Ji-Sheng Han

Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies

Abstract Brain functions are regulated by chemical messengers that include neurotransmitters and neuropeptides. Recent studies have shown that acupuncture or electrical stimulation in specific frequencies applied to certain body sites can facilitate the release of specific neuropeptides in the CNS, eliciting profound physiological effects and even activating self-healing mechanisms. Investigation of the conditions controlling this neurobiological reaction could have theoretical and clinical implications

Acupuncture and endorphins.

Acupuncture and electroacupuncture (EA) as complementary and alternative medicine have been accepted worldwide mainly for the treatment of acute and chronic pain. Studies on the mechanisms of action have revealed that endogenous opioid peptides in the central nervous system play an essential role in mediating the analgesic effect of EA. Further studies have shown that different kinds of neuropeptides are released by EA with different frequencies. For example, EA of 2 Hz accelerates the release of enkephalin, beta-endorphin and endomorphin, while that of 100 Hz selectively increases the release of dynorphin. A combination of the two frequencies produces a simultaneous release of all four opioid peptides, resulting in a maximal therapeutic effect. This finding has been verified in clinical studies in patients with various kinds of chronic pain including low back pain and diabetic neuropathic pain.

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.

Effect of low- and high-frequency TENS on Met-enkephalin-Arg-Phe and dynorphin A immunoreactivity in human lumbar CSF

&NA; Transcutaneous nerve stimulation (TENS) treatment was given for 30 min to 37 patients divided into 3 groups of 10 patients and 1 group of 7 patients. Two groups received low‐frequency (2 Hz) and the other 2 groups high‐frequency (100 Hz) stimulation. A diagnostic lumbar cerebrospinal fluid (CSF) sample was obtained immediately before and after stimulation. The CSF samples were subjected to analysis of immunoreactive (ir) opioid peptides, Met‐enkephalin‐Arg‐Phe (MEAP) from preproenkephalin and dynorphin A (Dyn A) from preprodynorphin, respectively. Low frequency TENS applied on the hand and the leg resulted in a marked increase (367%, P < 0.05) of ir‐MEAP but not ir‐Dyn A, whereas high‐frequency (100 Hz) TENS produced a 49% increase in ir‐Dyn A (P < 0.01) but not ir‐MEAP. This is the first report in humans that 2 Hz and 100 Hz peripheral stimulation induces differential release of peptides from preproenkephalin and preprodynorphin, respectively.

Bidirectional modulatory effect of orphanin FQ on morphine-induced analgesia: antagonism in brain and potentiation in spinal cord of the rat

1 The present study was designed to investigate further the effects of the newly discovered orphanin FQ (OFQ)‐the endogenous ligand for the orphan opioid receptor (called, e.g., ORL1 and LC132)‐on pain modulation in the rat. We used the tail‐flick assay as a nociceptive index. 2 When injected into a cerebral ventricle, OFQ (4 fmol‐10 nmol) has no effect on basal tail‐flick latency by itself at any dose, but dose‐dependently antagonizes systemic morphine analgesia (400 fmol‐50 nmol). 3 Injected intrathecally, OFQ (3 and 10 nmol) displayed an analgesic effect without producing motor dysfunction, and potentiated morphine analgesia (1 and 10 nmol). 4 The anti‐opioid effect of OFQ in rat brain and the high level of expression of LC132/ORL1 receptor in the locus coeruleus indicated a possible role of OFQ in the precipitation of opiate withdrawal symptoms. However, no such precipitation was observed by OFQ in morphine‐dependent rats.

Relations between brain network activation and analgesic effect induced by low vs. high frequency electrical acupoint stimulation in different subjects: a functional magnetic resonance imaging study.

Two- or 100-Hz electrical acupoint stimulation (EAS) can induce analgesia via distinct central mechanisms. It has long been known that the extent of EAS analgesia showed tremendous difference among subjects. Functional MRI (fMRI) studies were performed to allocate the possible mechanisms underlying the frequency specificity as well as individual variability of EAS analgesia. In either frequencies, the averaged fMRI activation levels of bilateral secondary somatosensory area and insula, contralateral anterior cingulate cortex and thalamus were positively correlated with the EAS-induced analgesic effect across the subjects. In 2-Hz EAS group, positive correlations were observed in contralateral primary motor area, supplementary motor area, and ipsilateral superior temporal gyrus, while negative correlations were found in bilateral hippocampus. In 100-Hz EAS group, positive correlations were observed in contralateral inferior parietal lobule, ipsilateral anterior cingulate cortex, nucleus accumbens, and pons, while negative correlation was detected in contralateral amygdala. These results suggest that functional activities of certain brain areas might be correlated with the effect of EAS-induced analgesia, in a frequency-dependent dynamic. EAS-induced analgesia with low and high frequencies seems to be mediated by different, though overlapped, brain networks. The differential activations/de-activations in brain networks across subjects may provide a neurobiological explanation for the mechanisms of the induction and the individual variability of analgesic effect induced by EAS, or that of manual acupuncture as well.

Acupuncture analgesia: areas of consensus and controversy.

