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Orphanin FQ (OFQ/N) and its receptor, opioid receptor-like receptor-1 (ORL-1), are expressed throughout steroid-responsive limbic and hypothalamic circuits that regulate female ovarian hormone feedback and reproductive behavior circuits. The arcuate nucleus of the hypothalamus (ARH) is a brain region that expresses OFQ/N and ORL-1 important for both sexual behavior and modulating estradiol feedback loops. Within the ARH, the activation of the OFQ/N-ORL-1 system facilitates sexual receptivity (lordosis) through the inhibition of β-endorphin neuronal activity. Estradiol initially activates ARH β-endorphin neurons to inhibit lordosis. Simultaneously, estradiol upregulates coexpression of OFQ/N and progesterone receptors and ORL-1 in ARH β-endorphin neurons. Ovarian hormones regulate pre- and postsynaptic coupling of ORL-1 to its G protein-coupled signaling pathways. When the steroid-primed rat is nonreceptive, estradiol acts pre- and postsynaptically to decrease the ability of the OFQ/N-ORL-1 system to inhibit ARH β-endorphin neurotransmission. Conversely, when sexually receptive, ORL-1 signaling is restored to inhibit β-endorphin neurotransmission. Although steroid signaling that facilitates lordosis converges to deactivate ARH β-endorphin neurons, estradiol-only facilitation of lordosis requires the activation of ORL-1, but estradiol+progesterone does not, indicating that multiple circuits mediate ovarian hormone signaling to deactivate ARH β-endorphin neurons. Research on the role of OFQ/N-ORL-1 in ovarian hormone feedback loops is just beginning. In the rat, OFQ/N may act to terminate gonadotropin-releasing hormone and luteinizing hormone release under positive and negative feedbacks. In the ewe, it appears to directly inhibit gonadotropin-releasing hormone release to mediate progesterone-negative feedback. As a whole, the localization and actions of OFQ/N-ORL-1 system indicate that it may mediate the actions of estradiol and progesterone to synchronize reproductive behavior and ovarian hormone feedback loops., (© 2015 Elsevier Inc. All rights reserved.)

Background and Purpose: Peripheral sensitization contributes to pathological pain. While prostaglandin E2 (PGE2) and nerve growth factor (NGF) sensitize peptidergic C‐nociceptors (TRPV1+), glial cell line‐derived neurotrophic factor (GDNF) sensitizes non‐peptidergic C‐neurons (IB4+). The sigma‐1 receptor (sigma‐1R) is a Ca2+‐sensing chaperone known to modulate opoid analgesia. This receptor binds both to TRPV1 and the μ opioid receptor, although the functional repercussions of these physical interactions in peripheral sensitization are unknown. Experimental Approach: We tested the effects of sigma‐1 antagonism on PGE2‐, NGF‐, and GDNF‐induced mechanical and heat hyperalgesia in mice. We used immunohistochemistry to determine the presence of endomorphin‐2, an endogenous μ receptor agonist, on dorsal root ganglion (DRG) neurons. Recombinant proteins were used to study the interactions between sigma‐1R, μ‐ receptor, and TRPV1. We used calcium imaging to study the effects of sigma‐1 antagonism on PGE2‐induced sensitization of TRPV1+ nociceptors. Key Results: Sigma1 antagonists reversed PGE2‐ and NGF‐induced hyperalgesia but not GDNF‐induced hyperalgesia. Endomorphin‐2 was detected on TRPV1+ but not on IB4+ neurons. Peripheral opioid receptor antagonism by naloxone methiodide or administration of an anti‐endomorphin‐2 antibody to a sensitized paw reversed the antihyperalgesia induced by sigma‐1 antagonists. Sigma‐1 antagonism transfers sigma‐1R from TRPV1 to μ receptors, suggesting that sigma‐1R participate in TRPV1‐μ receptor crosstalk. Moreover, sigma‐1 antagonism reversed, in a naloxone‐sensitive manner, PGE2‐induced sensitization of DRG neurons to the calcium flux elicited by capsaicin, the prototypic TRPV1 agonist. Conclusion and Implications: Sigma‐1 antagonism harnesses endogenous opioids produced by TRPV1+ neurons to reduce hyperalgesia by increasing μ receptor activity. [ABSTRACT FROM AUTHOR]

