females were ex- Copyright 0 1986 Society for Neuroscience 0270-6474/86/051424-09$02.00/O amined separately in order to distinguish any sex differences 1424 The Journal of Neuroscience Opioid Systems and Cerebellar Development 1425 that might occur. Our results indicate that endogenousopioid systemsare important trophic factors that determine the course of cerebellar neuro-ontogeny. Materials and Methods Animals and drug protocol 65 Newbornanimals (day 0) from random-bred Sprague-Dawley female rats were culled to eight pups per mother. All animals were housed under standard laboratory conditions as described elsewhere (Zagon and 5 McLaughlin, 1985a, b). Beginning on day 1, pups were given daily I- 55 subcutaneous injections of either 1 or 50 mg/kg naltrexone or sterile 3 water (control) until weaning (day 21). Solutions of naltrexone were i prepared by dissolving naltrexone hydrochloride (Endo Laboratories, 3 Garden City, NY) in sterile water; dosages are expressed as salts. Rat pups were weighed periodically and appropriate dosage adjustments ti 45 made. B Histological procedures On day 21, at least six male and six female offspring selected from at 35 least four different litters from each treatment group were weighed, anesthetized with chloral hydrate, and killed by cardiac perfusion with 10% neutral buffered formalin. Whole brains were removed and im- mersed in formalin for 3 d. Using an Olympus X-Tr dissecting micro- scope with an ocular micrometer, macroscopic dimensions of the brain (to be reported in another communication) and cerebellum were re- :.:.: corded. Cerebellar width was determined by measuring the greatest ::::: 50 NTX distance parallel to the long folial axis. Cerebella were dissected from the brain stem, by transecting the peduncles as close to the cerebellum Figure 1. Brain and cerebellar weights of 21-d-old rats subjected to as possible, and weighed. Cerebella were then bisected in the midsagittal daily injections of 1 or 50 mg/kg naltrexone, or sterile water, throughout plane, embedded in polyester wax, and sectioned at 8 pm. Midsagittal preweaning development. Bar indicates SEM. Significantly different from sections were stained with hematoxylin and eosin, gallocyanin, or pro- controls at p < 0.05 (*) or p < 0.01 (**). targol (Zagon and Lasher, 1977) for histological and morphometric studies. Morphometric analysis sections from at least six rats/sex/treatment group. The length of the Purkinje cell layer in each section of lobule VIII was measured with an Matched sections of the cerebellum were projected (Bausch and Lomb Apple Graphics Tablet and Apple II Plus computer. The number of microprojector) at 22 x onto an Apple Graphics Tablet. The boundaries Purkinje cells per section was then divided by length of the Purkinje of the entire cerebellum, and molecular (MOL), internal granule (IGL), cell layer examined in order to obtain “Purkinje cell packing density.” and medullary (MED) layers were traced and area1 measurements re- The “area of the average Purkinje cell domain” was calculated by di- corded
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