Central μ-opioid receptor antagonism blocks glucoprivic LH pulse suppression and gluconeogenesis/feeding in female rats

Endocrinology ◽  
2021 ◽  
Author(s):  
Hitomi Tsuchida ◽  
Narumi Kawai ◽  
Koki Yamada ◽  
Marina Takizawa ◽  
Naoko Inoue ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Glucose Utilization ◽  
Marker Gene ◽  
Reproductive Function ◽  
Female Rats ◽  
Μ Opioid Receptor ◽  
Lh Release ◽  
Feedback Level ◽  
Gene Expressing ◽  
Estradiol 17Β

Abstract Energetic status often affects reproductive function, glucose homeostasis and feeding in mammals. Malnutrition suppresses pulsatile release of the gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) and increases gluconeogenesis and feeding. The present study aims to examine whether β-endorphin-μ-opioid receptor (MOR) signaling mediates the suppression of pulsatile GnRH/LH release, and an increase in gluconeogenesis/feeding induced by malnutrition. Ovariectomized female rats treated with a negative feedback level of estradiol-17β (OVX + low E2) receiving 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, intravenously (iv), were used as a malnutrition model. An administration of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a selective MOR antagonist, into the 3 rd ventricle blocked the suppression of the LH pulse and increase in gluconeogenesis/feeding induced by iv 2DG administration. Histological analysis revealed that arcuate Kiss1 (kisspeptin gene)-expressing cells and preoptic Gnrh1 (GnRH gene)-expressing cells co-expressed little Oprm1, while around 10% of arcuate Slc17a6 (glutamatergic marker gene)-expressing cells co-expressed Oprm1. Further, the CTOP treatment decreased the number of fos-positive cells in the paraventricular nucleus (PVN) in OVX + low E2 rats treated with iv 2DG, but failed to affect the number of arcuate fos-expressing Slc17a6-positive cells. Taken together, these results suggest that the central β-endorphin-MOR signaling mediates the suppression of pulsatile LH release and that the β-endorphin may indirectly suppress the arcuate kisspeptin neurons, a master regulator for GnRH/LH pulses during malnutrition. Furthermore, the current study suggests that central β-endorphin-MOR signaling is also involved in gluconeogenesis and an increase in food intake by directly or indirectly acting on the PVN neurons during malnutrition in female rats.

Neuropharmacological analysis of the control of LH secretion in gonadectomized male and female rats: altered hypothalamic responses to inhibitory neurotransmitters in long-term castrated rats

1988 ◽  
Vol 119 (1) ◽  
pp. 15-21 ◽  
Author(s):  
O. F. X. Almeida ◽  
K. E. Nikolarakis ◽  
A. Herz
Keyword(s):  
Opioid Receptor ◽  
Female Rats ◽  
Male Rats ◽  
Dopaminergic Agonists ◽  
Male And Female ◽  
Opioid Agonists ◽  
Male And Female Rats ◽  
Lh Release ◽  
Lh Secretion

ABSTRACT The control of LHRH and LH by neurotransmitters and neuromodulators such as the endogenous opioid peptides is essentially the same in intact adult male and female rats: adrenergic and dopaminergic agonists stimulate LH release and opioid agonists inhibit it. Several weeks after gonadectomy, however, the contribution of the endogenous ligands of adrenergic, dopaminergic and opioidergic receptors to the control of LHRH is altered. A detailed pharmacological analysis in long-term ovariectomized females confirmed previous reports that adrenergic and dopaminergic agonists still enhance secretion of LHRH and LH and opioid receptor agonists still suppress it. A similar investigation in long-term castrated males also confirmed previous reports that opioid agonists fail to block LH secretion. In addition, we have found that while adrenergic and dopaminergic agonists cause increases in serum concentrations of LH, adrenoreceptor and dopamine receptor antagonists do not inhibit LH release in long-term castrates. Furthermore, the opioid antagonist naloxone does not raise serum LH levels in either sex after long-term gonadectomy. These observations therefore imply reduced opioidergic, dopaminergic and adrenergic transmission, in relation to LHRH release, after longterm castration. In addition, opioid receptor activity (assessed by responsiveness to an opioid receptor agonist) of female rats is maintained, whereas that of male rats is lost, after long-term gonadectomy. J. Endocr. (1988) 119, 15–21

Estrogen regulation of μ-opioid receptor mRNA in the forebrain of female rats

1997 ◽  
Vol 47 (1-2) ◽  
pp. 134-138 ◽  
Author(s):  
Vanya Quiñones-Jenab ◽  
Shirzad Jenab ◽  
Sonoko Ogawa ◽  
Charles Inturrisi ◽  
Donald W Pfaff
Keyword(s):  
Opioid Receptor ◽  
Female Rats ◽  
Estrogen Regulation ◽  
Receptor Mrna ◽  
Μ Opioid Receptor

scholarly journals Advanced age attenuates the antihyperalgesic effect of morphine and decreases μ-opioid receptor expression and binding in the rat midbrain Periaqueductal Gray in male and female rats

