Transgenic increase in the ß-endorphin concentration in cerebrospinal fluid alleviates morphine-primed relapse behavior through the µ opioid receptor in rats.

BACKGROUND: Opioid-primed relapse is a global burden. Although current strategies have improved, optimal therapy is urgently needed. METHODS: A recombinant adenovirus (Ad-NEP) expressing ß-endorphin (ß-EP) was designed and injected intracerebroventricularly (icv) into the right lateral ventricle in rats. Spatial and temporal ß-EP expression in the lateral ventricle wall, subventricular zone and adjacent choroid plexus and the ß-EP concentration in the cerebrospinal fluid (CSF) were observed during a 21-day period. A morphine priming-induced conditioned place preference (CPP) rat model was established. The ß-EP-ir neuron counts, CSF ß-EP concentration, and CPP score, which were used to evaluate morphine-primed reinstatement following extinction, were recorded 7 days after the icv injection. Additionally, the rats were pretreated with the irreversible µ opioid receptor antagonist ß-funaltrexamine (ß-FNA) and the selective κ opioid receptor antagonist nor-binaltorphimine (nor-BNI) to identify the receptor-dependent mechanism. RESULTS: Both peak ß-EP expression in target neurons and the peak CSF ß-EP concentration occurred 7 to 8 days after Ad-NEP icv injection. The sustainable increase in the CSF ß-EP concentration was correlated with a decrease in the CPP score 7 days after the Ad-NEP icv injection. Furthermore, reinstatement was almost reversed by ß-FNA pretreatment 24 hours before the behavioral test, but nor-BNI had little effect. CONCLUSION: The increasing cerebrospinal fluid ß-endorphin concentrations showed that the therapeutic effect on opioid relapse occurred predominantly through a µ opioid receptor-dependent mechanism. The Ad-NEP adenovirus can be considered an alternative therapy for opioid relapse.

[Analgesic effect of buccal acupuncture on acute arthritis in rabbits and underlying mechanisms].

OBJECTIVE: To observe the analgesic effect of acupuncture and to explore its central analgesic mechanism in rheumatoid arthritis rabbits.
 Methods: A total of 60 flap-eared white rabbits were randomly assigned into a normal control group (n=6), a model group (n=6), a body-acupuncture group (n=24), and a buccal acupuncture group (n=24). The later 2 groups were further randomly assigned into 0, 0.5, 1, and 2 h subgroups, with 6 cases in each group. The rheumatoid arthritis model was established by induction of egg-albumin. In the body acupuncture group, bilateral "Xiyan" and "Zusanli" were punctured for 15 s while in the buccal acupuncture group, acupuncture was applied to "Xi" for 15 s, with the needle retaining for 30 min. The pain threshold was detected with PL-200, taking struggle movements of rabbits as a measurement index, response latency from irradiation to struggling movements as the rabbit's pain threshold. The contents of ß-endorplhin (ß-EP) and cholecystokinin-8 (CCK-8) in cerebrospinal fluid were examined by radioimmunoassay.
 Results: Compared with the control group, pain threshold and CCK-8 levels decreased significantly (P<0.01) and the concentration of ß-EP significantly increased (P<0.05) in the model group. The pain threshold in the body-acupuncture group and the buccal acupuncture group at 0 and 1 h (P<0.05 or P<0.01) increased significantly, while the ß-EP and CCK-8 contents in the body-acupuncture group and the buccal acupuncture group were significantly higher than those in the model group (P<0.01 or P<0.05). Both ß-EP and CCK-8 contents in the buccal acupuncture group at 0 h were significantly higher than those in the body-acupuncture group (P<0.05).
 Conclusion: The analgesic effect of buccal acupuncture is superior to that of body-acupuncture. Both buccal acupuncture and body-acupuncture can effectively raise the pain threshold in acute arthritis rabbits, which is closely associated with their effects in the up-regulation of ß-EP and CCK-8 contents in cerebrospinal fluid.

Cerebrospinal fluid and plasma ß-endorphin levels in children with cerebral malaria.

