Brain Endorphins Research Articles

The origins and function of musical performance.

Music is widely recognised as a human universal, yet there is no agreed explanation for its function, or why and when it evolved. I summarise experimental evidence that the primary function of musicking lies in social bonding, both at the dyadic and community levels, via the effect that performing any form of music has on the brain's endorphin system (the principal neurohormonal basis for social bonding in primates). The many other functions associated with music-making (mate choice, pleasure, coalition signalling, etc) are all better understood as derivative of this, either as secondary selection pressures or as windows of evolutionary opportunity (exaptations). If music's function is primarily as an adjunct of the social bonding mechanism (a feature it shares with laughter, feasting, storytelling and the rituals of religion), then reverse engineering the problem suggests that the capacity for music-making most likely evolved with the appearance of archaic humans. This agrees well with anatomical evidence for the capacity to sing.

Laughter and its role in the evolution of human social bonding.

In anthropoid primates, social grooming is the principal mechanism (mediated by the central nervous system endorphin system) that underpins social bonding. However, the time available for social grooming is limited, and this imposes an upper limit on the size of group that can be bonded in this way. I suggest that, when hominins needed to increase the size of their groups beyond the limit that could be bonded by grooming, they co-opted laughter (a modified version of the play vocalization found widely among the catarrhine primates) as a form of chorusing to fill the gap. I show, first, that human laughter both upregulates the brain's endorphin system and increases the sense of bonding between those who laugh together. I then use a reverse engineering approach to model group sizes and grooming time requirements for fossil hominin species to search for pinch points where a phase shift in bonding mechanisms might have occurred. The results suggest that the most likely time for the origin of human-like laughter is the appearance of the genus Homo ca 2.5 Ma.This article is part of the theme issue ‘Cracking the laugh code: laughter through the lens of biology, psychology and neuroscience’.

Endorphinergic Enhancement Attenuation of Post-traumatic Stress Disorder (PTSD) via Activation of Neuro-immunological Function in the Face of a Viral Pandemic.

Polymorphic gene variants, particularly the genetic determinants of low dopamine function (hypodopaminergia), are known to associate with Substance Use Disorder (SUD) and a predisposition to PTSD. Addiction research and molecular genetic applied technologies supported by the National Institutes of Health (NIH) have revealed the complex functions of brain reward circuitry and its crucial role in addiction and PTSD symptomatology. It is noteworthy that Israeli researchers compared mice with a normal immune system with mice lacking adaptive immunity and found that the incidence of PTSD increased several-fold. It is well established that raising endorphinergic function increases immune response significantly. Along these lines, Blum's work has shown that D-Phenylalanine (DPA), an enkephalinase inhibitor, increases brain endorphins in animal models and reduces stress in humans. Enkephalinase inhibition with DPA treats Post Traumatic Stress Disorder (PTSD) by restoring endorphin function. The Genetic Addiction Risk Severity (GARS) can characterize relevant phenotypes, genetic risk for stress vulnerability vs. resilience. GARS could be used to pre-test military enlistees for adaptive immunity or as part of PTSD management with customized neuronutrient supplementation upon return from deployment. Based on GARS values, with particular emphasis on enhancing immunological function, pro-dopamine regulation may restore dopamine homeostasis. Recognition of the immune system as a "sixth sense" and assisting adaptive immunity with Precision Behavioral Management (PBM), accompanied by other supportive interventions and therapies, may shift the paradigm in treating stress disorders.

Stereotypies in sows during chronic stress.

In pig husbandry sows are fixed in such a way that they undergo a chronic loss of control over their environment. In these conditions sows develop stereotypies that are associated with a specific activation of brain endorphins. Stereotyping itself reduces some neuroendocrine stress symptoms. During stress at least two coping styles can be distinguished in many mammals and birds. These types are found again in the stressed sows which either maintain a high or a low level of stereotypies. The low stereotyping sows show the strongest signs of uneasiness.

