Mu-Opioids Suppress GABAergic Synaptic Transmission onto Orbitofrontal Cortex Pyramidal Neurons with Subregional Selectivity.

The orbitofrontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Administering opioids to the OFC can alter the hedonic reaction to food rewards and increase their consumption in a subregion-specific manner. However, it is unknown how mu-opioid signaling influences synaptic transmission in the OFC. Thus, we investigated the cellular actions of mu-opioids within distinct subregions of the OFC. Using in vitro patch-clamp electrophysiology in brain slices containing the OFC, we found that the mu-opioid agonist DAMGO produced a concentration-dependent inhibition of GABAergic synaptic transmission onto medial OFC (mOFC), but not lateral OFC (lOFC) neurons. This effect was mediated by presynaptic mu-opioid receptor activation of local parvalbumin (PV+)-expressing interneurons. The DAMGO-induced suppression of inhibition was long lasting and not reversed on washout of DAMGO or by application of the mu-opioid receptor antagonist CTAP, suggesting an inhibitory long-term depression (LTD) induced by an exogenous mu-opioid. We show that LTD at inhibitory synapses is dependent on downstream cAMP/protein kinase A (PKA) signaling, which differs between the mOFC and lOFC. Finally, we demonstrate that endogenous opioid release triggered via moderate physiological stimulation can induce LTD. Together, these results suggest that presynaptic mu-opioid stimulation of local PV+ interneurons induces a long-lasting suppression of GABAergic synaptic transmission, which depends on subregional differences in mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascade. These findings provide mechanistic insight into the opposing functional effects produced by mu-opioids within the OFC.SIGNIFICANCE STATEMENT Considering that both the orbitofrontal cortex (OFC) and the opioid system regulate reward, motivation, and food intake, understanding the role of opioid signaling within the OFC is fundamental for a mechanistic understanding of the sequelae for several psychiatric disorders. This study makes several novel observations. First, mu-opioids induce a long-lasting suppression of inhibitory synaptic transmission onto OFC pyramidal neurons in a regionally selective manner. Second, mu-opioids recruit parvalbumin inputs to suppress inhibitory synaptic transmission in the mOFC. Third, the regional selectivity of mu-opioid action of endogenous opioids is due to the efficacy of mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascades. These experiments are the first to reveal a cellular mechanism of opioid action within the OFC.

Social Laughter Triggers Endogenous Opioid Release in Humans.

The size of human social networks significantly exceeds the network that can be maintained by social grooming or touching in other primates. It has been proposed that endogenous opioid release after social laughter would provide a neurochemical pathway supporting long-term relationships in humans (Dunbar, 2012), yet this hypothesis currently lacks direct neurophysiological support. We used PET and the µ-opioid-receptor (MOR)-specific ligand [11C]carfentanil to quantify laughter-induced endogenous opioid release in 12 healthy males. Before the social laughter scan, the subjects watched laughter-inducing comedy clips with their close friends for 30 min. Before the baseline scan, subjects spent 30 min alone in the testing room. Social laughter increased pleasurable sensations and triggered endogenous opioid release in thalamus, caudate nucleus, and anterior insula. In addition, baseline MOR availability in the cingulate and orbitofrontal cortices was associated with the rate of social laughter. In a behavioral control experiment, pain threshold-a proxy of endogenous opioidergic activation-was elevated significantly more in both male and female volunteers after watching laughter-inducing comedy versus non-laughter-inducing drama in groups. Modulation of the opioidergic activity by social laughter may be an important neurochemical pathway that supports the formation, reinforcement, and maintenance of human social bonds.SIGNIFICANCE STATEMENT Social contacts are vital to humans. The size of human social networks significantly exceeds the network that can be maintained by social grooming in other primates. Here, we used PET to show that endogenous opioid release after social laughter may provide a neurochemical mechanism supporting long-term relationships in humans. Participants were scanned twice: after a 30 min social laughter session and after spending 30 min alone in the testing room (baseline). Endogenous opioid release was stronger after laughter versus the baseline scan. Opioid receptor density in the frontal cortex predicted social laughter rates. Modulation of the opioidergic activity by social laughter may be an important neurochemical mechanism reinforcing and maintaining social bonds between humans.

An exploratory review of the electroacupuncture literature: clinical applications and endorphin mechanisms.