OBJECTIVES: Cerebral malaria (CM) is the most lethal form of malaria, yet its pathogenesis is not fully understood. Cytoadherence, sequestration, alterations in cytokine expression, inflammation, and microvascular obstruction are all hypothesized to be important in the aetio-pathogenesis of coma which characterizes cerebral malaria and the death which sometimes result. Beta (ß)-endorphin has been postulated to be involved in the pathogenetic processes of inflammation and cytokine expression, although the exact role is unknown. The aim of this study was to determine the levels of ß-endorphin in cerebrospinal fluid (CSF) and plasma of children with CM and compare the levels of ß-endorphin in the plasma of children with CM with that of apparently healthy age- and sex-matched controls at Ile-Ife, Nigeria. MATERIALS AND METHODS: Additional to the standard investigation for CM, CSF and venous blood samples were obtained from the subjects for the determination of ß-endorphin levels. RESULTS: Forty children with CM were studied along with forty age- and sex-matched controls. The mean CSF ß-endorphin (± SD) level for the children with CM was 1.8 ± 0.9 pmol/L. The mean plasma ß-endorphin levels at admission (3.1 ± 2.0 pmol/L) and discharge (4.1 ± 3.3 pmol/L) were higher in children with CM than in the control subjects (2.7 ± 0.7 pmol/L). However, only the mean plasma ß-endorphin levels at discharge was significantly higher than that of controls (p = .012). CONCLUSION: Children with CM had higher mean plasma ß-endorphin levels compared to the controls and there was increased production of ß-endorphins in children with CM during the course of the illness.

Evaluation of CSF and plasma biomarkers of brain melanocortin activity in response to caloric restriction in humans.

The melanocortin neuronal system, which consists of hypothalamic proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, is a leptin target that regulates energy balance and metabolism, but studies in humans are limited by a lack of reliable biomarkers to assess brain melanocortin activity. The objective of this study was to measure the POMC prohormone and its processed peptide, ß-endorphin (ß-EP), in cerebrospinal fluid (CSF) and AgRP in CSF and plasma after calorie restriction to validate their utility as biomarkers of brain melanocortin activity. CSF and plasma were obtained from 10 lean and obese subjects after fasting (40 h) and refeeding (24 h), and from 8 obese subjects before and after 6 wk of dieting (800 kcal/day) to assess changes in neuropeptide and hormone levels. After fasting, plasma leptin decreased to 35%, and AgRP increased to 153% of baseline. During refeeding, AgRP declined as leptin increased; CSF ß-EP increased, but POMC did not change. Relative changes in plasma and CSF leptin were blunted in obese subjects. After dieting, plasma and CSF leptin decreased to 46% and 70% of baseline, CSF POMC and ß-EP decreased, and plasma AgRP increased. At baseline, AgRP correlated negatively with insulin and homeostasis model assessment (HOMA-IR), and positively with the Matsuda index. Thus, following chronic calorie restriction, POMC and ß-EP declined in CSF, whereas acutely, only ß-EP changed. Plasma AgRP, however, increased after both acute and chronic calorie restriction. These results support the use of CSF POMC and plasma AgRP as biomarkers of hypothalamic melanocortin activity and provide evidence linking AgRP to insulin sensitivity.

Acupuncture at distant myofascial trigger spots enhances endogenous opioids in rabbits: a possible mechanism for managing myofascial pain.

BACKGROUND AND AIM: Acupuncture applied at myofascial trigger points (MTrPs) of distant anatomical regions, to reduce pain in a patient's area of primary complaint, is one strategy that is available to manage myofascial pain. However, the endogenous opioid-mediated analgesic mechanism of distant acupuncture associated with pain control is still unclear. This aims of this study were to evaluate the changes in enkephalin and ß-endorphin in serum, spinal cord, dorsal root ganglion (DRG) and muscle induced by acupuncture at distant myofascial trigger spots (MTrSs, similar to human MTrPs) in rabbits, to explore its underlying remote analgesic mechanism. METHODS: Acupuncture at MTrSs of a distant muscle (gastrocnemius) was performed either for one session or five daily sessions in rabbits. The levels of enkephalin and ß-endorphin in proximal muscle (biceps femoris), serum, DRGs and spinal cords (L5-S2) were then determined by immunoassay immediately and 5 days after treatment. RESULTS: Immediately after treatment, acupuncture comprising both one dose and five doses significantly enhanced spinal enkephalin expression and serum ß-endorphin levels (p<0.05). However, only five-dose acupuncture significantly enhanced the ß-endorphin levels in the biceps femoris and DRGs (p<0.05), while 1-dose acupuncture did not (p>0.05). Furthermore, 5 days after treatment, significantly increased levels of spinal enkephalin and serum ß-endorphin persisted in animals that received 5-dose acupuncture (p<0.05). CONCLUSIONS: This study demonstrates that interactions within the endogenous opioid system may be involved in the remote effects of acupuncture treatment and could be a potential analgesic mechanism underlying MTrP pain management.

