Gestational exposure to loud noise alters the development and postnatal responsiveness of humoral and cellular components of the immune system in offspring.

Gestational exposure of the female to environmental toxins can alter immune function in the offspring. We have recently shown that prenatal maternal stress, that is, stress applied to or induced in the female during pregnancy, can also alter the development of humoral immunocompetence in the offspring and their hormonal and immunologic responses to postnatal stress. This report presents data from two experiments on the effects of prenatal exposure to loud noise-prenatal sound stress (PSS)-on the development and responsiveness of in vitro and in vivo humoral and cellular immune function in the offspring. Pregnant rats were exposed daily from Day 15 to Day 21 of gestation to an inescapable loud noise (an 85- to 90-decibel fire alarm bell) delivered randomly for 1 hr. In developing offspring, PSS produced age-dependent and mitogen-specific alterations in lymphoproliferative activity and reduced immunoglobulin G levels at Postnatal Day 21. Antibody titers to herpes simplex virus type 1 were also reduced. Exposure to loud noise before or after infection produced an additional reduction in titers in these offspring. Arthus skin reaction (AR) to old tuberculin was reduced by PSS. Combined prenatal/postnatal sound stress further reduced this response and the AR to bovine serum albumin (BSA). Delayed hypersensitivity reaction to BSA was reduced in PSS offspring; postnatal sound stress enhanced the reaction to both antigens, but only in males. Antibody titers to BSA were increased by PSS; adjuvant-induced inflammation was attenuated by postnatal sound stress. These data suggest that in utero exposure to loud noise, which can occur in the workplace, is toxic to the developing immune system.

Experimental allergic encephalomyelitis in adult DA rats subjected to neonatal handling or gentling.

The present study investigated the effect of daily handling and gentling between postnatal days 1 and 28 on experimental allergic encephalomyelitis (EAE) in 8-week old DA rats. Handling consisted of removing pups from the mother, and placing them in the novel cage for 15 min. The gentling procedure included handling accompanied by 3 min of dorsal tactile stimulation before returning the pups to the nest cage. Adult rats of both sexes handled in infancy showed increased susceptibility to EAE, as revealed by higher incidence of the disease, and more severe clinical signs. Anti-myelin basic protein (MBP) autoantibodies were increased in handled males, and decreased in handled females, compared to controls. Gentling induced aggravation of clinical signs and histopathological lesions of EAE in males, while in gentled females suppression was observed. These results indicated that both neonatal handling and gentling aggravated EAE induced in adult male rats. In female rats handling exacerbated, and gentling suppressed clinical EAE. The overall effect of neonatal manipulations was more pronounced in males. Furthermore, in mothers separated from their offspring due to handling and gentling, and immunized for EAE at day 28 postpartum, earlier appearance of clinical signs, and increased frequency of relapses compared to control dams was recorded.

Suppression of experimental allergic encephalomyelitis in offspring of DA and Wistar rats following immunization of mother with encephalitogen.

Immunization of female rats with encephalitogen before gestation, during gestation, and during lactation differentially decreased susceptibility to experimental allergic encephalomyelitis (EAE) in their offspring. The most pronounced suppression, revealed by lowered incidence and weaker clinical signs of the disease, was observed in offspring of mothers immunized before gestation and during lactation in both Dark August (EAE-susceptible), and Wistar (EAE-relatively resistant) rat strains. Induction of EAE in mothers during pregnancy only delayed the onset of the disease in DA progeny. The overall effect on EAE in offspring did not depend on the disease intensity in mothers. Our results suggest that anti-myelin basic protein (MBP) antibodies passively transferred from mothers are not responsible for the observed protection in offspring.

Opioid receptor-mediated suppression of humoral immune response in vivo and in vitro: involvement of kappa opioid receptors.