The clinical practice of acupuncture is growing in popularity world-wide. In parallel, interest in the scientific basis of acupuncture has been increasing, as reflected by a dramatic rise in the number of scientific publications on acupuncture and related techniques (ART) in the recent decade [16]. After 40 years of extensive studies, compelling evidence has been obtained to support acupuncture as a useful tool for treating a spectrum of diseases. In fact, more than 40 disorders have been endorsed by the World Health Organization (WHO) as conditions that can benefit from acupuncture treatment. Pain is particularly sensitive to acupuncture. As such, in a total of 3975 acupuncture research articles published from 1991 to 2009, 1647 (41%) focus on pain and analgesia [16]. Many comprehensive review articles on acupuncture analgesia have been published in recent years [61,62,72]. In this article, with strict limitation of space, we will concentrate on summarizing the areas of consensus and the controversy stemming from research published in the recent decades on the clinical efficacy and the basic mechanisms of acupuncture. For example, should we mainly use manual needling in clinical trials or could we also use electroacupuncture (EA)? Is acupuncture little more than a placebo effect? Why are there so many negative reports in large scale clinical trials? In clinical practice, should we put emphasis mainly on the specificity of meridians and acupoints, or should we also care about the characteristics of the stimulation? We believe that a timely review is important for guiding future efforts to advance this ancient medical art, utilizing the ever growing modern knowledge and technology, as a beneficial, safe and cost effective option in our global health care system.

Analgesia induced by electroacupuncture of different frequencies is mediated by different types of opioid receptors: another cross-tolerance study

The cross-tolerance technique was used to analyze the receptor mechanisms of analgesia induced by electroacupuncture (EA) of 2 Hz, 100 Hz, or 2-15 Hz. (1) Rats were given EA stimulation of 2 Hz, 100 Hz and 2-15 Hz for 30 min with 30 min intervals successively. The percentage increase in tail-flick latency (TFL) was taken to indicate the intensity of EA analgesia. Rats made tolerant to repeated intrathecal injection of the mu-opioid agonist ohmefentanyl (OMF, 15 pmol, Q2h x 5) or the delta-opioid agonist DPDPE (10 nmol, Q2h x 5) showed a cross tolerance to both 2 Hz- and 2-15 Hz-, but not to 100 Hz-EA analgesia; and rats made tolerant to kappa-opioid agonist dynorphin-(1-13) (5 nmol, Q2h x 5) showed a cross-tolerance to 100 Hz- and 2-15 Hz-, but not to 2 Hz-EA analgesia; (2) Rats made tolerant to 2-15 Hz EA showed cross-tolerance to either 2 Hz- or 100 Hz-EA analgesia; (3) Rats made tolerant to either 2 Hz- or 100 Hz-EA were still reactive to 2-15 Hz-EA. The results indicate that 2 Hz-EA analgesia is mediated by mu- and delta-receptors, 100 Hz-EA analgesia by kappa-receptor, and 2-15 Hz-EA analgesia by combined action of mu-, delta- and kappa-receptors in the spinal cord of the rats.

Endomorphin-1 mediates 2 Hz but not 100 Hz electroacupuncture analgesia in the rat.

This work was designed to elucidate the possible involvement of endogenous endomorphin-I (EM1) in analgesia induced by electroacupuncture of low or high frequencies. Taking radiant heat tail flick latency (TFL) as an indication of nociception, rats were subjected to intrathecal (i.t.) injection of 10 microl antiserum against EM1 (EM1-AS) or normal rabbit serum (NRS, as control) and then followed by 2 or 100 Hz electroacupuncture stimulation for 30 min. The analgesia induced by 2 Hz electroacupuncture was attenuated by i.t. injection of EM1-AS at 1:10 and 1:100 but not at 1:1000 dilution. No such suppressive effect was observed for 100 Hz EA analgesia when EM1-AS was injected i.t. at any dilutions. These results indicate that EM1 is involved in 2 Hz but not 100 Hz electroacupuncture analgesia at spinal level.

Cholecystokinin octapeptide (CCK-8): Antagonism to electroacupuncture analgesia and a possible role in electroacupuncture tolerance

&NA; The analgesic effect produced by electroacupuncture (EA) stimulation in the rat was dose‐dependently antagonized by cholecystokinin octapeptide (CCK‐8) administered intracerebroventricularly (i.c.v.) or intrathecally (i.th) at a dose range of 0.25–4 ng. This effect had an immediate onset and lasted for at least 4 h. CCK‐8 per se, however, did not affect baseline tail flick latency. Rats subjected to prolonged EA stimulation developed EA tolerance as well as cross‐tolerance to morphine. These tolerances could be postponed or reversed by i.c.v. or i.th injection of antiserum against CCK‐8. While CCK‐8 antagonized opioid analgesia, it did not affect analgesia induced by 5‐hydroxytryptamine (5‐HT) or norepinephrine (NE). Moreover, CCK‐8 antiserum did not alter the basic level of nociception, nor did it potentiate EA analgesia in naive rats. It is concluded that prolonged EA stimulation results in a profound release of opioids which may trigger the release of CCK‐8 in the central nervous system to counteract the opioid component of EA analgesia. This mechanism may account, at least in part, for the development of EA tolerance.