Clinical study of cerebrospinal fluid neuropeptides in patients with primary trigeminal neuralgia.

OBJECTIVES: To investigate the expression levels of calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and ß-endorphin in the cerebrospinal fluid (CSF) and peripheral blood of patients with primary trigeminal neuralgia (TN). PATIENTS AND METHODS: We included 20 patients with primary TN who underwent percutaneous radiofrequency thermocoagulation and collected four types of samples from all of them: sample A: CSF samples; sample B: peripheral blood samples; sample C: peripheral blood samples collected one day before the operation; sample D: peripheral blood samples withdrawn one day after the operation. Another 20 CSF samples of patients with nervous system disease or gynecological disease were collected as a control (sample E). Samples A and B were obtained at the same time. We also evaluated the expression of CGRP, SP, ß-endorphin, and VIP by visual analog scale (VAS) scores one day before and one day after the operation. In addition, heart rate (HR) at baseline and at the time of sample collection, mean arterial pressure (MAP), and all side effects of the procedure were recorded. RESULTS: Significance were found concerning about CGRP, SP, ß-endorphin, and VIP in TN patients and the controls (P<0.001). The expression of CGRP, SP, and VIP in sample A was higher than that in sample E. However, the ß-endorphin level in sample A was lower than that in sample E. There was a positive correlation between sample A and B regarding the expression of CGRP, SP, ß-endorphin, and VIP (P<0. 01). There was no relationship between the time of disease onset and the expression of CGRP, SP, ß-endorphin, and VIP in sample A and sample B (P>0.05). No difference was detected between the neuropeptides levels in samples B and C (P>0.05). Notably, VAS in sample D was significantly lower than that in sample C (P<0.01). Finally, there was no difference between the intraoperative HR and MAP values in the studied samples. CONCLUSION: In primary TN patients, the blood levels of CGRP, SP, ß-endorphin, and VIP were associated with those in CSF samples. There was a significant difference between the levels of the four neuropeptides in CSF and control samples. Our results also indicated that the levels of neuropeptides in blood samples can be tested for those in CSF. The disease onset and duration exerted insignificant effects on the production and release of CGRP, SP, ß-endorphin, and VIP.

Endocannabinoids, through opioids and prostaglandins, contribute to fever induced by key pyrogenic mediators.

This study aims to explore the contribution of endocannabinoids on the cascade of mediators involved in LPS-induced fever and to verify the participation of prostaglandins and endogenous opioids in fever induced by anandamide (AEA). Body temperature (Tc) of male Wistar rats was recorded over 6h, using a thermistor probe. Cerebrospinal fluid concentration of PGE2 and ß-endorphin were measured by ELISA after the administration of AEA. Intracerebroventricular administration of the CB1 receptor antagonist AM251 (5µg, i.c.v.), reduced the fever induced by IL-1ß (3ng, i.c.v.), TNF-α (250ng, i.c.v.), IL-6 (300ng, i.c.v.), corticotrophin release factor (CRH; 2.5µg, i.c.v.) and endothelin (ET)-1 (1pmol, i.c.v.), but not the fever induced by PGE2 (250ng, i.c.v.) or PGF2α (250ng, i.c.v.). Systemic administration of indomethacin (2mgkg(-1), i.p.) or celecoxib (5mgkg(-1), p.o.) reduced the fever induced by AEA (1µg, i.c.v.), while naloxone (1mgkg(-1), s.c.) abolished it. The increases of PGE2 and ß-endorphin concentration in the CSF induced by AEA were abolished by the pretreatment of rats with AM251. These results suggest that endocannabinoids are intrinsically involved in the pyretic activity of cytokines (IL-1ß, TNF-α, IL-6), CRH and ET-1 but not the PGE2 or PGF2α induced fevers. However, anandamide via CB1 receptor activation induces fever that is dependent on the synthesis of prostaglandin and opioids.