The selective kappa opioid receptor agonist MR 2034 exerted pronounced suppression of plaque-forming cell (PFC) response following intraperitoneal (i.p.) administration in the rat. Pretreatment with preferential kappa and mu opioid receptor antagonists MR 2266 and naloxone, respectively, revealed that this effect was mediated mainly by kappa, and to a low extent by mu opioid receptors. Intracerebroventricular (i.c.v.) administration of quaternary naltrexone (QNtx) moderately attenuated, whereas i.p. given QNtx completely prevented the suppressive effect of MR 2034, suggesting a peripheral mechanism of action, and only minor involvement of brain opioid receptors. MR 2034 markedly decreased the PFC response of spleen cells obtained from in vivo immunized rats, treated in vitro with the opiate. The immunosuppressive action of MR 2034 in vitro was completely and partially blocked by equimolar concentrations of MR 2266 and naloxone, respectively. Antagonists alone produced stimulation of PFC following i.p. administration in the rat, but did not affect PFC response upon in vitro treatment. These results suggest that peripheral kappa opioid receptors down-regulate primary humoral immune response in the rat, and that this effect may be produced by direct interference with plasma cell activity.

Maternal deprivation and early weaning modulate experimental allergic encephalomyelitis in the rat.

The present experiment deals with the effect of maternal deprivation (MD) and early weaning (EW) on the development and course of experimental allergic encephalomyelitis (EAE) in Dark August (DA) rats. Five litters (five to nine pups per liter) were subjected to MD (4 h daily) from Day 1 until Day 28. EW rats were weaned on Day 15 (EW-15, five litters) or Day 21 (EW-21, four litters). Control rats and MD rats were weaned on Day 28. At the age of 8 weeks, rats were immunized with guinea pig spinal cord in complete Freund's adjuvant and clinical signs of EAE were recorded daily. On Day 18 after immunization, rats were bled and sacrificed. Brain and spinal cord were examined histologically for EAE lesions. Serum anti-rat myelin basic protein (MBP) antibodies were detected by ELISA. MD female rats exhibited suppression of neurological and histological signs of EAE in comparison with control rats. MD and control females showed elevated anti-MBP antibody level compared to MD and control males. EW-15 female rats demonstrated potentiation of neurological signs of EAE compared to control females. EW-21 females developed more severe clinical signs and histological lesions compared to control females. These results show that neonatal experiences, such as maternal deprivation and early weaning, influence the development of EAE in adult DA rats.

Opposing activities of brain opioid receptors in the regulation of humoral and cell-mediated immune responses in the rat.

The role of brain delta- and kappa-opioid receptors in the regulation of PFC response, Arthus hypersensitivity reactions and delayed hypersensitivity reactions was studied following intracerebroventricular (i.c.v.) administration of opioid receptor agonists and antagonists. Eight-week-old male Wistar rats, with polyethylene cannulae inserted into the lateral brain ventricles, were i.c.v. treated with different doses of delta-opioid receptor agonist methionine-enkephalin (Met-Enk), delta-opioid receptor antagonist ICI 174864, kappa-opioid receptor agonist MR 2034, and kappa-opioid receptor antagonist MR 2266. In rats sensitized for plaque-forming cell (PFC) assay, the first drug injection was given 1 h prior to immunization, and then every 24 h until day 4. One h after the last treatment, rats were sacrificed and (PFC) assay performed. In rats immunized for hypersensitivity skin reactions, the first drug injection was given 1 h before immunization, and then every 48 h until day 14. Skin reactions were elicited one h after the last drug administration. Opioid receptor agonists Met-Enk and MR 2034 stimulated and suppressed PFC response, Arthus and delayed skin reactions respectively. ICI 174864 decreased the number of PFC and intensity of hypersensitivity skin reactions whereas MR 2266 increased the number of PFC, but did not affect to a greater extent hypersensitivity reactions. Stimulation of PFC produced by 1 microgram/kg of Met-Enk was completely blocked with 10 and 50 micrograms/kg of ICI 174864. MR 2034-induced suppression was partially and completely antagonized with 10 and 50 micrograms/kg of MR 2266 respectively. The present results suggest that brain opioid receptors differentially affect humoral and cell-mediated immune responses.

Asymmetrical modulation of immune reactivity in left- and right-biased rats after ipsilateral ablation of the prefrontal, parietal and occipital brain neocortex.

