Research on the neurophysiological mechanisms of acupuncture: review of selected studies and methodological issues.

This presentation reviews studies that contribute to an understanding of the neurophysiological mechanisms of acupuncture. A 1973 study, using volunteer medical students, looked into acupuncture's analgesic effect on experimentally induced pain and suggests that humoral factors may mediate acupuncture-induced analgesia. In a study of the possible role of the cerebrospinal fluid transmission of pain suppression effects of acupuncture, cerebrospinal fluid from acupuncture-treated rabbits was infused into recipient rabbits. The analgesic effect was observed in the recipient rabbits, suggesting that acupuncture-induced analgesia may be mediated by substances released in the cerebrospinal fluid. Studies of electroacupuncture in rats revealed that both low-frequency and high-frequency stimulation could induce analgesia, but that there are differential effects of low- and high-frequency acupuncture on the types of endorphins released. In another study, low-frequency electroacupuncture, given as median nerve stimulation in cats, was shown to protect the myocardium by inhibiting sympathetic pressor response and increasing myocardial oxygen demand. The development of neuroimaging tools, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), make noninvasive studies of acupuncture's effects on human brain activity possible. Studies using PET have shown that thalamic asymmetry present among patients suffering from chronic pain was reduced after the patients underwent acupuncture treatment. Other studies, using fMRI, have pointed to relationships between particular acupoints and visual-cortex activation. These powerful new tools open the possibility to new scientific studies of this ancient therapy.

Electroacupuncture: mechanisms and clinical application.

Acupuncture is an ancient Chinese method to treat diseases and relieve pain. We have conducted a series of studies to examine the mechanisms of this ancient method for pain relief. This article reviews some of our major findings. Our studies showed that acupuncture produces analgesic effect and that electroacupuncture (EA) is more effective than manual acupuncture. Furthermore, electrical stimulation via skin patch electrodes is as effective as EA. The induction and recovering profiles of acupuncture analgesia suggest the involvement of humoral factors. This notion was supported by cross-perfusion experiments in which acupuncture-induced analgesic effect was transferred from the donor rabbit to the recipient rabbit when the cerebrospinal fluid (CSF) was transferred. The prevention of EA-induced analgesia by naloxone and by antiserum against endorphins suggests that endorphins are involved. More recent work demonstrated the release of endorphins into CSF following EA. In addition, low frequency (2 Hz) and high frequency (100 Hz) of EA selectively induces the release of enkephalins and dynorphins in both experimental animals and humans. Clinical studies suggesting its effectiveness for the treatment of various types of pain, depression, anxiety, spinally induced muscle spasm, stroke, gastrointestinal disorders, and drug addiction were also discussed.

[Changes in the concentration of endogenous opiates in the blood and cerebrospinal fluid during acute painful stimuli and protective electroacupuncture analgesia]. / Izmeneniia kontsentratsii éndogennykh opiatov v plazme krovi i spinnomozgovoi zhidkosti pri ostrom bolevom razdrazhenii pod zashchitoi élektroigloanalgezii.

The concentrations of endogenous opiates (beta-endorphin, methionine-enkephalin, leucine-enkephalin) in the spinal fluid and arterial blood plasma has been studied in 16 dogs, using the model of acute pain stimulation under electroacupuncture analgesia (EAA). It has been shown that pain stimulation under EAA is accompanied by a significant increase in methionine-enkephalin++ and leucine-enkephalin concentrations (by 244 and 69.4%, respectively) in the spinal fluid. beta-endorphin level tends to increase. There is also a trend towards the reduction in beta-endorphin and methionine-enkephalin concentrations in the arterial blood plasma, which is indicative of effective antinociceptive stimulation of the endogenous opiate system. However, by the end of the first hour a decrease of methionine-enkephalin and leucine-enkephalin levels in the spinal fluid was paralleled by a trend towards beta-endorphin and methionine-enkephalin increase and a significant leucine-enkephalin increase in arterial blood plasma, which can account for the exhaustion of the opiate system.