2020 ◽  
Author(s):  
Evan F. Fullerton ◽  
Myurajan Rubaharan ◽  
Mary C. Karom ◽  
Richard I. Hanberry ◽  
Anne Z. Murphy
Keyword(s):  
Opioid Receptor ◽  
Receptor Expression ◽  
Female Rats ◽  
Advanced Age ◽  
Adult Males ◽  
Male And Female ◽  
Male And Female Rats ◽  
Age Related ◽  
Μ Opioid Receptor ◽  
The Impact

AbstractThe present study investigated the impact of advanced age on morphine modulation of persistent inflammatory pain in male and female rats. The impact of age, sex, and pain on μ-opioid receptor (MOR) expression and binding in the ventrolateral PAG (vlPAG) was also examined using immunohistochemistry and receptor autoradiography. Intraplantar administration of Complete Freund’s adjuvant induced comparable levels of edema and hyperalgesia in adult (2-3mos) and aged (16-18mos) male and female rats. Morphine potency was highest in adult males, with a two-fold decrease in morphine EC50 observed in aged versus adult males (10.22mg/kg versus 5.19mg/kg). Adult and aged female rats also exhibited significantly higher EC50 values (10.69 mg/kg and 9.00 mg/kg, respectively) compared to adult males. The upward shift in EC50 from adult to aged males was paralleled by a reduction in vlPAG MOR expression and binding. The observed age-related reductions in morphine potency and vlPAG MOR expression and binding have significant implications in pain management in the aged population.

Effects of treatment with the opioid antagonists naloxone and naltrexone on LH secretion and on sexual maturation in immature female rats

1988 ◽  
Vol 117 (2) ◽  
pp. 237-243 ◽  
Author(s):  
H. M. A. Meijs-Roelofs ◽  
P. Kramer
Keyword(s):  
Opioid Receptor ◽  
Sexual Maturation ◽  
Female Rats ◽  
Opioid Antagonists ◽  
Short Term ◽  
Neonatal Treatment ◽  
Serum Lh ◽  
Naltrexone Treatment ◽  
Lh Release ◽  
Lh Secretion

ABSTRACT The effects on sexual maturation of the opioid receptor antagonists naloxone and naltrexone were studied in the female rat. Neonatal treatment (days 1–10) with either naloxone (2·5 mg/kg at 6-h intervals) or naltrexone (20 or 50 mg/kg per day) did not advance sexual maturation as judged by age and body weight at vaginal opening and first ovulation. After treatment with naltrexone (20 mg/kg) first ovulation occurred 2·3 days earlier than in saline-treated control rats but this could be attributed to a growth-stimulating effect of naltrexone; the effect was not observed with 50 mg/kg. An effect of neonatal treatment with naloxone on serum LH levels was seen at 23 days of age (155±36 (s.e.m.) vs 14±4 μg LH/1 in controls, P<0·01), but not at 29 or 33 days of age, at 2 days before first ovulation nor at first pro-oestrus. There were no differences in the number of ova released at first oestrus, nor in the length of the first cycle. Neonatal treatment with naltrexone (50 mg/kg per day) did not alter the response to treatment with human chorionic gonadotrophin at 28–31 days of age: ovulation of a mean of 7·3 ova was induced on day 32 in both naltrexone- and saline-treated rats. Naltrexone treatment (four daily injections of 20 mg/kg at 2-h intervals) at 28–32 days of age advanced first ovulation by 4·4 days in about 40% of the rats. Short-term effects of naloxone and naltrexone treatment on LH secretion were studied in 15-day-old rats and a clear increase in serum LH concentration was seen 15 min after injection; LH levels were similar with the various doses of antagonist used (2·5 and 20 mg naloxone/kg; 2·5, 20 and 50 mg naltrexone/kg). At 30 min after injection LH levels were still maximal if the 2·5 mg/kg dose of either antagonist was used, whereas with the higher doses a significant (P<0·01) decrease in the level of LH was observed, indicating a longer-lasting effect of the lower (2·5 mg/kg) dose of antagonist on LH secretion. No differences in effectiveness were seen between the supposedly short-lasting opioid receptor antagonist naloxone and the supposedly long-lasting antagonist naltrexone. It was concluded that neonatal treatment with the opioid antagonists naloxone and naltrexone did not specifically influence sexual maturation. The antagonists clearly increased LH secretion in short-term experiments. Treatment with naltrexone at 28–32 days of age advanced first ovulation in 40% of the rats, a result that is in agreement with a possible opiatergic influence on the gradually increasing LH release during the final phase of sexual maturation. The effects of the opioid antagonist naltrexone on the LH release mechanism did not parallel its reported long-lasting effects on nociceptive response, no long-lasting increase of LH release was seen, and the timecourse of the LH response was the same using the antagonists naloxone and naltrexone. J. Endocr. (1988) 117, 237–243