Electroacupuncture (EA) is widely used in clinical practice and research, as well as in experimental investigations into the mechanisms of acupuncture. This study explores publication trends in clinical and experimental studies of EA (1975-2011) for pain and non-pain research; EA use for different clinical conditions (1974-2012); and the relation of EA research, including stimulation frequency, to opioid peptide mechanisms. Appropriate PubMed 'all fields' searches were conducted, identified studies were classified using PubMed filters and manually, and data extracted into tables. A total of 2916 clinical studies were located, of which 19% involved EA. Additionally, 3344 animal studies were located, of which 48% involved EA. The publication rate of EA studies per year has risen over time, but the percentage of studies of pain has fallen from 60% to 25%. The conditions most commonly treated with EA are musculoskeletal, neurological, obstetric and gastrointestinal, along with intraoperative and postoperative analgesia. EA studies, particularly with low frequency stimulation, are more likely to support the role of endogenous opioid mechanisms than manual acupuncture studies, and opioid release is more likely in the central nervous system than the circulation. EA is increasingly used in clinical and especially experimental research, particularly for non-pain conditions. Acupuncture does release endogenous opioids, but this probably depends on 'dosage', with the evidence more consistent and convincing for EA than for manual acupuncture. Different frequencies of EA appear to activate different endogenous opioid mechanisms.

Adapted cold shower as a potential treatment for depression.

Depression is a debilitating mood disorder that is among the top causes of disability worldwide. It can be characterized by a set of somatic, emotional, and behavioral symptoms, one of which is a high risk of suicide. This work presents a hypothesis that depression may be caused by the convergence of two factors: (A) A lifestyle that lacks certain physiological stressors that have been experienced by primates through millions of years of evolution, such as brief changes in body temperature (e.g. cold swim), and this lack of "thermal exercise" may cause inadequate functioning of the brain. (B) Genetic makeup that predisposes an individual to be affected by the above condition more seriously than other people. To test the hypothesis, an approach to treating depression is proposed that consists of adapted cold showers (20 degrees C, 2-3 min, preceded by a 5-min gradual adaptation to make the procedure less shocking) performed once or twice daily. The proposed duration of treatment is several weeks to several months. The following evidence appears to support the hypothesis: Exposure to cold is known to activate the sympathetic nervous system and increase the blood level of beta-endorphin and noradrenaline and to increase synaptic release of noradrenaline in the brain as well. Additionally, due to the high density of cold receptors in the skin, a cold shower is expected to send an overwhelming amount of electrical impulses from peripheral nerve endings to the brain, which could result in an anti-depressive effect. Practical testing by a statistically insignificant number of people, who did not have sufficient symptoms to be diagnosed with depression, showed that the cold hydrotherapy can relieve depressive symptoms rather effectively. The therapy was also found to have a significant analgesic effect and it does not appear to have noticeable side effects or cause dependence. In conclusion, wider and more rigorous studies would be needed to test the validity of the hypothesis.

Integration of hypnosis with acupuncture: possible benefits and case examples.

Acupuncture treatment uses ultrafine needles which are inserted into specified points on the skin (acupoints). Acupuncture can help alleviate pain and inflammation, possibly through the increased release of pituitary beta-endorphins and ACTH. Hypnosis can also help alleviate pain syndromes, and may have centrally mediated immunomodulatory effects. The use of these 2 treatments simultaneously may potentially assist and augment the effects of each another. Two case reports where both treatments are used together are presented: One showing how hypnosis can help in the treatment of painful acupoints, the other how the response to acupuncture may be augmented by hypnosis in the treatment of headache. Controlled trials of this combined treatment are warranted.

Ocular hypotension induced by electroacupuncture.

The purpose of this study was to investigate the effects of electroacupuncture (EA) on aqueous humor dynamics in rabbits. EA stimulation was performed through two acupuncture needles placed in close proximity to the sciatic nerve. The sites of needle entry were anesthetized. After 1 hr of EA stimulation, intraocular pressure (IOP) decreased and was accompanied by reductions of blood pressure and aqueous humor flow rate. The maximum reduction of IOP was 9 mmHg at 3 hr and decreases in norepinephrine and dopamine levels in aqueous humor occurred simultaneously. In addition, EA stimulation induced an 8-fold increase of endorphin levels in aqueous humor. Ocular hypotension induced by EA lasted for more than 9 hrs and was antagonized by naloxone pretreatment. Furthermore, the EA-induced ocular hypotension was reduced markedly in sympathetically denervated eyes compared with the response of intact, normal eyes. Antagonism of EA-induced ocular hypotension by naloxone, suppression of aqueous humor flow and catecholamine levels by EA and elevation of endorphin levels in aqueous humor by EA indicate that opioids/opiate receptors are involved in modulating ocular hydrodynamics in response to EA.

