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Endomorphins are endogenous peptides that have high affinity and selectivity for the mu-opiate receptor and potent analgesic activity. The distributions of endomorphin 1 (Tyr-Pro-Trp-Phe-NH2; EM1) and endomorphin 2 (Tyr-Pro-Phe-Phe-NH2; EM2) in the rat central nervous system were determined by immunocytochemistry with two antisera, each demonstrating clear preference for the target antigen. Perikarya expressing EM2-like immunoreactivity were present in the posterior hypothalamus, whereas those expressing EM1-like immunoreactivity were present in both the posterior hypothalamus and the nucleus of the solitary tract (NTS). EM1-like immunoreactivity was more widely and densely distributed throughout the brain than was EM2-like immunoreactivity, whereas EM2-like immunoreactivity was more prevalent in the spinal cord than was EM1-like immunoreactivity. The greatest density of EM1-like-immunoreactive fibers was detected in the parabrachial nucleus and the NTS, with notable staining in the septum, diagonal band, bed nucleus of the stria terminalis, organum vasculosum, nucleus of Meynert, paraventricular thalamic nucleus, posterior hypothalamic nucleus, periaqueductal gray, locus coeruleus, nucleus accumbens, and amygdala. The greatest density of EM2-like-immunoreactive fibers was detected in the superficial laminae of the spinal cord dorsal horn and the nucleus of the spinal trigeminal tract. The overall pattern of immunoreactivities was similar in rat, mouse, and guinea pig, but some differences were observed. In many but not in all locations, immunoreactive fibers were prominently present in regions in which mu receptors are reported to be concentrated. The neuroanatomical results suggest that endomorphins participate in modulating nociceptive and autonomic nervous system processes and responsiveness to stress.

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Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2) are peptides recently isolated from brain that show the highest affinity and selectivity for the mu (morphine) opiate receptor of all the known endogenous opioids. The endomorphins have potent analgesic and gastrointestinal effects. At the cellular level, they activate G-proteins (35S-GTP gamma-S binding) and inhibit calcium currents. Support for their role as endogenous ligands for the mu-opiate receptor includes their localization by radioimmunoassay and immunocytochemistry in central nervous system regions of high mu receptor density. Intense EM-2 immunoreactivity is present in the terminal regions of primary afferent neurons in the dorsal horn of the spinal cord and in the medulla near high densities of mu receptors. Chemical (capsaicin) and surgical (rhizotomy) disruption of nociceptive primary afferent neurons depletes the immunoreactivity, implicating the primary afferents as the source of EM-2. Thus, EM-2 is well-positioned to serve as an endogenous modulator of pain in its earliest stages of perception. In contrast to EM-2, which is more prevalent in the spinal cord and lower brainstem, EM-1 is more widely and densely distributed throughout the brain than EM-2. The distribution is consistent with a role for the peptides in the modulation of diverse functions, including autonomic, neuroendocrine, and reward functions as well as modulation of responses to pain and stress.

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Evidence is presented that the recently discovered endogenous mu-selective agonist, endomorphin-2, is localized in primary sensory afferents. Endomorphin-2-like immunoreactivity was found to be colocalized in a subset of substance P- and mu opiate receptor-containing fibers in the superficial laminae of the spinal cord and spinal trigeminal nucleus. Disruption of primary sensory afferents by mechanical (deafferentation by dorsal rhizotomy) or chemical (exposure to the primary afferent neurotoxin, capsaicin) methods virtually abolished endomorphin-2-like immunoreactivity in the dorsal horn. These results indicate that endomorphin-2 is present in primary afferent fibers where it can serve as the endogenous ligand for pre- and postsynaptic mu receptors and as a major modulator of pain perception.

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Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) are endogenous ligands that have greater affinity and selectivity for the mu-opiate receptor than any other known mammalian peptide. A polyclonal antiserum, screened for specificity to endomorphin-2 by immunodot-blot assay and preabsorption controls, was used for localization of this peptide. Immunocytochemistry performed on the brainstem, spinal cord, and sensory ganglia of rats by the avidin-biotin-peroxidase method revealed a continuous dense aggregation of endomorphin-2-like immunoreactive varicose fibers in the superficial laminae of the dorsal horn of the medulla and spinal cord. Immunoreactive fibers were detected in the dorsal root as well as within the dorsal root ganglia. The results suggest that endomorphin-2 is synthesized in primary sensory neurons in ganglia, transported to the superficial dorsal horn, and released near neurons expressing mu receptors. Its distribution appears to represent a functional unit likely to be associated with modulation of nociceptive stimuli.