Do low levels of beta-endorphin in the cerebrospinal fluid indicate defective top-down inhibition in patients with chronic neuropathic pain? A cross-sectional, comparative study.

OBJECTIVE: Pain medicine still lacks mechanism-specific biomarkers to guide diagnosis and treatment, and defective top-down modulation is an important factor in the pathophysiology of chronic pain conditions. Using modern analytical tools and advanced multivariate statistical analysis, the aim of this study was to revisit two classical potential biomarkers of pro- and anti-nociception in humans (substance P and beta-endorphin), focusing particularly on the cerebrospinal fluid (CSF). DESIGN: Cross-sectional, comparative, observational study. SUBJECTS: Patients with chronic, post-traumatic and/or post-surgical, neuropathic pain refractory to conventional treatment (N = 15) and healthy controls (N = 19) were included. METHODS: Samples were taken from CSF and blood, and levels of substance P and beta-endorphin were investigated using a Luminex technology kit. RESULTS: We found low levels of beta-endorphin in the CSF of neuropathic pain patients (66 ± 11 pcg/mL) compared with healthy controls (115 ± 14 pcg/mL) (P = 0.017). Substance P levels in the CSF did not differ (20 ± 2 pcg/mL, 26 ± 2, P = 0.08). However, our multivariate data analysis showed that belonging to the patient group was associated with low levels of both substances in the CSF. A higher correlation between the levels of beta-endorphin and substance P in CSF was found in healthy controls than in patients (rs = 0.725, P < 0.001 vs. rs = 0.574, P = 0.032). CONCLUSIONS: Patients with chronic neuropathic pain due to trauma or surgery had low levels of beta-endorphin in the CSF. We speculate that this could indicate a defective top-down modulation of pain in chronic neuropathic pain. Our results also illustrate the importance of taking a system-wide, multivariate approach when searching for biomarkers.

A systematic literature review of cerebrospinal fluid biomarkers in delirium.

BACKGROUND: Cerebrospinal fluid (CSF) analysis has great potential to advance understanding of delirium pathophysiology. METHODS: A systematic literature review of CSF studies of DSM or ICD delirium was performed. RESULTS: In 8 studies of 235 patients, delirium was associated with: elevated serotonin metabolites, interleukin-8, cortisol, lactate and protein, and reduced somatostatin, ß-endorphin and neuron-specific enolase. Elevated acetylcholinesterase predicted poor outcome after delirium and higher dopamine metabolites were associated with psychotic features. CONCLUSIONS: No clear conclusions emerged, but the current literature suggests multiple areas for further investigation with more detailed studies.

Non-suicidal self-injurious behavior, endogenous opioids and monoamine neurotransmitters.

BACKGROUND: Self-inflicted injury, including cutting or burning, is the most frequent reason for psychiatric visits to medical emergency departments. This behavior, particularly when there is no apparent suicidal intent, is poorly understood from both biological and clinical perspectives. OBJECTIVE: To examine the role of endogenous opioids and monoamine neurotransmitters in non-suicidal self-injury (NSSI). METHODS: We compared cerebrospinal fluid (CSF) levels of endogenous opioids, 5 hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA) in individuals with a history of repetitive non-suicidal self-injury with a diagnostically-matched group of individuals who had never engaged in non-suicidal self-injury. History of suicidal behavior, demographic background and psychopathology was assessed. All patients were diagnosed with a Cluster B personality disorder (i.e. borderline, antisocial, narcissistic or histrionic) (N=29) and had a history of at least one suicide attempt. Fourteen participants had a history of repeated non-suicidal self-injurious behavior (NSSI) in adulthood and 15 did not (no NSSI). RESULTS: The NSSI group had significantly lower levels of CSF beta-endorphin and met-enkephalin when compared with the non-NSSI group. CSF dynorphin, HVA and 5-HIAA levels did not differ. Severity of depression, hopelessness and overall psychopathology was greater in the NSSI group. CONCLUSION: beta-endorphin and met-enkephalin, opioids acting upon receptors involved in mediating stress-induced and physical pain analgesia respectively, are implicated in NSSI. Serotonergic and dopaminergic dysfunctions do not appear to be related to NSSI. Based on our findings, we propose a model of non-suicidal self-injury. Our results suggest that drugs acting on the opioid system warrant exploration as pharmacological treatments for NSSI.