THE EFFECT OF ELECTRICAL STIMULATION OF THE EAR POINTS ON THE PLASMA ACTH AND GH LEVEL IN HUMANS

The effect of electrical stimulation of the ear points on the plasma ACTH and GH level was investigated in healthy female subjects. Electrical stimulation by 20 pulses/sec for 20 min. induced an elevation of plasma GH; however, no changes were found in the plasma level of ACTH at 20 min. after the needle removal. The mechanism of action of electroacupuncture in inducing GH secretion may involve the brain endorphin, serotoninergic and catecholaminergic systems. The results obtained from the determination of ACTH suggest the conclusion that electroacupuncture did not induce stress and the increased level of GH may be due to specific effects of electrical stimulation on the neuroendocrine processes.

CSF levels of receptor-active endorphins in schizophrenic patients: Correlations with symptomalogy and monoamine metabolites

Cerebrospinal fluid (CSF) levels of an opioid receptor-active, chromatographically separated endorphin fraction (Fraction I) were measured in 45 schizophrenic patients and 18 healthy volunteers. Significantly increased levels of Fraction I differentiated the patient group from controls, with no difference being found between newly admitted untreated and chronic previously neuroleptic-treated subjects. Fraction I levels did not correlate with age, weight, height, duration of illness, total time hospitalized, or age when symptoms first appeared. No differences were found between patients with or without a family history of schizophrenia. Fraction I levels were negatively correlated with “hallucinations” and “indecision” on the Comprehensive Psychopathological Rating Scale. Increased levels of Fraction I were associated with low levels of the dopamine metabolite homovanillic acid in drug-free schizophrenics. This relationship was not present after neuroleptic treatment or in healthy controls. No relationship was found between Fraction I and the serotonin metabolite 5-hydroxyindoleacetic acid. Neuroleptic treatment did not significantly change Fraction I levels; when only patients above the control range were considered, however, a significant decrease was observed. The data support our previous hypothesis of an increased opioid activity in schizophrenia and further indicate a concominant dysfunction of brain endorphin and dopamine activity in schizophrenic patients.

Effects of exercise training on brain opioid peptides and serum LH in female rats

In order to investigate the effects of long-term exercise training on brain endorphin systems, and the latter's possible effects on the hypothalamic-pituitary-gonadal axis, female Wistar rats were subjected to daily treadmill running. A sedentary control group was also employed. After 8 weeks of training, and just prior to sacrifice, one-half of each group received a final fatiguing bout of exercise. Thus the final four groups consisted of a trained-fatigued (TF), trained-nonfatigued (TN), control-fatigued (CF), and control-nonfatigued (CN) group. Regional brain levels of beta-endorphin (βE), methionine enkephalin and leucine enkephalin (LE) were assayed with independent RIAs from the nucleus accumbens, cortex, caudate-putamen, septum, amygdala, anterior and posterior hypothalamus, substantia nigra and ventral tegmentum. Diestrus serum levels of luteinizing hormone (LH), follicle stimulating hormone and prolactin (PRL) were also determined. Fatiguing resulted in a decrease in serum LH levels as well as an increase in βE content in the nucleus accumbens, and LE content in the ventral tegmentum. Finally, TF animals exhibited less LE in the amygdala than the TN rats. Taken together, these changes in brain endorphins may indicate an acute, fatigue-running modulation of the hypothalamic-pituitary-gonadal axis.

Mechanism of neuroadenolysis of the pituitary for cancer pain control.