Paraventricular Dynorphin A Neurons Mediate LH Pulse Suppression Induced by Hindbrain Glucoprivation in Female Rats

Endocrinology ◽  
2020 ◽  
Vol 161 (11) ◽  
Author(s):  
Hitomi Tsuchida ◽  
Parvin Mostari ◽  
Koki Yamada ◽  
Sae Miyazaki ◽  
Yuki Enomoto ◽  
...  
Keyword(s):  
Receptor Gene ◽  
Critical Role ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Central Administration ◽  
Dynorphin A ◽  
Gonadotropin Secretion ◽  
Feedback Level ◽  
Estradiol 17Β

Abstract Malnutrition suppresses reproductive functions in mammals, which is considered to be mostly due to the inhibition of pulsatile gonadotropin-releasing hormone (GnRH)/gonadotropin secretion. Accumulating evidence suggests that kisspeptin neurons in the arcuate nucleus (ARC) play a critical role in the regulation of pulsatile GnRH/gonadotropin release. The present study aimed to examine if the hypothalamic dynorphin A (Dyn) neurons mediate the suppression of GnRH/luteinizing hormone (LH) pulses during malnutrition. Ovariectomized rats treated with a negative feedback level of estradiol-17β-treated (OVX+E2) were administered with intravenous (iv) or fourth cerebroventricle (4V) 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, to serve as a malnutrition model. Central administration of a Dyn receptor antagonist blocked the iv- or 4V-2DG-induced suppression of LH pulses in OVX+E2 rats. The 4V 2DG administration significantly increased the number of Pdyn (Dyn gene)-positive cells co-expressing fos in the paraventricular nucleus (PVN), but not in the ARC and supraoptic nucleus (SON), and the iv 2DG treatment significantly increased the number of fos and Pdyn-co-expressing cells in the PVN and SON, but decreased it in the ARC. The E2 treatment significantly increased Pdyn expression in the PVN, but not in the ARC and SON. Double in situ hybridization for Kiss1 (kisspeptin gene) and Oprk1 (Dyn receptor gene) revealed that around 60% of ARC Kiss1-expressing cells co-expressed Oprk1. These results suggest that the PVN Dyn neurons, at least in part, mediate LH pulse suppression induced by the hindbrain or peripheral glucoprivation, and Dyn neurons may directly suppress the ARC kisspeptin neurons in female rats.

scholarly journals Activation of Peripheral μ-opioid Receptors by Dermorphin [d-Arg2, Lys4] (1–4) Amide Leads to Modality-preferred Inhibition of Neuropathic Pain

2016 ◽  
Vol 124 (3) ◽  
pp. 706-720 ◽  
Author(s):  
Vinod Tiwari ◽  
Fei Yang ◽  
Shao-Qiu He ◽  
Ronen Shechter ◽  
Chen Zhang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Side Effects ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Dynamic Range ◽  
Pain Treatment ◽  
Female Rats ◽  
Male Rats ◽  
Μ Opioid Receptor ◽  
Μ Opioid Receptors

Abstract Background Opioids have long been regarded as the most effective drugs for the treatment of severe acute and chronic pain. Unfortunately, their therapeutic efficacy and clinical utility have been limited because of central and peripheral side effects. Methods To determine the therapeutic value of peripheral μ-opioid receptors as a target for neuropathic pain treatment, the authors examined the effects of dermorphin [d-Arg2, Lys4] (1–4) amide (DALDA), a hydrophilic, peripherally acting μ-opioid receptor agonist, in male and female rats with spinal nerve ligation–induced neuropathic pain. The authors also utilized behavioral, pharmacologic, electrophysiologic, and molecular biologic tools to characterize DALDA’s possible mechanisms of action in male rats. Results DALDA, administered subcutaneously, had 70 times greater efficacy for inhibiting thermal (n = 8 to 11/group) than mechanical hypersensitivity (n = 6 to 8/group) in male rats. The pain inhibitory effects of DALDA on mechanical and heat hypersensitivity were abolished in animals pretreated with systemic methylnaltrexone (n = 7 to 9/group), a peripheral μ-opioid receptor antagonist. In the spinal wide-dynamic range neurons, systemic DALDA inhibited C-fiber–mediated, but not A-fiber–mediated, response in neuropathic male rats (n = 13). In primary sensory neurons, DALDA inhibited the capsaicin-induced [Ca2+] increase more than the β-alanine–induced [Ca2+] increase (n = 300); capsaicin and β-alanine activate subpopulations of neurons involved in the signaling of heat and mechanical pain, respectively. DALDA-treated rats (n = 5 to 8/group) did not exhibit motor deficits and locomotor impairment suggesting that it does not induce central side effects. Conclusions These findings suggest that DALDA may represent a potential alternative to current opioid therapy for the treatment of neuropathic pain and is likely to be associated with minimal adverse effects.

Sign in / Sign up

Export Citation Format

Share Document