Exposure to nitrous oxide stimulates a nitric oxide-dependent neuronal release of beta-endorphin in ventricular-cisternally-perfused rats.

We have previously shown that the antinociceptive effect of nitrous oxide (N(2)O) in the rat hot plate test is sensitive to antagonism by antisera against the endogenous opioid peptide beta-endorphin. Moreover, N(2)O-induced antinociception is reduced by inhibition of nitric oxide (NO) production in the brain. To test the hypothesis that N(2)O might stimulate an NO-dependent neuronal release of beta-endorphin, we conducted a ventricular-cisternal perfusion with artificial cerebrospinal fluid (aCSF) in urethane-anesthetized Sprague-Dawley rats. Ten-minute fractions of aCSF perfusate were collected from separate groups of room air-exposed rats, N(2)O-exposed rats, and L-NAME-pretreated, N(2)O-exposed rats; they were then analyzed for their content of NO metabolites and beta-endorphin. Compared to room air control, exposure to 70% N(2)O increased perfusate levels of the NO metabolites nitrite and nitrate as well as beta-endorphin. Pretreatment of rats with L-N(G)-nitro arginine methyl ester, an inhibitor of NO synthase, prevented the N(2)O-induced increases in nitrite, nitrate and beta-endorphin. These findings demonstrate in an in vivo rat model that N(2)O may stimulate an NO-dependent neuronal release of beta-endorphin.

Preference for dietary fat induced by release of beta-endorphin in rats.

AIMS: To determine whether beta-endorphin contributes to the ingestion of and preference for dietary oil, we examined the relationship between the dynamics of beta-endorphin, before and after the ingestion of corn oil, and the intake volume of corn oil. MAIN METHODS: Rats were offered 5% corn oil for 20 min for 5 consecutive days so they could acquire a preference for corn oil. On day 6, seven groups of rats were presented with the oil for defined time periods, and we measured the beta-endorphin levels in the serum and cerebrospinal fluid (CSF) before and after the presentation of corn oil as well as the consumed volume of corn oil at defined time points. KEY FINDINGS: Beta-endorphin levels in serum and CSF were significantly increased 15 min after the ingestion of corn oil, followed by a rapid decrease and maintenance at the basal level throughout the rest of the experimental period. The intake of corn oil was the lowest in the time period of 15-30 min, when the beta-endorphin level reached a peak value. The intake volume of corn oil might be inversely correlated with beta-endorphin levels in serum and CSF. The pretreatment of naloxone, an antagonist of the opioid receptor, decreased the initial licking rate for corn oil and increased the latency for corn oil in the licking test. SIGNIFICANCE: The beta-endorphin was rapidly released after oil ingestion, which contributed to the hedonic preference and ingestive behavior for fat.

Extracellular biotransformation of beta-endorphin in rat striatum and cerebrospinal fluid.

Numerous studies have investigated the behavioural effects of beta-endorphin, both endogenous and exogenously applied. However, the potential for biotransformation of beta-endorphin in the extracellular space of the brain has not been previously directly addressed in vivo. Utilising microinfusion/microdialysis and matrix-assisted laser desorption/ionisation mass spectrometry, we investigated beta-endorphin biotransformation in the striatum of rats. We infused 1.0 nmol beta-endorphin into the striatum of adult male Fischer rats and observed rapid cleavage resulting in beta-endorphin 1-18, as well as several fragments resulting from further N-terminal degradation. In vitro studies with incubation of full-length beta-endorphin, with and without protease inhibitors, in the incubation fluid of isolated striatal slices indicate that beta-endorphin is initially cleaved predominantly at the Phe(18)-Lys(19), position, as well as at the Leu(17)-Phe(18) position. Investigations of cerebrospinal fluid revealed similar enzymatic cleavage of beta-endorphin. The observed pattern of cleavage sites (Phe(18)-Lys(19) and Leu(17)-Phe(18)) is consistent with published in vitro studies of purified insulin-degrading enzyme cleavage of beta-endorphin. The binding affinities of full-length beta-endorphin, as well as previously identified beta-endorphin fragments alpha-endorphin (beta-endorphin 1-16) and gamma-endorphin (beta-endorphin 1-17), and the fragment identified in the present study, beta-endorphin 1-18, at heterologously expressed mu, delta and kappa-opioid receptors, respectively, were determined; the affinity of the truncation fragments is reduced at each of the receptors compared to the affinity of full length beta-endorphin.