Several theories have been advanced to explain how neuroadenolysis of the pituitary (NALP) relieves cancer pain. Interference with hormonal regulation, interruption of pain pathways and a compensatory overproduction of brain endorphins have been proposed. The purpose of the present experimental study is to determine whether neuronal activity of the pituitary gland, as related to the primary somatosensory cortex (PSC), may be involved in the pain perception pathway influenced by NALP, using EEG and tooth pulp evoked potentials (TPEPs). Pituitary activity showed a high voltage slow activity which slowed after alcohol injection into the sella turcica. When naloxone was injected after NALP, a rhythmic high voltage activity appeared in the pituitary gland. After NALP, the TPEP recorded from the PSC disappeared, while NALP induced an increase in the amplitude of the TPEP in the pituitary gland. An injection of naloxone severely decreased this response in the pituitary gland, in contrast to changes in the PSC where the original response reappeared after an injection of naloxone. Our hypothesis is that an increase of TPEPs (hyperactivity) in the pituitary gland is produced after alcohol wounding (wounding effect), leading to a decrease of pain response in the sensory cortex (decrease of TPEPs). This wound effect may be influenced by endorphins, because naloxone, a specific antagonist of opiate receptors, reversed the changes in TPEPs in both places.

In rats, the behavioral profile of CCK-8 related peptides resembles that of antipsychotic agents

The action of some CCK-8 related peptides, desulphated CCK-8 (CCK-DS), the sulphated form of CCK-8 (CCK-8-S) and ceruletide was explored in a number of test procedures with rats, in which antipsychotic agents are active. Following injection into the nucleus accembens, all three peptides antagonized the hypolocomotion induced by low doses of apomorphine (10 ng). Ceruletide appeared to be the most potent in this respect (ED 50: approximately 5 pg). The increased locomotion observed following injection of relatively high doses of apomorphine (10 μg) into the nucleus accumbens was antagonized by local pretreatment with CCK-8-S, but not with CCK-8-DS or ceruletide. None of these CCK-8 related peptides affected the stereotyped sniffing response elicited by treatment with apomorphine or amphetamine (10 μg) given into the nucleus caudatus. Passive avoidance behavior was facilitated following subcuttaneous administration of 10 μg of CCK-8-related peptides 1 h before the retention test. The same peptides given into the nucleus accumbens (0.3 pg) however attenuated passive avoidance behavior. Intraventricular injection with CCK-8-DS and CCK-8-S induced a positive effect in various ‘grip tests’. Given subcutaneously, the CCK-8-related peptides decreased the rate of ambulation and rearing especially in the middle of the open field. These results indicate that CCK-8 related peptides, especially CCK-8-DS and ceruletide, exhibit behavioral effects that are similar to those observed following treatment with γ-type endorphins and that resemble the effects of antipsychotic agents. Very low doses of CCK-8 related peptides exert behavioral effects following injection into the nucleus accumbens, indicating that this brain area is extremely sensitive to the action of these peptides. It is postulated that certain peptides which are either present in neurons (like CCK-8-related peptides) or generated by brain endorphin systems (like γ-type endorphins) control the activity of specific neurons of the mesolimbic dopaminergic pathways. This may be of relevance for the purported antipsychotic action of these peptides.

Clinical strategies for evaluating ect mechanisms — pharmacological, biochemical and psychophysiological approaches

1. 1. Although ECT is a highly effective treatment for severe depression and other psychiatric syndromes, its mode of action is not known. 2. 2. Recent studies have suggested that effects of ECT on central neurotransmitter receptors may underlie its therapeutic action. 3. 3. The effects of chronically administered electroconvulsive shock on receptors for dopamine, serotonin, noradrenaline, acetylcholine and endorphins in rodent brain, are reviewed. 4. 4. Strategies for evaluating the relevance of these animal findings to mechanism of action of ECT in humans are discussed.

Morphine tolerance is associated with elevated levels of an uncharacterized endorphin (peak B) in mouse brain with no change in 3H-dihydromorphine binding

A partially characterized mouse brain endorphin was shown to be elevated (p 0.01 U-Test) in ICR strain mice that had been made tolerant but not dependent upon morphine (5 mg/kg sc., given for 32 days). The animals were tolerant to the antinociceptive effect of morphine as judged by the tail immersion assay (48°C) but showed no detectable dependence or withdrawal syndrome effects following the administration of naloxone (writhing, jumping, diarrhea or hypermotility) on day 33. No significant changes were seen in any other mouse brain endorphins (p 0.05 U-Test). Also there was no apparent change in the number or binding properties of 3H-dihydromorphine ( 3H-DHM) receptors (μ-receptors) in chronic morphine (CM) treated, as compared with chronic saline (CS) treated animals.