Although the interplay between endogenous opioids and dopamine (DA) in the basal ganglia (BG) is known to underlie diverse motor functions, few studies exist on their role in modulating speech and vocalization. Vocal impairment is a common symptom of Parkinson's disease (PD), wherein DA depletion affects striosomes rich in μ-opioid receptors (μ-ORs). Symptoms of opioid addiction also include deficiencies in verbal functions and speech. To understand the interplay between the opioid system and BG in vocalization, we used adult male songbirds wherein high levels of μ-ORs are expressed in Area X, a BG region which is part of a circuit similar to the mammalian thalamocortical-basal ganglia loop. Changes in DA, glutamate and GABA levels were analyzed during the infusion of different doses of the μ-OR antagonist naloxone (50 and 100 ng/ml) specifically in Area X. Blocking μ-ORs in Area X with 100 ng/ml naloxone led to increased levels of DA in this region without altering the number of songs directed toward females (FD). Interestingly, this manipulation also led to changes in the spectro-temporal properties of FD songs, suggesting that altered opioid modulation in the thalamocortical-basal ganglia circuit can affect vocalization. Our study suggests that songbirds are excellent model systems to explore how the interplay between μ-ORs and DA modulation in the BG affects speech/vocalization. [ABSTRACT FROM AUTHOR]

Background Endogenous opioids ( EO) acting on μ-opioid receptors in central and enteric nervous system ( ENS) control gastrointestinal motility but it is still unclear whether EO in ENS may control esophageal function in man, thus we will study the effects of methylnaltrexone ( MNTX), a peripherally selective, and naloxone ( NA), a non-selective μ-opioid receptor antagonist, on esophageal motility in healthy subjects. Methods Fifteen HV (6 M; 34.1 ± 0.6 years; BMI: 22.1 ± 0.1 kg/m2) underwent three esophageal high-resolution manometry impedance ( HRiM) studies with 10 saline swallows administered every 30 minutes: drug was administered after 30 minutes ( MNTX subcutaneously/ NA or saline intravenously), a solid meal after 90 minutes; measurements continued for 120 minutes postprandially. Key Results Methylnaltrexone did not significantly decrease the upper esophageal sphincter ( UES) percentage of relaxation preprandially (72.5 ± 5 vs 66.9 ± 4.6 and 73 ± 3.8%, ANOVA between placebo, MNTX and NA, P= NS) and postprandially (60 minutes: 68.2 ± 5.6 vs 61 ± 5.5 and 67.1 ± 5.6%; 120 minutes: 68 ± 5.9 vs 59.3 ± 5.2 and 67.7 ± 4.7%; ANOVA between placebo, MNTX and NA, P= NS). MNTX and NA did not significantly alter preprandial and postprandial LES resting pressures and integrated relaxation pressure ( ANOVA between placebo, MNTX and NA, all P= NS). Peak front velocity and distal contractile integral were not altered pre- and postprandially by MNTX and NA ( ANOVA between placebo, MNTX and NA, P= NS). Transient lower esophageal sphincter relaxations ( TLESRs') number was not altered by MNTX and NA ( ANOVA between placebo, MNTX and NA, all P= NS). Conclusions and Inferences The peripheral selective and non-selective μ-opioid receptor antagonists MNTX and NA, respectively, do not alter TLESRs occurrence and esophageal peristalsis. [ABSTRACT FROM AUTHOR]