Intrathecal coelectrotransfer of a tetracycline-inducible, three-plasmid-based system to achieve tightly regulated antinociceptive gene therapy for mononeuropathic rats.

For optimal use of antinociceptive gene therapy, it may be important to have extrinsic control of the expression of the transfected gene. To achieve this goal, we used a tetracycline-inducible system (Tet-On) composed of three plasmids coding for beta-endorphin, the tetracycline transcriptional activator rtTA, and the silencer tTS. The regulation of beta-endorphin expression was first assessed in cultures of dorsal root ganglion neurons. The three plasmids were then electrotransfected into the spinal cord of mononeuropathic rats and the analgesic potential of this therapy in vivo was evaluated by thermal-withdrawal latency and the mechanical-withdrawal threshold. Intraperitoneal injections of doxycycline were made to evaluate the possibility of exogenous upregulation of transfected beta-endorphin gene expression in vivo. The levels of beta-endorphin were analyzed by intrathecal microdialysis and radioimmunoassay. We found that, after doxycycline administration, the expression of beta-endorphin was rapid, stable, and tightly regulated (low background and high induction level) both in vitro and in vivo. The beta-endorphin protein was secreted into cerebrospinal fluid at a peak level of 53 pmol/L in dialysate, which was sufficient to inhibit neuropathic pain. In conclusion, tightly controlled expression of beta-endorphin can be obtained following intrathecal electrotransfer of a tetracycline-inducible, three-plasmid-based system, and doxycycline-dependent beta-endorphin protein expression in this system alleviates sciatic nerve constriction-induced limb pain.

Detection of beta-endorphin in the cerebrospinal fluid after intrastriatal microinjection into the rat brain.

We have investigated to what extent microinjected beta-endorphin could migrate from the rat brain parenchyma into the CSF compartment. Exogenous rat beta-endorphin (0.1 nmol) was microinjected into the left striatum 1 mm from the lateral ventricle in anesthetized male rats. CSF samples were collected at different time points up to 2 h post-injection from a catheter affixed to the atlanto-occipital membrane of the cisterna magna. Radioimmunoassay and mass spectrometry were performed on the CSF samples, and brain sections were immunostained for beta-endorphin and mu-opioid receptors. The beta-endorphin injected rats showed a marked increase in beta-endorphin immunoreactive (IR) material in the CSF, with a peak at 30-45 min post-injection, and this beta-endorphin-IR material existed mainly as the intact beta-endorphin peptide. The immunohistochemistry results revealed the appearance of distinct beta-endorphin-IR cell bodies in the globus pallidus and the bed nucleus of stria terminalis supracapsular part, regions distant from the injection site, at 2 h post-injection of exogenous beta-endorphin. The beta-endorphin-IR in several of the globus pallidus cell bodies colocalized with the mu-opioid receptor-IR at the cell surface. These findings show that upon delivery of synthetic beta-endorphin, there is a significant intracerebral spread of the injected peptide, reaching regions far from the site of injection via diffusion in the extracellular space and flow in the cerebrospinal fluid. This may be of relevance when interpreting studies based on intracerebral injections of peptides, and advances our knowledge regarding the migration of compounds within the brain.

Brain mechanisms of sweetness and palatability of sugars.

Sugars are sweet and palatable. Sweetness is detected by the neural system, whereas palatability may be detected within the neural and chemical systems in the brain. Sweetness is discriminated from other tastes by different receptor sites on taste bud cells, a different subset of fibers in the taste nerves, and different projection zones in the brain. The benzodiazepine and opioid systems are related to palatability, and the dopaminergic system mediates the motivation to consume palatable food.

Release of beta-endorphin immunoreactive material under perioperative conditions into blood or cerebrospinal fluid: significance for postoperative pain?