Long-lasting cardiovascular depressor response following sciatic stimulation in spontaneously hypertensive rats. Evidence for the involvement of central endorphin and serotonin systems

A naloxone-reversible long-lasting depressor response induced by a prolonged low frequency stimulation of the sciatic nerve in conscious spontaneously hypertensive rats (SHRs) was reported in a previous paper. In the present study pharmacological tools were used to further investigate the neurotransmitters involved in this phenomenon. Naloxone infusion (20–25 mg/kg/h following a bolus dose of 10 mg/kg i.v.) attenuated significantly the depressor response, while dexamethasone pretreatment had no such effect, suggesting an important role of the brain endorphin system, but not of the pituitary β-endorphin, in this depressor response. Since the concomitant increase in pain threshold produced by the sciatic stimulation exhibited a different time course of development and naloxone reversibility, it is suggested that the depressor response and the hypalgesic effect produced by the same stimulation are mediated via different types of opiate receptors in the brain. On the other hand, PCPA abolished the post-stimulatory depressor response whereas 5-HTP and zimelidine had additive effects on the sciatic stimulation-induced depressor response, suggesting the involvement of central serotonin systems in the mechanism of the response. The interaction between the central endorphin and the serotonin systems in the mediation of the post-stimulatory depressor response is discussed.

Opiate modification of amygdaloid-kindled seizures in rats

Male Long-Evans rats were stereotaxically implanted bilaterally with bipolar electrodes in the central amygdala. Rats were then kindled once daily for 1 sec until 3 consecutive Stage V [25] kindled seizures were elicited. On the following day, animals were injected (IP) with either saline, naloxone (10 mg/kg), naltrexone (10 mg/kg) or morphine sulfate (10 mg/kg) and again stimulated parameters the kindling stimulation parameters. Saline injected animals continued to show long bilateral AD's and behaviors (i.e., forelimb clonus, rearing, falling) typical of Stage V kindled animals. In contrast, rats injected with naloxone or naltrexone showed reduced behavioral seizures. Potentiation of post-ictal spiking by morphine in amygdaloid-kindled rats was also observed supporting previous reports [7,21]. In a second experiment, the reduction of kindled seizure severity by naloxone was systematically replicated. It is concluded that opiates can significantly modify amygaloid-kindled seizures, and that brain endorphins may play a role in the development of maintenance of an amygdaloid-kindled seizure focus.

Regional distribution of α- and γ-type endorphins in rat brain

The regional distribution of Met-enkephalin, ß-endorphin and α- and γ-type endorphins in rat brain was investigated. To that end, brains were dissected into anatomically defined areas. Acetic acid tissue extracts were fractionated using an HPLC system suitable for separation of endorphins and peptide concentrations were subsequently measured by specific radioimmunoassay systems. The distribution of Met-enkephalin and β-endorphin through the brain was fairly uneven and in accordance with results obtained by others. The peptides α-endorphin, γ-endorphin, des-Tyr-α-endorphin (DTαE) and des-Tyr-γ-endorphin (DTγE) were detectable in almost all brain areas. Their distribution, however, appeared to be uneven. Hypothalamus and septum showed the highest levels of α- and γ-type endorphins. These regions also contained high amounts of β-endorphin, underscoring a precursor function of this peptide in the formation of α- and γ-type fragments. In general, levels of α-endorphin were higher than those of des-Tyr-α-endorphin, whereas the opposite was found for γ- and des-Tyr-γ-endorphin.

Effect of intraventricular beta-endorphin and morphine on hypothalamic-pituitary-adrenal activity and the release of pituitary beta-endorphin.