High levels of endorphin and related pathologies of veterinary concern. A review.

The authors report information about endogenous opioid peptides (EOP), receptors, antagonists and their interference with pain, stress, endocrine and immune system. A relationship between EOP and calcium homeostasis, both at extracellular and intracellular level, has been observed. In vitro, beta-endorphin exerts different actions through calcium channel functionality in epithelial cells. In rat aorta and cerebral cortex: beta-endorphin or Naloxone alternatively influence oocyte maturation through the mu-receptor gene expression and intracellular calcium concentration in granulosa and cumulus cells. Calcium channel block is removed by administrating Naloxone and calcium. In vivo, Naloxone and calcium removes EOP induced apoptosis in granulosa cells; is the most safe therapy in cow's milk fever; allow to remove ovarian follicular cysts. A negative influence of opioids on immune response after vaccination was established; EOP-related metabolic problems in post-partum cows. Abnormal intestinal motility, in which a Ca++ influence is well known, can be removed by Naloxone and calcium administration. Calcium-related function and neuromodulation must be re-evaluated since high level of EOP are involved in many pathologies through their influence on calcium activity. The use of calcium salts and Naloxone offers a safe and supplementary therapeutical possibility, active in any condition of altered endogenous opioids.

The effect on opioid peptides in the rat brain, after chronic treatment with the anabolic androgenic steroid, nandrolone decanoate.

In recent years, an increase in abuse of anabolic androgenic steroids (AAS) has been seen among individuals not directly connected to sports. Clinical evidence suggests that abuse of these steroids may result in profound changes in personality, expressed by depressive symptoms, irritability and increased aggression. It is still unknown whether these alterations are related to changes in any particular transmitter system or whether they are persistent or reversible. In this study we focused on AAS effect on the endogenous dynorphin and enkephalin system in the brain. Male rats were given intramuscular injections of the AAS nandrolone decanoate (15 mg/kg), once daily for 2 weeks. The levels of the opioid peptide immunoreactivities (ir) were assessed by radioimmunoassay in two groups immediately after the treatment and in two other groups after additional 3 weeks without any drug treatment (recovery period). The result indicates that chronic AAS treatment increased the activity in the dynorphin B- and Met-enkephalin-Arg(6)Phe(7)-ir in the hypothalamus, striatum and periaqueductal gray (PAG) compared to controls. In addition, the steroid induced an imbalance between the dynorphin and the enkephalin opioid system in the nucleus accumbens, hypothalamus and PAG. This imbalance remained after the recovery period. Since increased peptide activity was found in brain regions regulating emotions, dependence, defensive reactions and aggression, it was suggested that the actual endogenous opioid systems are involved in previously reported AAS-induced changes in these behaviours.

Endogenous opioids implicated in the dynamics of experimental drug addiction: an in vivo autoradiographic analysis.

Endogenous opioids have been implicated in the neurobiological mechanisms underlying drug addiction. Although some information is available concerning effects of abused drugs on the endogenous opioid systems, the interpretation of these effects is hampered because data on the actual changes in the endogenous opioids during the dynamics of the drug addiction are lacking. The present report deals with changes in endogenous opioid activity before and after the daily self-administration session in rats offered cocaine or ethanol, using an in vivo autoradiographic receptor occupancy procedure. In separate saline-controlled experiments drug-naive rats were allowed to intravenously self-administer cocaine (30 microg/infusion) and ethanol (0.05%) for five consecutive daily sessions of 6 h. Immediately following the last session on day 5 or just before a scheduled next daily session on day 6, the rats were injected with [3H]diprenorphine and subsequently prepared for autoradiography. Decreased [3H]diprenorphine binding was observed throughout the subcortical brain after the daily session in cocaine, but hardly in animals self-administering ethanol. These changes are thought to reflect a direct or an indirect effect of the drug on endogenous opioid systems. Before the daily session, the [3H]diprenorphine binding was decreased in restricted areas of the mesocorticolimbic system and of the thalamus in both cocaine and ethanol self-administering animals. These data suggest that release of endogenous opioids at the time the desire for cocaine or ethanol is high, which may be pertinent for drug-induced craving and relapse of drug addicts.