We report here on the lateralized brain immunomodulation in male Wistar rats, a phenomenon related to the rotational bias of animal and the site of cortical lesion. Rats assigned to left- and right-rotators in a cylindrical Plexiglass rotometer were subjected to the ablation of the ipsilateral prefrontal cortex (PFC), parietal cortex (PC) and occipital cortex (OC) and sensitized with bovine serum albumin (BSA) in complete Freund's adjuvant. Intact and sham-lesioned left-biased animals demonstrated increased Arthus and delayed hypersensitivity skin reactions and antibody production to BSA in comparison with corresponding right-biased animals. PFC ablation decreased humoral and cellular immune responses to BSA in left- but increased in right-biased rats. Lesioning of PC decreased humoral immune reactions in left- but increased in right-rotating animals. OC ablation failed to produce immunological abnormalities. These results suggest that immunopotentiation is associated with the left neocortex, and immunosuppression with the right neocortex. The prefrontal cortex appears to be particularly associated with immune reactions.

Neonatal sound stress and development of experimental allergic encephalomyelitis in Lewis and DA rats.

This experiment deals with the effect of neonatal sound stress on the susceptibility of rats in adult life to the induction of experimental allergic encephalomyelitis (EAE). Two inbred strains of rats, Lewis and DA, highly susceptible to EAE were used. On postnatal days 15, 18 and 21, animals of both sexes were sound stressed in a sound attenuated chamber (90dB, 60 rings/5 sec during 1 h, on a variable interval schedule) in the presence or absence of the mother. Experimental groups were as follows: (a) pups stressed without the mother (SP); (b) pups stressed in the presence of the mother (SPM); (c) control nonstressed pups separated from the mother (CP), and (d) control nonstressed pups undisturbed in their nest cages (CPM). Rats were weaned on postnatal day 28. At the age of 8 weeks, all groups were immunized with guinea pig spinal cord in complete Freund's adjuvant. Signs of EAE were recorded daily until the day 20 after immunization when animals were bled and sacrificed. Serial sections of cerebrum, cerebellum and spinal cord were examined histologically for the presence of mononuclear cell infiltrates. Anti-myelin basic protein (MBP) antibodies were detected in serum samples using ELISA technique. Stressed Lewis rats (groups SP and SPM) compared to control groups CP and CPM, developed more severe EAE as revealed by a higher aggregate clinical score, more pronounced histological lesions and increased production of anti-MBP antibodies. The presence of the mother during stress session (group SPM) prolonged the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Quaternary naltrexone: its immunomodulatory activity and interaction with brain delta and kappa opioid receptors.

To investigate the role of brain opioid receptors in immune reactions, quaternary naltrexone (QNtx), a nonselective opioid antagonist which does not cross the brain-blood barrier, was tested for its immunomodulatory activity and ability to antagonize immunological changes produced by centrally applied delta-receptor agonist methionine-enkephalin (Met-Enk) and kappa-opioid receptor agonist MR 2034. Plaque-forming cell (PFC) response served as an immunological model. For this purpose, different groups of Wistar rats were centrally (intracerebroventricularly, i.c.v.) and peripherally (intraperitoneally, i.p., or subcutaneously, s.c.) treated with different doses of Met-Enk. MR 2034 and QNtx. Centrally injected Met-Enk and MR 2034 induced a dose-dependent potentiation and suppression of PFC response, respectively. Small amounts of i.c.v. given QNtx produced a dose-dependent increase in the number of PFC, whereas peripherally administered antagonist potentiated immune response in a dose-independent manner. A dose of 10 micrograms/kg of QNtx given i.c.v. completely abolished the immunopotentiation by Met-Enk. However, a large dose of 5 mg/kg of QNtx given s.c., did not affect the Met-Enk-induced immunoenhancement. Immunosuppression produced by i.c.v. injected MR 2034 was totally abrogated by prior i.c.v. application of QNtx, but partially blocked by s.c. administration of the antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral and immunological events induced by electrical stimulation of the rat midbrain periaqueductal gray region.