The effects of intraventricular (i.v.t.) morphine sulfate (MS) and beta-endorphin (beta-EP) on pituitary-adrenal activity and the release of pituitary beta-EP were studied in rats. Pituitary-adrenal activity was monitored by measuring plasma corticosterone (CS) levels. 45 min after i.v.t. injection, both MS and beta-EP caused dose-related increases in plasma CS, with beta-EP being approximately ten times more potent on a molar basis. MS injected i.v.t. at 0.3, 1.0, 3.0 and 10.0 microgram did not cause a significant reduction in pituitary immunoreactive (i.r.) beta-EP, but did cause an increase in plasma i.r. beta-EP at 3 microgram of MS. beta-EP injected i.v.t. at 1.5 microgram caused a reduction of pituitary i.r. beta-EP. Since i.v.t.-injected beta-EP may have contributed to the measured plasma i.r. beta-EP, a nonimmunoreactive analog (Des-Asn20-beta c-EP) was used to assess the change in plasma i.r. beta-EP. 5 microgram of DES-Asn20-beta c-EP injected i.v.t. caused increases in plasma i.r. beta-EP and CS, as well as a 40% reduction in pituitary i.r. beta-EP. The concomitant intraperitoneal (i.p.) injection of naloxone HCl (10 mg/kg) significantly blocked the increase in plasma CS induced by 5 microgram of beta-EP. When naloxone HCl, 10 mg/kg was injected alone, a significant increase in plasma CS was found. The results indicate that i.v.t. beta-EP is more potent than MS in causing the release of pituitary ACTH and beta-EP. These findings are consistent with a role for brain endorphins in the regulation of CRF release.

Redistribution of endorphin and enkephalin immunoreactivity in the rat brain and pituitary after in vivo treatment with colchicine or cytochalasin B

The effects of intracerebroventricular injection of colchicine or cytochalasin B were compared on radioimmunoassayable endorphin and enkephalin in several rat brain regions and pituitary gland. In addition, colchicine effects on brain immunoreactivity were also assessed by immunocytochemistry. Colchicine treatment increased endorphin levels in the hypothalamus without changing pituitary levels. Cytochalasin B did not change brain endorphin levels but increased pituitary content. These contrasting drug effects probably reflect the neuronal nature of the brain endorphin system and the endocrine nature of the pituitary system. Colchicine treatment also increased enkephalin radioimmunoreactivity in the hypothalamus with a corresponding decrease in the pituitary. This colchicine effect is compatible with reduced axonal transport of enkephalin in a hypothalamo-neurohypophysial pathway: immunocytochemistry after colchicine reveals stained hypothalamic neurons not seen normally. However, colchicine treatment did not alter enkephalin radioimmunoassay values in the other brain regions, even when these regions also revealed groups of cell bodies not seen in normal brain. This inconsistency between unchanged assay values and increased cell reactivity might be explained in part if most enkephalin neurons have short axons; thus, colchicine arrest of axonal transport might cause a local redistribution of enkephalin immunoreactive material that would not be detected by radioimmunoassay due to the limitations of tissue dissection. These results demonstrate the enhanced interpretive value of data obtained from both radioimmunoassay and immunocytochemistry.

Pharmacological modulation of opiate-like peptide systems

Our presently somewhat limited knowledge of the modulation of the content, release and turnover of endorphins in brain and pituitary by acute and chronic drug treatment is reviewed and discussed particularly in relation to the problem of addiction. In vitro studies in striatal slices and isolated anterior and intermediate/posterior lobes of the pituitary point to the existence of specific interactions between endorphins and neurotransmitters. In vivo studies have revealed acute GABA-mediated effects of benzodiazepines upon striatal levels of met-enkephalin activity. Morphine exerts no acute effects upon endorphin levels, but decreases the levels of particular endorphins in specific areas of brain and pituitary after long-term treatment; somewhat similar effects are observed after prolonged intake of ethanol, whereas chronic haloperidol treatment results in an increase in levels of endorphins in brain and pituitary. Incorporation studies employing the intermediate/posterior lobe of the pituitary have revealed that the changes in beta-endorphin levels produced by prolonged treatment with morphine or haloperidol reflect a respective depressed or enhanced synthesis of the beta-endorphin precursor pro-opiocortin, whilst the enzymatic processing of this precursor remains unmodified. Studies in cell-free preparations demonstrated that m-RNA extracted from the intermediate/posterior lobes of chronically morphinized rats possesses a decreased "activity".