Cholecystokinin-8S increases dynorphin B, aspartate and glutamate release in the fronto-parietal cortex of the rat via different receptor subtypes.

The effect of sulphated cholecystokinin-8 (CCK-8S) on extracellular dynorphin B, aspartate, glutamate and GABA levels in the rat fronto-parietal cortex was investigated with in vivo microdialysis. The peptide was infused through the microdialysis probe trying to mimic local CCK-8S release. Basal levels of dynorphin B were around 20 pM, aspartate 100 nM, glutamate 600 nM and GABA 30 nM. CCK-8S (10 microM) induced a approximately 3-fold increase in extracellular dynorphin B, aspartate and glutamate levels, while GABA levels were only slightly increased. The effect of CCK-8S was restricted to the stimulated neocortex. Systemic pretreatment with the CCKB antagonist, L-365, 260, but not with the CCKA antagonist, L-364, 718, significantly antagonised the effect of CCK-8S on cortical dynorphin B and aspartate release. However, both CCKA and CCKB antagonists inhibited the increase in cortical glutamate levels. Thus, the present results indicate that cortical CCK release exerts a stimulatory modulation on cortical dynorphin B and aspartate release via the CCKB receptor subtype, and on glutamate release via both CCKA and CCKB receptor subtypes. Considering electrophysiological evidence that CCK increases neuronal firing rates in many brain regions, it may be suggested that CCK represents a stimulatory system modulating the function of the neocortex.

[Angiotensin II release and anti-electroacupuncture analgesia in spinal cord].

Changes in the content of angiotensin II (A II) immunoreactivity (ir) in rat spinal perfusate induced by electroacupuncture (EA) stimulation of different frequencies were measured by radioimmunoassay (RIA). The results were analyzed in relation to the role of opioid receptor. (1) 2 Hz EA produced a 20% (P > 0.05) decrease in A II -ir content in the spinal perfusate. 15 Hz EA produced an even more decrease (62%, P < 0.01), whereas 100 Hz produced a significant increase (65%, P < 0.05). (2) The release in spinal A II -ir produced by 15 Hz EA was reversed by the opioid antagonist naloxone to a of 125% highter than that of the control (P < 0.05), suggesting that 15 Hz EA may accelerate the release of endogenous opioids to suppress the release of A II. (3) This was substantiated by the finding that intrathecal (i.t.) injection of the selective mu agonist ohmefentanyl produced a dramatic suppression (20%, P < 0.05) of A II release, but not by delta and kappa agonist. (4) Intrathecal injection of salarasin, the angiotensin receptor antagonist, produced a significant potentiation of the analgesia produced by 100 Hz EA, but not that produced by 2 or 15 Hz EA. It is concluded that 15 Hz EA may induce the release of endogenous opioids acting on mu opioid receptor so as to suppress A II release, and that 100 Hz EA may accelerate the release of A II serving as a brake for 100 Hz EA-induced analgensia. Removal of the brake by angiotensin antagonist may be advised as an adjunct for the potentiation of 100 Hz EA-induced analgesia.

[Lethargic form of acute intestinal intussusception in an infant]. / Forme léthargique d'invagination intestinale aiguë du nourrisson.

BACKGROUND: Intussusception encephalopathy, a misleading form in which neurological symptoms are obvious, is classic but rarely described. CASE REPORT: A 21 month-old infant was admitted because he had suffered from fluctuating consciousness and apathy for a few hours. Vomiting occurred soon afterwards. Search for dehydration, meningitis, encephalitis, poisoning... was negative; the abdomen was tender leading to ultrasonography that showed a sausage-shaped tumor. The ileocolic intussusception was successfully reduced with a gas enema. CONCLUSION: A striking degree of lethargy associated with vomiting may overshadow to a considerable extent the classical intestinal manifestations. A possible endogenous opioid poisoning by massive secretion of endorphins during pain's paroxysm is one of the hypotheses explaining this type of presentation.