Abstract: Significant opioid-dependent changes occur during the fourth postnatal week in supraspinal sites (rostroventral medulla [RVM], periaqueductal grey [PAG]) that are involved in the descending control of spinal excitability via the dorsal horn (DH). Here we report developmentally regulated changes in the opioidergic signalling within the PAG and DH, which further increase our understanding of pain processing during early life. Microinjection of the μ-opioid receptor (MOR) agonist DAMGO (30ng) into the PAG of Sprague-Dawley rats increased spinal excitability and lowered mechanical threshold to noxious stimuli in postnatal day (P)21 rats, but had inhibitory effects in adults and lacked efficacy in P10 pups. A tonic opioidergic tone within the PAG was revealed in adult rats by intra-PAG microinjection of CTOP (120ng, MOR antagonist), which lowered mechanical thresholds and increased spinal reflex excitability. Spinal adminstration of DAMGO inhibited spinal excitability in all ages, yet the magnitude of this was greater in younger animals than in adults. The expression of MOR and related peptides were also investigated using TaqMan real-time polymerase chain reaction and immunohistochemistry. We found that pro-opiomelanocortin peaked at P21 in the ventral PAG, and MOR increased significantly in the DH as the animals aged. Enkephalin mRNA transcripts preceded the increase in enkephalin immunoreactive fibres in the superficial dorsal horn from P21 onwards. These results illustrate that profound differences in the endogenous opioidergic signalling system occur throughout postnatal development. [Copyright &y& Elsevier]

Background/Aims: Multiple opioid receptor (OR) types and endogenous opioid peptides exist in the spinal dorsal horn and there may be interactions among these receptor types that involve opioid peptides. In a previous study we observed that antinociceptive effects of the selective κ-opioid receptor (κOR) agonist, U50,488H, was attenuated in μ-opioid receptor (μOR) knockout mice as compared to wild-type mice when administered spinally. This suggests that an interaction between κORs and μORs exits in the spinal cord. The present study was aimed at investigating whether endogenous opioid peptides were involved in such interaction. Methods: We examined whether the presence of antibodies to endogenous opioid peptides, endomorphin-2, met-enkephalin and dynorphin A affected the antinociceptive effects of spinal U50,488H in rats. The tail-flick test was used to assess pain thresholds. Results: The increase in tail-flick latency after spinal U50,488H was attenuated when the rats were pretreated intrathecally with antiserum against endomorphin-2. Pretreatments with antisera against met-enkephalin and dynorphin A had no effect on U50,488H antinociception. The antisera alone did not affect pain threshold. Conclusion: The results suggest that endomorphin-2, an endogenous opioid peptide highly selective to the μOR, plays a role in antinociception induced by κOR activation in the spinal cord. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The biological effects of endomorphins (EMs) are short-lasting due to their rapid degradation by endogenous enzymes. Competing enzymatic degradation is an approach to prolong EM bioavailability. In the present study, a series of tetra- and tripeptides of similar to EMs structure was synthesized and tested in vitro and in vivo for their ability to inhibit degradation of EMs. The obtained results indicated that, among the series of analogs, the tetrapeptide Tyr–Pro–d–ClPhe–Phe–NH2 and the tripeptide Tyr–Pro–Ala–NH2, which did not bind to the μ-opioid receptors, were potent inhibitors of EM catabolism in rat brain homogenate. In vivo, these two peptides significantly prolonged the analgesic and antidepressant-like effects, induced by exogenous EMs, by blocking EM degrading enzymes. These new potent inhibitors may therefore increase the level and the half life of endogenous EMs and could be used in a new therapeutic strategy against pain and mood disorders, based on increasing of EM bioavailability. [Copyright &y& Elsevier]