We report here on the immunological and behavioral alterations induced by stimulation of the mesencephalic periaqueductal gray matter (PAG), a component of the brain aversive system. Male Wistar rats were implanted with stimulating electrodes in the caudal dorsolateral part of the PAG. After recovery, animals were screened for aversive behavior, characterized by running, jumping, vocalization or freezing reaction. Then, rats were subdivided to those which could control aversive stimulation (AS) by switch-off response (cAS group) and those which could not interrupt AS (uAS group). After sensitization with bovine serum albumin (BSA) in complete Freund's adjuvant, rats were stimulated 3 times/week for 40 days, each session lasting 30 min/rat. Immunological assessment included antibody production and hypersensitivity skin reactions to BSA 14 and 21 days after immunization. A behavioral profile of aversively stimulated animals was determined by a poststartle response, open field (OF) activity and two-way shuttle-box avoidance task. The results revealed elevated antibody production to BSA in cAS and lowered in uAS rats, compared to sham-stimulated and intact controls. Arthus and delayed hypersensitivity skin reactions increased in PAG-stimulated animals on day 14 but not on day 21 after immunization. Poststartle response was enhanced both in cAS and uAS rats. Along with immunopotentiation, administration of cAS produced hyperactivity in OF test and facilitation of the active avoidance learning, whereas uAS caused only moderate suppression of rearing in a novel OF environment. Physiological implications and possible mechanisms that may account for PAG-mediated immunobehavioral changes are outlined.

kappa-Opioid receptor functions: possible relevance to experimental allergic encephalomyelitis.

The present study deals with the influence of preferential kappa-opioid agonist MR 2034 on experimental allergic encephalomyelitis (EAE). For this purpose, 9-week-old male Dark August rats were treated intraperitoneally with 0.2 mg/kg of MR 2034 as follows: (a) from the day of EAE induction until sacrifice; (b) from the day of EAE induction until the appearance of neurological signs, and (c) from the appearance of neurological signs until sacrifice. Repeated injections of MR 2034 given during the whole period of observation produced the most pronounced suppression of EAE clinical signs, histological lesions in the brain and spinal cord, and anti-myelin basic protein antibody production. These results suggest that kappa-opioid receptors may be involved in the development of EAE.

Effect of early experience on behavior and immune response in the rat.

The effect of maternal deprivation (MD) and preweaning handling on open field (OF) behavior, body and organ weights (spleen, thymus, and adrenals), and humoral immune response (plaque-forming cell response and antibody production) in adult male and female Wistar rats was studied. Maternal deprivation took place either for 28 postnatal days (2 h/day), or on days 15, 18, and 21 (2 h/day), whereas handling was performed daily during 28 postnatal days for 3 min. Sex differences were found both in behavior and immune response. The MD rats showed ambulatory hyperactivity in OF tests, females being more active than males, and a marked suppression of the PFC response. Handled rat's behavior was distinguishable from MD rats by an increased curiosity. Female handled rats were more active in the OF and their antibody production was higher. Male handled rats showed higher defecation scores and lower plaque-forming cell response. These results present evidence for a deprivation syndrome and immunosuppressive behavior in MD rats. Several mechanisms that may account for these immunobehavioral results are outlined.

Brain-applied magnetic fields and immune response: role of the pineal gland.

In an attempt to clarify the mechanisms underlying immunopotentiation induced by prolonged exposure of the rat brain to static magnetic fields, and to evaluate the role of the pineal gland in that phenomenon, experiments were carried out on the following groups of adult rats (maintained under a 12 hr light/12 hr dark photoperiod): pinealectomized rats (Px); rats with micromagnets implanted to the occipito-parietal region of the skull (M); rats pinealectomized and implanted with micromagnets to the skull (PxM); sham-pinealectomized rats with non-magnetic beads implanted to the occipito-parietal area of the skull (ShPxMx); and intact controls (IC). Twenty-one days after surgery, animals of all groups were immunized with sheep red blood cells and tested for plaque forming cell (PFC) response and serum hemagglutinin level. Humoral immune reactions decreased significantly in Px rats, while increased markedly in M rats in comparison to the ShPxMx and IC controls. Compromised immune function induced by pinealectomy was restored by prolonged exposure of the brain to magnetic fields (PxM rats). Thus reconstituted immune responsiveness in PxM rats reached the level observed in controls, but was lower than that in M rats. The results imply that magnetic fields applied to the rat brain may exert their immunoenhancing activity in the absence of the pineal gland. However, this activity of magnetic fields is more pronounced in the presence of the pineal organ. The latter finding suggests the involvement of the pineal in the immunopotentiation induced by magnetic fields, but does not imply that magnetic fields operate solely via the pineal gland.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain self-stimulation and immunity: effect on humoral and cell-mediated immune responses.