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Peripheral and central atrial natriuretic factor (ANF) concentrations were measured across the rat's estrous cycle. Vaginal smears were obtained from adult Sprague-Dawley rats maintained under controlled illumination (L/D: 14/10, onset 05.00 h). ANF concentrations in plasma, cardiac atria, pituitary and nine microdissected brain regions of females (n = 5-13) were determined by radioimmunoassay during either early proestrus (09.00-11.00 h), late proestrus (17.00-19.00 h), estrus (09.00-11.00 h), early metestrus (09.00-11.00 h) and late metestrus (17.00-19.00 h). Patterns of cyclic ANF immunoreactivity in plasma and atria were inversely related to each other, with plasma levels being significantly elevated during early metestrus when atrial levels were significantly decreased. Statistically significant central fluctuations in ANF levels during the estrous cycle were only found in the hypothalamic periventricular region (hPVA) and in the dorsal raphe (DR). ANF levels declined in both regions after late proestrus. Results indicate a relationship between ANF activity and cyclic patterns of fluid volume regulation and with phasic reproductive hormonal events.

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The ability of female rats to express maternal behavior following pre- or postpuberally-administered lesions of the medial preoptic area (MPOA) was investigated. Female Sprague-Dawley rats were electrolytically or sham-lesioned at either 28-30 days of age or 65-70 days of age and housed together in groups of 6-8 in "enriched" environments. Subsequently, the animals were mated and moved to individual cages just prior to parturition. Indices of maternal proficiency included nest ratings, pup retrieval time, percentage of pups with milk in their stomachs, and percentage of pup mortality. All animals in which lesions had substantially damaged the MPOA demonstrated significant deficits in all indices. Age at which the lesion was administered had no effect. In contrast to the recovery of male sexual behavior that has been reported for rats following prepuberally administered MPOA lesions, no recovery of maternal behaviors was seen in this study. Reasons for this lack of recovery may include the greater complexity of physiological and behavioral processes involved in maternal behavior in comparison to the rather stereotypical response patterns of male sexual behavior.

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Serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and norepinephrine (NE) concentrations in seven brain regions were compared in sexually refractory, physically active, and inactive male rats. Also examined were 5-HIAA/5-HT and DOPAC/DA concentration ratios. Sexually refractory males were permitted uninterrupted copulation with successive receptive females until they failed to mount or ejaculate in a set period. Physically active males ran in motor-driven activity wheels except during the postejaculatory refractory periods of experimental animals, and inactive males remained alone in testing arenas. Significant group differences were found only in monoamine concentrations in the medial preoptic area (MPOA) and the medial forebrain bundle (MFB). In the MPOA, 5-HT concentration was elevated in sexually refractory males, as was DA in both refractory and active animals. In the MFB, 5-HT concentration was increased in active males. MFB DOPAC levels of sexually refractory rats significantly correlated inversely with their ejaculation totals, as did MFB and dorsal raphe (DR) NE levels. The results suggest that the MPOA is a forebrain target for inhibitory influences on male rat sexual behavior of ascending serotonergic fibers and that increased MFB 5-HT and MPOA DA may be associated with general activity.

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In rats, gonadal steroid hormones present during the neonatal period produce permanent or "organizational" effects that play a role in the sexual differentiation of the brain and sexually dimorphic patterns of behavior. Because there exists a sexually dimorphic pattern in the development of hypertension in the spontaneously hypertensive rat (SHR), we examined the influence of neonatal gonadal hormones on arterial pressure and body weight in these rats. Male SHR rats were castrated or sham-operated (controls) on their day of birth. Female rats received 1.25 mg testosterone propionate (TP) or sesame oil vehicle on their 2nd day of life. Sham-operated males and TP and oil females were gonadectomized at 81 days of age. To examine the transient or "activational" effects of gonadal steroid hormones, testosterone implants were placed subcutaneously in all rats at 128 days of age and were removed at 170 days of age. The rats were killed at 202 days of age, and selected organ weights were determined. During the original treatment, days 44-79, blood pressure in castrated males was comparable to that of control females, whereas blood pressure in neonatal TP females was not different from that of control males. When exposed to testosterone in adulthood, blood pressure increased more in neonatal TP female rats than in control females. Partial correlation analysis indicated that differences in body weights among the groups could not account for their variances in blood pressure. These data suggest that the neonatal gonadal hormone milieu contributes significantly to the sexually dimorphic pattern of hypertension development in the SHR.