The function of beta-endorphin immunoreactive material (IRM) released under perioperative conditions remains to be clarified. In 17 patients undergoing orthopedic surgery, we determined beta-endorphin IRM in venous blood plasma and in cerebrospinal fluid (CSF) before surgery (t(A)); after termination of surgery and general anesthesia, but still under spinal anesthesia (t(B)); on occurrence of postoperative pain (t(C)); and 1 day after the operation (t(D)). Pain severity was rated by the patients by using a visual analog scale. Patients felt postoperative pain (t(C)), but they felt no pain at times t(A), t(B), and t(D). beta-Endorphin IRM plasma levels before surgery (t(A)) or with postoperative pain (t(C)) proved to be significantly higher than levels determined just after surgery, but still under spinal anesthesia (t(B)), or those determined 1 day after the operation (t(D)); beta-endorphin IRM plasma levels at times t(A) and t(C) correlated positively with postoperative pain severity (t(C)). beta-Endorphin IRM CSF levels after surgery, but still under spinal anesthesia (t(B)), were significantly higher than levels determined at times t(A), t(C), or t(D). No correlation was found between beta-endorphin IRM CSF levels and pain severity. In conclusion, postoperative pain severity appears to be related to beta-endorphin IRM levels in plasma before surgery as well as with postoperative pain; the analgesic significance of this material remains to be elucidated.

Cutaneous analgesia, hemodynamic and respiratory effects, and beta-endorphin concentration in spinal fluid and plasma of horses after acupuncture and electroacupuncture.

OBJECTIVE: To determine cutaneous analgesia, hemodynamic and respiratory effects, and beta-endorphin concentration in spinal fluid and plasma of horses after acupuncture and electroacupuncture (EA). ANIMALS: 8 healthy 10- to 20-year-old mares that weighed between 470 and 600 kg. PROCEDURE: Each horse received 2 hours of acupuncture and 2 hours of PAES at acupoints Bladder 18, 23, 25, and 28 on both sides of the vertebral column as well as sham needle placement (control treatment). Each treatment was administered in a random order. At least 7 days elapsed between treatments. Nociceptive cutaneous pain threshold was measured by use of skin twitch reflex latency (STRL) and avoidance to radiant heat (< or = 50 degrees C) in the lumbar area. Skin temperature, cardiovascular and respiratory variables, and beta-endorphin concentration in spinal fluid (CSF-EN) and plasma (plasma-EN) were measured. RESULTS: Acupuncture and PAES significantly increased STRL and skin temperature. The CSF-EN was significantly increased from baseline values 30 to 120 minutes after onset of PAES, but it did not change after acupuncture and control treatments. Heart and respiratory rates, rectal temperature, arterial blood pressure, Hct, total solids and bicarbonate concentrations, base excess, plasma-EN, and results of blood gas analyses were not significantly different from baseline values after acupuncture, PAES, and control treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of PAES was more effective than acupuncture for activating the spinal cord to release beta-endorphins into the CSF of horses. Acupuncture and PAES provided cutaneous analgesia in horses without adverse cardiovascular and respiratory effects.

Scientific bases of acupuncture analgesia.

The present paper was to review the physiological bases of acupuncture analgesia (AA) on normal subjects, patients, and animals. Effect of acupuncture on pain perception in normal subjects was studied and compared with sham acupuncture. It was shown that the analgesic effect of acupuncture has its physiological basis. Using neurophysiological, neuropharmacological, neurobiochemical and neuromorphological methods, the neurohumoral mechanism of AA was studied from the peripheral neural pathway of acupuncture sensation (De-Qi sensation in Chinese traditional medicine) to the central neuromodulatory effect of AA. It was indicated that needling of acupuncture point could activate the afferent fibers of peripheral nerves to elicit De-Qi sensation, then ascended mainly through the ventro-lateral funiculi, which conducted pain and temperature sensation upward to the brain, activated the antinociceptive system including certain brain nuclei. modulators (opioid peptides), neurotransmitters, through the descending inhibitory pathway resulting in analgesia. Especially the clinical and laboratory results indicated that the endogenous opiate peptides (EOP) participated in AA from the presynaptic level to the receptor sites, which provided a scientific basis for understanding the mechanism of AA. Substantial evidences have been accumulated that acupuncture has prominent analgesic effect; but it fails to give sufficient analgesia during operation. Some effective measures to improve the therapeutic effect of acupuncture, such as the combination of acupuncture with drugs, the selection of suitable EA parameters and optimal time spacing should be adopted.