Investigation on cerebrospinal fluid opioids and neurotransmitters related to spinal cord stimulation.

The purpose of this study was to assess the biochemical mechanisms underlying spinal cord stimulation (SCS). Seventeen patients with chronic pain were investigated by measuring cerebrospinal fluid concentrations of endogenous opioids and biogenic amines before and during dorsal column stimulation. Basal cerebrospinal fluid beta-endorphin levels were below the normal range. No significant change of norepinephrine, epinephrine, dopamine, beta-endorphin, beta-lipotropin, or adrenocorticotropic hormone levels were found after SCS. A 50% increase of cerebrospinal beta-endorphin and beta-lipotropin levels occurred in 6 out of 16 patients, namely those where SCS gave the major pain relief. These data confirm the derangement of the endogenous opioid system in chronic pain conditions and suggest that the beta-endorphin response to SCS could have clinical value in predicting the success of treatment.

On the relationship between clonidine hypotension and brain beta-endorphin in the spontaneously hypertensive rat: studies with alpha adrenergic and opiate blockers.

The relationship between the centrally mediated hypotensive and bradycardic effects of clonidine to central alpha-2 adrenergic receptor activation, brain beta-endorphin (BE) release and opiate receptor activation was studied in chloralose-anesthetized spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats, using a cerebroventricular perfusion system. Prior treatment of SHRs with i.v. naloxone (2 or 4 mg/kg) or i.c.v. yohimbine (10 or 20 micrograms/kg) reduced the hypotension and bradycardia induced by i.c.v. clonidine, but in Wistar-Kyoto rats naloxone had no similar blocking effects. Prazosin (20 micrograms/kg i.c.v.) reduced the clonidine bradycardia but not the hypotension in SHRs. Hypotension in the SHRs due to i.c.v. alpha-methylnorepinephrine (20 micrograms/kg) was reduced by both naloxone and yohimbine whereas alpha-methylnorepinephrine bradycardia was reduced by yohimbine but not by naloxone. Prior hypothalamic lesions in the SHRs reduced clonidine hypotension, but not bradycardia, and interfered with naloxone blockade of the residual clonidine hypotensive effect. Clonidine lowered immunoreactive BE levels in SHR hypothalamus, medulla and pituitary but did not change BE levels in the i.c.v. perfusate. The findings support the idea that in the SHRs, clonidine hypotension results from alpha-2 adrenergic stimulation of brain, causing BE release and central opiate receptor activation, and they suggest that the hypothalamus is involved in these interactions. Also, clonidine hypotension and bradycardia appear to involve different mechanisms in brain.

Cerebrospinal fluid dynorphin1-17 and beta-endorphin in late pregnancy and six months after delivery. No influence of acupuncture treatment.

Cerebrospinal fluid (CSF) levels of dynorphin A and beta-endorphin were measured by radioimmunoassay in 62 primiparae in term pregnancy before onset of labour. In 50 of these women acupuncture (AP) treatment was given in an antenatal preparation procedure. In 15 of the AP-treated women, CSF samples were further obtained six months after delivery. Median values for dynorphin A were 7.5 pmol/l in AP-treated women and 6.4 pmol/l in non-treated controls. The puerperal median value for dynorphin A was 7.6 pmol/l. Median values for beta-endorphin were 7.1 pmol/l in AP-treated women and 5.7 pmol/l in non-treated controls. The median beta-endorphin value after delivery was 7.3 pmol/l. There was no significant difference in CSF dynorphin A or beta-endorphin levels between the AP-treated women and non-treated controls in late pregnancy. Consequently, the present study does not support the theory of a positive influence on either the dynorphin or the beta-endorphin system by manual AP. Within subject comparisons of dynorphin-A and beta-endorphin failed to indicate any significant trend in samples obtained in late pregnancy and 6 months after delivery, and there was no increased activity in either the dynorphin or the beta-endorphin system in late pregnancy, as reflected by CSF levels.

beta-Endorphin-like immunoreactivity in cerebrospinal fluid of patients with Alzheimer's disease and Parkinson's disease.