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When administered during the critical perinatal period, estrogen permanently modifies both male and female reproductive function. This study evaluated the influence of exogenous estrogen administered during this time on the hypothalamic LHRH content and on gonadotropin secretion in adult male and female rats. LHRH content in the preoptic-anterior hypothalamic (PO/AH) and midhypothalamic (MH) areas of neonatally estrogenized rats (1 mg on postpartum day 2) and of control male and female rats during the estrous cycle was determined by radioimmunoassay between 80 and 90 days of age. LHRH content was significantly greater in the PO/AH of neonatally estrogenized females than in estrogenized males whereas no differences in LHRH content of the PO/AH existed between control male and female rats. Neonatal administration of estrogen resulted in increased LHRH content in the MH of female rats and decreased LHRH content in male rats, as in the PO/AH; however, these differences were less marked in the MH and not statistically significant. The marked increase in serum LH concentration present in control cycling females in proestrus was abolished by neonatal estrogen treatment. Exposure to neonatal estrogen reduced FSH concentrations in males. The data are consistent with the concept that the hypothalamic-pituitary system is modified by estrogen circulating during the period of sexual differentiation. LHRH synthesis and release appear to be directly modified by neonatal estrogen. The effects of neonatal estrogen treatment in the PO/AH and MH areas may possibly involve two disparate types of alterations of developing LHRH neurons which modulate gonadotropin secretion in the adult rat.

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LHRH perikarya and processes were compared in 6, 9, and 11 day old normal and estrogenized male and female rats. Estradiol benzoate was administered SC in 1 or 1000 microgram amounts when the animals were 2 days old. Control animals received either an equivalent amount of the oil vehicle or no injection. After perfusion with Bouin's solution, brains were embedded in paraffin and sectioned 6 mu coronally through the entire brain. The peroxidase-antiperoxidase immunocytochemical technique was used to assess the development of LHRH cells and fibers. The primary antiserum to LHRH was Arimura's antiserum #743. LHRH immunopositive perikarya were present in the septal-preoptic but not in the arcuate-median eminence regions. No immunopositive reaction product was present following treatment with antiserum #743 absorbed with LHRH. At each of the three ages, the amount of detectable LHRH cell bodies was considerably greater in normal males than in females. The high dose of estrogen reduced the quantity of LHRH perikarya localized in the male and increased it in the female. LHRH processes formed a "rostral" pathway in proximity with the organum vasculosm of the lamina terminalis (OVLT) in the vicinity of the rostral preoptic area and a "caudal" one extending through the arcuate-median eminence region. Many more LHRH immunopositive processes were visualized in normal males than in female siblings on days 9 and 11. The high dosage of estrogen also reduced the amount of LHRH immunoreactive material in 9 and 11 day old males but not in equivalent age females. The data are consistent with the findings that the hypothalamic-pituitary-gonadal inhibitory system functions earlier in the male than in the female and that the LHRH system can be modified by estrogen circulating during the period of sexual differentiation.

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Long-term exposure to constant dim illumination dissociated the circadian activity rhythms of female rats. Evaluation of this phenomenon by visual and spectral analysis indicated that ultradian rhythms survive the breakdown of circadian organization.

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Decline in reproductive success was compared in normal and neonatally androgenized female rats permitted to receive 1 or 5 ejaculations during each of 7, 5, 3, or 1 mating test. Exposing the females to .5 microgram of testosterone propionate on Day 3 of life increased their age-related rate of decline in the number of successful pregnancies and offspring born in each litter as well as in behavioral receptivity. In both normal and neonatally androgenized animals, fertility and receptivity were greater in animals receiving five ejaculations rather than one ejaculation and in those having multiple pregnancies rather than a single or no prior pregnancy. Perinatally androgenized animals appear to provide a useful model for studying factors influencing age-dependent reproductive processes.

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Male rats injected on Day 3 neonatally with .01, .1, 1, 10, 100, or 1,000 micrograms of estradiol benzoate (EB), 10,000 microgram of testosterone propionate (TP), or sesame oil were subsequently examined for testicular, penile, and accessory organ development. Sexual behavior was evaluated during therapy with fluoxymesterone (FM) and then with TP. Estradiol benzoate in dosages greater than 1.0 micrograms delayed testicular descent, reduced the size and hormone responsiveness of reproductive organs, and decreased sexual behavior in a dose-dependent manner. The 10,000-microgram dosage of neonatal TP delayed testicular descent and reduced sexual behavior to levels near those of the 10--100 micrograms EB groups, but it produced no significant penile or accessory organ changes. Neither reduced peripheral organ development nor inhibited neonatal testicular secretions fully explain reductions in male behavior following large dosages of neonatal TP. Neonatal androgen may reduce the responsiveness of central nervous system neurons governing male sexual behavior after being converted to estrogen or by directly altering steroid receptor systems.

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