Naltrexone Does Not Reverse the Inhibitory Effect of Chronic Restraint on Gonadotropin Secretion in the Intact Male Rat

González-Quijano, M.I.; Ariznavarreta, C.; Martín, Ana Isabel; Treguerres, Jesus A.F.; López-Calderón, Asunción

doi:10.1159/000125933

Cited by 24 publications

(8 citation statements)

References 27 publications

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“…Moreover, administering RFRP to adult male rats suppresses plasma LH levels (13), as does exposure to stress (3,4). In the present study, we show a direct correlation between stress-induced increases in RFRP expression and reduction in plasma LH.…”

Section: Discussionsupporting

confidence: 66%

“…Centrally, it leads to activation of the hypothalamic-pituitaryadrenal (HPA) axis, which in turn leads to suppression of HPG activity through inhibition of gonadotropin-releasing hormone (GnRH) secretion (1,2). Downstream of GnRH, the functional effects of stress on reproduction can be seen with suppression of luteinizing hormone (LH) release from the pituitary (3,4) and suppression of sexual behavior (5,6). The stress effect on HPG function appears to be mediated by the adrenal stress hormones glucocorticoids (GCs).…”

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confidence: 99%

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Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats

Kirby

Geraghty

Ubuka

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

311

220

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The subjective experience of stress leads to reproductive dysfunction in many species, including rodents and humans. Stress effects on reproduction result from multilevel interactions between the hormonal stress response system, i.e., the hypothalamic-pituitary-adrenal (HPA) axis, and the hormonal reproductive system, i.e., the hypothalamic-pituitary-gonadal (HPG) axis. A novel negative regulator of the HPG axis known as gonadotropin-inhibitory hormone (GnIH) was recently discovered in quail, and orthologous neuropeptides known as RFamide-related peptides (RFRPs) have also been identified in rodents and primates. It is currently unknown, however, whether GnIH/RFRPs influence HPG axis activity in response to stress. We show here that both acute and chronic immobilization stress lead to an up-regulation of RFRP expression in the dorsomedial hypothalamus (DMH) of adult male rats and that this increase in RFRP is associated with inhibition of downstream HPG activity. We also show that adrenalectomy blocks the stress-induced increase in RFRP expression. Immunohistochemistry revealed that 53% of RFRP cells express receptors for glucocorticoids (GCs), indicating that adrenal GCs can mediate the stress effect through direct action on RFRP cells. It is thought that stress effects on central control of reproduction are largely mediated by direct or indirect effects on GnRH-secreting neurons. Our data show that stress-induced increases in adrenal GCs cause an increase in RFRP that contributes to hypothalamic suppression of reproductive function. This novel insight into HPA-HPG interaction provides a paradigm shift for work on stress-related reproductive dysfunction and infertility, and indicates that future work on stress and reproductive system interactions must include investigation of the role of GnIH/RFRP.GnIH ͉ reproduction ͉ RFRP S tress has acute and chronic effects on many aspects of vertebrate physiology and behavior. Reproduction is a key life-history component that is often adversely affected by physical and psychological stressors. The negative impact of stress occurs at several levels of the vertebrate hypothalamic-pituitary-gonadal (HPG) axis. Centrally, it leads to activation of the hypothalamic-pituitaryadrenal (HPA) axis, which in turn leads to suppression of HPG activity through inhibition of gonadotropin-releasing hormone (GnRH) secretion (1, 2). Downstream of GnRH, the functional effects of stress on reproduction can be seen with suppression of luteinizing hormone (LH) release from the pituitary (3, 4) and suppression of sexual behavior (5, 6). The stress effect on HPG function appears to be mediated by the adrenal stress hormones glucocorticoids (GCs). In male mammals, systemic GC administration inhibits circulating gonadotropin levels (7), decreases seminal vesicle weight, and results in fewer implantation sites and viable fetuses in female mates (8). However, hypothalamic corticotropinreleasing hormone (CRH) has also been strongly implicated in stress effects on reproduction (2, 9, 10).Gonadotropin i...

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Section: Discussionsupporting

confidence: 66%

mentioning

confidence: 99%

Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats

Kirby

Geraghty

Ubuka

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

311

220

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“…Chronic immobili zation or restraint stress inhibits LH secretion [l, 2], but it also suppresses the testicular response to gonadotropin [3,4], However, the effect of stress on LH secretion is highly variable. In male rats, immobilization or restraint stress has been reported to decrease [1,2], have no effect [3,4], or increase [5] basal blood levels of LH. Some of these differences are probably related to the intensity or dura tion of the stressor.…”

mentioning

confidence: 99%

Effect of a Peripheral and a Central Acting Opioid Antagonist on the Testicular Response to Stress in Rats