beta-Endorphin-like immunoreactivity (beta-EP-LI) in cerebrospinal fluid (CSF) was measured in 42 patients with Alzheimer's disease (AD), 36 patients with Parkinson's disease (PD), and 35 controls. Values for patients with Alzheimer's disease (10.9 +/- 2.8 pmol/l) seemed to be lower than those for controls (12.9 +/- 2.5 pmol/l) (P less than 0.05). In addition, the severely demented patients had lower values than the moderately demented (P less than 0.01). In patients with Parkinson's disease no significant difference in beta-EP-LI values was observed compared to the controls. The data suggest, that processing of pro-opiomelanocortin, precursor of beta-endorphin, and the mechanism of cognitive impairment may differ in Alzheimer's disease and Parkinson's disease.

Clinical studies on neurophysiological and biochemical basis of acupuncture analgesia.

From November 1965 to December 1978, about 10,635 cranio-cerebral operations were performed under acupuncture anesthesia in 24 neurosurgical departments in China. The extensive clinical practices have proved that acupuncture surely has analgesic effect. So far most researches upon the mechanism for analgesia by acupuncture were based on animal experiments, but not confirmed or evidenced in human beings. For this reason, a series of clinical studies upon the neurophysiological and biochemical basis for acupuncture analgesia has been made utilizing the facilities of a neurologic clinic provided that the patient's condition is not adversely affected and therapeutic efficiency is enhanced. The results are summarized as follows.

[Effects of electroacupuncture on beta-endorphin contents in rats].

Effects of electroacupuncture (EA) on pain threshold and beta-endorphin (beta-End) contents in plasma, pituitary (Pit), hypothalamus (Hyp) and cerebrospinal fluid (CSF) were studied in nontreated, dexamethasone (Dex) treated and adrenalectomized (Adrex) male SD rats by the use of specific determination of rat beta-End (combination of HPLC and RIA). EA increased pain threshold and plasma beta-End with no effect on beta-End contents in Pit, Hyp and CSF. Dex did not affect control pain threshold, but tended to reduce EA-induced increase in pain threshold (EA-analgesia, EAA) and EA-induced increase in plasma beta-End. Adrex increased plasma beta-End without change in control pain threshold. Adrex tended to reduce EAA, but a tendency of further increase in plasma beta-End was observed after addition of EA. Adrex increased Pit beta-End, but no further change in Pit beta-End was observed after addition of EA. A positive correlation between plasma beta-End and plasma ACTH was observed in nontreated, Dex treated and Adrex rats. No correlation between plasma beta-End and potency of EAA was observed in nontreated, Dex treated and Adrex rats. The hind-paw pressure test without EA increased plasma beta-End to the same degree as that produced by EA, and it produced no analgesia. These results suggest that Pit beta-End may not be mainly involved in the development of EAA.

Long-term high frequency transcutaneous electrical nerve stimulation (hi-TNS) in chronic pain. Clinical response and effects on CSF-endorphins, monoamine metabolites, substance P-like immunoreactivity (SPLI) and pain measures.

Eighteen patients with chronic pain syndromes of organic origin were treated by means of high frequency transcutaneous nerve stimulation (hi-TNS). The CSF levels of receptorassayable Fraction I and II endorphins, substance P-like immunoreactivity (SPLI), and the monoamine metabolites 5-HIAA, HVA and MOPEG were measured before and after one week of daily treatment. Furthermore, the effects on experimental pain measures were determined. The therapeutic effect was evaluated after 30 days and 3 months of treatment. Patients with low initial concentrations of endorphins in CSF, lower than those observed in healthy volunteers, tended to have the best response to hi-TNS. There were significant increases in Fraction I endorphins and SPLI in CSF, most pronounced in the patients who responded. There were no significant changes in 5-HIAA, HVA or MOPEG in CSF. However, in early responders, the serotonin metabolite 5-HIAA tended to decrease as contrasted to an increase in non-responders. The difference between the groups was statistically significant. Confirming our earlier studies, the therapy induced changes in pain measures showed a significant, positive correlation with increasing Fraction I endorphins in CSF. Our results suggest that hi-TNS induces central changes in the endorphinergic, serotonergic and possibly substance-P-ergic systems.