1 Whole-cell patch recordings were made from substantia gelatiosa (SG) neurons in transverse lumbar spinal cord slices of 15- to 30- day-old rats. 2 Endomorphin 1 (EM-1) or EM-2 (≤ l0 μM) hyperpolarized or induced un outward current in 26 of the 66 SG neurons. The 1 -V relationship showed that the peptide activates an inwardly rectifying K[sup+] current. 3 EM-1 or EM-2 (0.3-10 μM) suppressed short-latency excitatory postsynaptic currents (EPSCs) and long-latency inhibitory postsynaptic currents (IPSs) in nearly all SG neurons tested or short-latency IPSCs in six of the10 SG neurons. [Met[sup5]] enkephalin or [D-Ala[sup2], N -Me-phe[sup4], Gly[sup3]-ol] enkephalin (DAMGO)) (1-10 μM) depressed EPSCs and IPSCs. EM-I or EM-2 depressed synaptic responses without causing a significant change in holding currents or inward currents induced by glutamate. 4 Glutamate also evoked a short-latency outward current in five SG neurons or a biphasic current in two neurons; the outward current was blocked by tetrodotoxin (TTX, 0.3 μM) or bicuculline (10 μM). EM-1 or DAMGO (1 or 5μM) attenuated the glutamate-evoked outward or biphasic currents in lour of the seven SG neurons. 5 EM-1 (1μM) reduced the frequency. but not the amplitude of miniature EPSCs or miniature IPSCs. 6 Naloxone (1μM) or the selective μ-opioid receptor antagonist β-funaltrexamine (β-FNA. 25.μM) antagonized the action of EM; EM-induced hyperpolarizations persisted in the presence of the k-opioid receptor antagonist (nor-binaltlorphimine dihydrochloride, I,μM) and or &osigma;-opioid receptor antagonis (naltrindole hydrochloride, l μM). 7 It may be concluded that EM acting on μ-opioid receptors hyperpolarizes a population of SG neurons by activating an inwardly rectifying K[sup+] current, and attenuates exctitatory and inhibitory synaplic currents evoked in a population of SG neurons, probably by a presynaptic site of action. [ABSTRACT FROM AUTHOR]

The midbrain periaqueductal gray matter (PAG) is an important brain region for the coordination of μ-opioid-induced pharmacological actions. The present study was designed to determine whether newly isolated μ-opioid peptide endomorphins can activate G proteins through μ-opioid receptors in the PAG by monitoring the binding to membranes of the non-hydrolyzable analog of GTP, guanosine-5′-O-(3-[[sup 35] S]thio)triphosphate ([[sup 35] S]GTPγS). An autoradiographic [[sup 35] S]GTPγS binding study showed that both endomorphin-1 and -2 produced similar anatomical distributions of activated G proteins in the mouse midbrain region. In the mouse PAG, endomorphin-1 and -2 at concentrations from 0.001 to 10 μM increased [[sup 35] S]GTPγS binding in a concentration-dependent manner and reached a maximal stimulation of 74.6 ± 3.8 and 72.3 ± 4.0%, respectively, at 10 μM. In contrast, the synthetic selective μ-opioid receptor agonist [D-Ala[sup 2] ,NHPhe[sup 4] ,Gly-ol]enkephalin (DAMGO) had a much greater efficacy and produced a 112.6 ± 5.1% increase of the maximal stimulation. The receptor specificity of endomorphin-stimulated [[sup 35] S]GTPγS binding was verified by coincubating membranes with endomorphins in the presence of specific μ-, δ- or κ-opioid receptor antagonists. Coincubation with selective μ-opioid receptor antagonists β-funaltrexamine or D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH[sub 2] (CTOP) blocked both endomorphin-1 and-2-stimulated [[sup 35] S]GTPγS binding. In contrast, neither δ- nor κ-opioid receptor antagonist had any effect on the [[sup 35] S]GTPγS binding stimulated by either endomorphin-1 or -2. These findings indicate that both endomorphin-1 and -2 increase [[sup 35] S]GTPγS binding by selectively stimulating μ-opioid receptors with intrinsic activity less than that of DAMGO and suggest that these new endogenous ligands might be partial agonists for μ-opioid receptors in the mouse PAG.Copyright © 2000 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]