Classification of endorphins/enkephalins in brain physiology and pathology (based on EEG and clinical study of synthetically-modified methionine-enkephalin)

1. 1. Endorphins, substances isolated from the brain and the pituitary gland, were found to have opiate-like activity via opiate receptors in the brain. Special types of brain endorphins are the enkephalins, pentapeptides which have leucin or methionine as a terminal amino acid. Methionine-enkephalin was recognised as an amino acid sequence from a larger peptide hormone of the anterior pituitary gland, beta-lipotropin. 2. 2. FK 33-824, a synthetically-modified methionine-enkephalin, was the subject of our study. FK 33-824 induced a short-term improvement in the symptoms of 5 of 7 psychotic patients. 3. 3. An EEG investigation of this compound in 20 normal volunteers (compared with placebo in 8 of them) indicated typical changes in electrical activity in the conventional description and spectral-analytic evaluation, viz. an increase in alpha and beta activity with a simultaneous decrease in slow waves. The changes after FK 33-824 differ from placebo changes and from the well known changes seen after opioid alkaloids.

Distribution of active and inactive forms of endorphins in rat pituitary and brain.

The recent isolation and identification of alpha-N-acetyl forms of the C-Fragment of lipotropin (beta-endorphin, residues 61-91) and the C'-Fragment (residues 61-87) [Smyth, D.G., Massey, D.E., Zakarian, S. & Finnie, M. (1979) Nature (London) 279, 252-254] has led to a study of their distribution in the pituitary and brain of the rat. Regions were mapped by the method of immunofluorescent staining and the reactive peptides were determined by immunoassay after extraction, gel filtration, and ion exchange chromatography. The major immunoreactive peptides in both lobes of the pituitary were found to be C'-Fragment and N-acetyl C'-Fragment, which are weakly active or inactive as opiates; the C-Fragment and its N-acetyl derivative represented minor components. This indicates that in the rat the circulating "endorphins" released from pituitary would have little morphinomimetic activity. The same four immunoreactive peptides were observed in rat brain. In the hippocampus the C'-Fragment was the principal component in the midbrain there was more C-Fragment but C'-Fragment predominated; in the hypothalamus the C-Fragment was the major peptide, almost to the exclusion of the other peptides. The results demonstrate that the processing of lipotropin is under differential control in anatomically distinct regions of the central nervous system. The processing of lipotropin in the hypothalamus is directed specifically to the production of lipotropin C-Fragment.

Naloxone alters pain perception and somatosensory evoked potentials in normal subjects : M.S. Buchsbaum, G.C. Davis and W.E. Bunney, Nature (Lond.), 270 (1977) 620–622

THE discovery of opiate-like peptides (endorphins) in brain, blood and cerebrospinal fluid1–4 raises questions as to the physiological role of these substances. Given the prominent analgesic effects of opiates, the regulation of pain perception is a candidate for endorphin action. Endorphins microinjected into the periacqueductal grey matter of rats induce analgesia which is reversed by naloxone, a pure narcotic antagonist5. If endorphins play an active part in the regulation of pain, then naloxone administered to man should alter pain appreciation. Naloxone has not been shown to have analgesic, respiratory, euphoric, pupillary or electroencephalogram (EEG) effects in man6. Studies in rats7,8 and one early study in man9 have suggested slight hyperalgesic effects with naloxone. El-Sobky et al.10 failed to demonstrate naloxone effects on electric shock pain judgments in five subjects. In the experiments reported here, subjects were divided into pain sensitive and pain insensitive subgroups. The insensitive subjects found shocks significantly more painful after naloxone administration while the sensitive group experienced them as less painful. Evoked potentials showed similar significant group differences. These results suggest that individual differences in pain sensitivity may relate to differences in an endorphin system.