This study was designed to evaluate the effect of intracranial self-stimulation (ICSS) on specific immunological reactivity in the rat. Male Wistar rats were implanted with stimulating electrodes in the lateral hypothalamus (LH) and ventral tegmental area (VTA). After recovery from surgery and screening procedure, animals were allowed to self-stimulate 30 minutes daily during different periods of time before or after immunization with sheep red blood cells (SRBC) and bovine serum albumin (BSA). We report here on the in vivo immunoregulating effects of ICSS on plaque-forming cell (PFC) response, hemagglutinin production to SRBC, and antibody titer and hypersensitivity skin reactions to BSA. The effects produced were dependent on the brain area which was stimulated, time relationship of ICSS and immunization, type of immune reaction, and antigen used for immunization. Therefore, ICSS appears to be a significant tool in the regulation of the immune system function, and thus provides further evidence of the interconnections between the immune system and behavior.

Locus ceruleus and immunity. III. Compromised immune function (antibody production, hypersensitivity skin reactions and experimental allergic encephalomyelitis) in rats with lesioned locus ceruleus is restored by magnetic fields applied to the brain.

This study deals with the relationship between the immunosuppression induced by electrolytic lesions placed into the nucleus locus cerules and the immunopotentiation produced by micromagnets implanted to the parietal area of the skull. The following groups of rats were set up: LC, rats with lesioned locus ceruleus; ShL, sham-lesioned animals bearing non-magnetic beads in the brain parietal region; M, rats with micromagnets of 60 mT influx density in the parietal part of the skull; LCM, animals with impaired locus ceruleus and magnetic beads placed in the parietal area of the skull; and IC, intact control rats. Animals of all groups were tested for plaque-forming cell response, circulating antibodies to sheep red blood cells and bovine serum albumin, Arthus and delayed hypersensitivity skin reactions to bovine serum albumin and old tuberculin, and experimental allergic encephalomyelitis. In LC-rats, humoral and cell-mediated immune reactions were compromised. On the other hand, immune responses in M-rats were significantly potentiated. In LCM-rats, however, the immunosuppression induced by destruction of the locus ceruleus was abrogated by prolonged exposure of the brain parietal region to the magnetic fields, i.e. immune reactivity of LCM-rats was quite similar to that of control IC- and ShL-animals. Several mechanisms may account for the immunomodulating effects produced by lesioning of the locus ceruleus and exposure of the brain to magnetic fields. Noradrenergic, serotoninergic, dopaminergic and peptidergic neurotransmitters, as well as growth hormones and immunopeptides, produced within the central nervous system or elsewhere, may be implicated as necessary for the interactions among the brain, immune apparatus and magnetic fields.

Locus ceruleus and immunity. II. Suppression of experimental allergic encephalomyelitis and hypersensitivity skin reactions in rats with lesioned locus ceruleus.

Rats with lesions restricted to the locus ceruleus were tested for immune inflammatory reactions. In these rats, Arthus and delayed skin hypersensitivity reactions to bovine serum albumin and old tuberculin were suppressed. The ablation of locus ceruleus completely inhibited the development of clinical signs of experimental allergic encephalomyelitis, markedly diminished the occurrence and intensity of lesions in the central nervous system, and significantly reduced the production of antibody against the rat brain myelin basic protein. These results establish a link between the locus ceruleus and immune inflammatory reactions in the rat.