Akinbami

Taylor²,

Collins³

et al. 1994

Neuroendocrinology

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The possible involvement of opioid receptors in mediating the inhibitory effects of immobilization stress on testicular steroidogenesis was determined in adult male rats. Unstressed controls and animals exposed to 3 h of immobilization stress were injected subcutaneously with either vehicle or 1 or 10 mg/ kg body weight (BW) of naloxone or naltrexone methobromide (NMB; an opioid receptor antagonist that does not cross the blood-brain barrier) at the beginning of and at 1.5 h of the stress period. Animals were sacrificed at 2 h (30 min after the second injection of antagonist) or 3 h (90 min after the second injection of antagonist) of stress. Plasma LH was not affected by stress, but 30 min after naloxone (1 or 10 mg/kg BW) injection, LH was elevated in both control and stressed rats above levels in vehicle-injected animals. By 90 min after naloxone injection, plasma LH had declined to levels comparable to those in vehicle-injected animals. NMB had no effect on plasma LH concentrations in either control or stressed rats. Three hours of stress reduced plasma testosterone (T) levels by 60% in vehicle-injected animals. This effect of stress on plasma T levels was antagonized by the 10 mg/kg BW dose of naloxone and 1 or 10 mg/kg BW of NMB. The ability of naloxone to reverse the effect of stress on plasma T levels was likely related to its ability to stimulate LH secretion, but NMB normalized plasma T values in stressed animals without altering plasma LH concentrations. Only the highest dose of NMB increased plasma T levels in unstressed control animals. The activities (V_max) of testicular 17 α-hydroxylase and 17,20-lyase were significantly reduced by 3 h of stress. K_m values for both enzymes were unchanged in stressed rats. Both naloxone and NMB normalized the activity of both enzymes in stressed animals, but did not alter the activity of the enzymes in unstressed rats. These results demonstrate that NMB, a peripheral acting opioid antagonist, counteracts the inhibitory effect of stress on plasma T levels and on testicular activity of 17 α-hydroxylase and 17,20-lyase independent of an effect on plasma LH concentrations. The study provides evidence for the involvement of peripheral opioid receptors (perhaps testicular opioid receptors) in mediating the inhibitory effect of immobilization stress on testicular steroidogenesis. Data from this study also supports the hypothesis that opioids directly modulate testicular testosterone secretion in unstressed control animals.

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“…In the gonadectomized rat, [LEND-and DYN-synthesizing neurons have both been identified as part of the neural circuitry mediating acute footshock-induced de creases in LH [ 16], and there is evidence that activation of p-END neurons in this stress paradigm may be mediated by CRF [17], The role of EOP in the inhibitory LH response to chronic stress, however, is less clear. Current findings suggest that EOP involvement may depend upon the nature and/or severity of the chronic stress stimulus, since opioid receptor antagonism can reverse chronic sur gical-[5], but not chronic restraint stress-induced de creases in circulating LH [37], The coexistence of GR with P-END [38] and CRF immunoreactivity [39][40][41] supports the possibility of a modulatory impact of gluco corticoids on neurons synthesizing these neuropeptides. Observations that DEX-induced decreases in plasma LH are reversed by opioid receptor antagonists [42,43] strengthen the hypothesis that proopiomelanocortin (POMC) peptide-producing neurons may function as neu ral substrates for central inhibitory effects of glucocorti coids on the GnRH-pituitary LH axis.…”

Section: Discussionmentioning

confidence: 73%

The Antiglucocorticoid, RU486, Attenuates Stress-Induced Decreases in Plasma-Luteinizing Hormone Concentrations in Male Rats

Briski¹,

Vogel²,

Mclntyre³

1995

Neuroendocrinology

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The present studies investigated the role of glucocorticoid receptors (GR) in the inhibitory effects of acute and chronic immobilization stress on pituitary luteinizing hormone (LH) release. Systemic administration of the GR antagonist, RU486, significantly attenuated the acute decline in circulating LH observed in intact male rats immobilized by encasement within paper cocoons. Whereas vehicle-injected controls exhibited a significant reduction in plasma LH between +1 and +5 h of stress, animals given subcutaneous (sc) injections of 2.5 mg RU846/kg did not exhibit a reduction in circulating LH until 4 h after initiation of stress. Plasma LH levels in the GR-treated group were significantly elevated compared to the vehicle controls between +1 and +3 h of stress. Repetitive exposure to the same stress stimulus 24 and 48 h later resulted in decreased plasma LH levels in the vehicle-treated rats, but not in the animals injected sc with RU486. Other studies showed that intracere-broventricular (icv) administration of RU486 (10.0 µg/rat) also blunted the inhibitory effects of acute and chronic immobilization stress on pituitary LH release. In experiments designed to evaluate whether activation of central GR can influence the magnitude and/or temporal characteristics of the LH secretory response to acute inhibitory stress, it was observed that animals pre-treated by icv injection of the GR agonist, RU362, exhibited a greater reduction in plasma LH levels during the first hour of stress, as compared to rats pretreated with vehicle alone.

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Naltrexone Does Not Reverse the Inhibitory Effect of Chronic Restraint on Gonadotropin Secretion in the Intact Male Rat

Cited by 24 publications

References 27 publications

Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats

Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats

Effect of a Peripheral and a Central Acting Opioid Antagonist on the Testicular Response to Stress in Rats

The Antiglucocorticoid, RU486, Attenuates Stress-Induced Decreases in Plasma-Luteinizing Hormone Concentrations in Male Rats

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