Contrast medium causes the apparent increase in beta-endorphin levels in human cerebrospinal fluid following brain stimulation.

Levels of beta-endorphin immunoreactivity in cerebrospinal fluid were measured in 12 chronic pain patients undergoing the surgical implantation of an electrode into the periventricular gray matter. Cerebrospinal fluid fractions were collected following placement of a cannula into the third ventricle, following injection of metrizamide contrast medium into the ventricles, following implantation of the electrode, and following electrical stimulation. A second set of samples was collected on a non-surgical day before and after stimulation. Levels of beta-endorphin immunoreactivity increased significantly from baseline levels to post-electrode implantation in one group of patients, but no significant change was seen following the onset of stimulation. Immunoreactivity increased significantly following metrizamide injection in a second group and was still elevated, in comparison to baseline, following electrode placement, but no increase was seen following the onset of stimulation. Levels of immunoreactive beta-endorphin did not increase in either group after stimulation on a post-surgical day, despite consistent reports of pain relief. Addition of metrizamide or a related contrast medium, iothalamate meglumine (Conray) to the beta-endorphin radioimmunoassay revealed that both compounds interfered with antigen-antibody binding and also quenched the gamma radiation emitted by iodinated peptide ligands. Due to these combined effects, the contrast media alone produced results similar to those of the beta-endorphin standard. Moreover, similar observations were made when contrast media were incorporated into radioimmunoassays for met-enkephalin, dynorphin and cholecystokinin octapeptide. These findings indicate that increased levels of beta-endorphin in cerebrospinal fluid are not directly associated with patient report of pain relief following periventricular gray stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Thalamic relay nucleus stimulation for relief of intractable pain. Clinical results and beta-endorphin immunoreactivity in the cerebrospinal fluid.

Deep brain stimulation (thalamic relay nucleus, periaqueductal gray and internal capsule) was applied to various cases of intractable pain, and the resulting degree of pain reduction and alteration in beta-endorphin immunoreactivity in the cerebrospinal fluid (CSF) were compared. The following results were obtained. (1) The studies on intractable pain revealed that the levels of beta-endorphin immunoreactivity in the CSF were lower than those in the control group. (2) Thalamic relay nucleus stimulation proved effective not only for deafferentiation pain, but also for somatogenic pain. No relationship was, however, noted between pain reduction and the rate of increase of beta-endorphin immunoreactivity in the CSF. (3) The incidence of stimulation tolerance following prolonged stimulation of the thalamic relay nucleus can be reduced to a minimum by administration of L-DOPA. It is concluded that the increase in beta-endorphin in the CSF is not the direct and major cause of pain reduction during treatment by thalamic relay nucleus stimulation. It may be assumed that neuronal facilitation on the monoaminergic descending pain inhibitory system plays a role in reducing pain.

Elevated immunoreactive beta-endorphin level in ventricular fluid after analgesic electrical stimulation of posteromedial hypothalamus.

Immunoreactive beta-endorphin (beta-EP) in the ventricular fluid of six carcinomatous patients was measured using a specific radioimmunoassay. The subjects were undergoing a surgical procedure for relief of chronic intractable pain. This procedure involved the focal stimulation and coagulation of the posteromedial hypothalamus. Samples of ventricular fluid were collected before and after the stimulation and serially after the coagulation. Prior to stimulation, beta-EP-like immunoreactivity (beta-EP-LI) was below 200 pg/ml. In all of the six patients with pain relief, electrical stimulation led to a marked increase in immunoreactive beta-EP. In three patients beta-EP levels remained high after electrical coagulation for 6-24 hrs. These results suggest that beta-EP-like material, released into the ventricular fluid, may contribute to the initial pain blockade that results from stimulation and coagulation of the posteromedial hypothalamus.