Biological Basis of Acupuncture

Introduction to Dr. Peng Li:

Dr. Peng Li has published hundreds of peer-reviewed papers on which he is the first or principle contributing author. He is a pioneer of research in the field of acupuncture. His work exemplifies how research on mechanisms of action, also referred to as efficacy research, must first be undertaken in order to scientifically prove how acupuncture works in the most basic physiological sense.

Dr. Peng Li was born in Shanghai, China and received his Medical Doctor degree from Shanghai First Medical College in 1955. In 1958, he completed his postdoctoral training from the Department of Acupuncture and Traditional Chinese Medicine from Hua San Hospital. In 1984, he completed postdoctoral training from the University of Birmingham, UK, in Physiology. He is currently on staff at UC Irvine School of Medicine where he is Project Scientist at the Samueli Center for Integrative Medicine. The Samueli Center is arguably the leading Complementary and Alternative Medicine research institution on the West coast.

Dr. Peng Li conducts double-blinded randomized controlled studies which is the highest standard for research in Western medicine. He has purposefully strived for the highest standards as an example for future acupuncture researchers to follow in his path. Dr. Li has made it easier for outcomes based, i.e., effectiveness, research to follow upon his ground breaking efficacy research. In other words, he toed the line so that new researchers in acupuncture could take a less constrictive approach to research that matters in clinical practice � outcomes/evidence based. The time has arrived for acupuncture research to prove itself according to the most rigorous western scientific standards of research if the profession is to survive in the world of evidence based medicine.

Dr. Peng Li presented his research and explained his beliefs to our group of doctorate students in 2006. He made it clear that, as the first generation of well-trained acupuncture doctors in the USA, we must continue where he left off. He said he will not be here in 50 years, so it is up to us to continue his work. He wants to pass the torch to future acupuncture researchers and has, therefore, set the standards high with his ground-breaking research on acupuncture efficacy. He is a brilliant and humble man whose legacy is providing scientific evidence of how acupuncture works physiologically that stands up to the strongest scrutiny by Western medicine.

Dr. Peng Li has hundreds of publications. Those that are, in the opinion of this writer, of greatest significance to acupuncture efficacy focus on effects of manual acupuncture versus electroacupuncture (EA), and how the cardiovascular system responds to acupuncture. This paper will review one of his most important publications, "Reversal of Reflex-Induced Myocardial Ischemia by Median Nerve Stimulation: A Feline Model of Electroacupuncture". Dr Li, the primary author, conducted the research in the USA at UC Irvine. The manuscript was accepted for publication in the Circulation Journal of Research, American Heart Association, appearing in volume 97, in March 1998.

Dr. Li designed his research to follow upon previous studies that suggested acupuncture may have therapeutic effects on hypertension, coronary heart disease, certain dysrhythmias, and myocardial infarctions. Recognizing that acupuncture was frequently used to treat these conditions he pointed out there was limited information on the mechanisms behind what were accepted as potential beneficial effects of acupuncture including EA as a treatment modality. He set out to investigate the underlying physiological mechanisms of how acupuncture or, in this case, EA reduced myocardial ischemia under an investigative model acceptable to physicians and the scientific community. In characteristic fashion, Dr. Li took a commonly practiced treatment method and figured a way to demonstrate how it worked.

This study was developed using a feline model anesthetized with Chloralose and instrumented to measure arterial blood pressure, left ventricular pressure, rate of change of ventricular pressure with respect to time (dp/dt), heart rate, left anterior descending (LAD) coronary blood velocity, and regional wall motion. A reflex induced reversible myocardial ischemia was provoked by applying bradykinins (BK) to the gallbladder. Application of (BK) to the gallbladder triggers an increase in myocardial oxygen demand (double product). It also reflexively activates the sympathetic nervous system to increase arterial blood pressure, increase heart rate, produces inflammation, ischemia and/or cholecystitis. To model clinical settings of myocardial ischemia associated with restricted coronary blood flow and coronary occlusion, the left anterior descending artery (LAD) was either partially occluded or a proximal diagonal branch was ligated and completely occluded. Direct stimulation to the median nerve was delivered at a low frequency (5 Hz) which was sufficient to produce a moderate paw twitch for 30 minutes. Median nerve stimulation served as a surrogate for EA which in clinical practice corresponds to Neiguan acupoint or PC6.

Li�s research hypothesis was that low-intensity electrical stimulation of predominant finely myelinated fibers in somatic nerves would reduce ischemia induced by reflex activation of the cardiovascular system. He also hypothesized that the mechanism responsible for the reduced myocardial ischemia could be traced to reduced myocardial oxygen demands and not an increase in blood flow based on a previous finding that acupuncture can lower blood pressure.

The second protocol was designed to test the validity of the findings of the mechanism of action found in his study. This additional protocol was designed to differentiate between the possibility that the mechanism of action was the result of decreased systolic blood pressure causing a mechanical effect and reduced myocardial oxygen demand responsible for reduced myocardial ischemia.

A third protocol was set up to identify the types of afferent fibers activated by median nerve stimulation.

Results of the Experiment:

The animal model of reflex-induced myocardial ischemia by the application of BK to the gallbladder resulted in a pronounced activation of the cardiovascular system indicated by increased arterial blood pressure, increased myocardial oxygen demand (double product), and wall thickening (WTh). The partial occlusion group without MNS had a 47% reduction in coronary blood velocity. The reduced coronary flow was not associated with changes in resting values of increased myocardial oxygen demand (double product), diastolic arterial pressure or regional function. There was no significant difference in the coronary resistance index during application of BK both before as well as during occlusion. There was a higher risk of infarction associated with the complete occlusion of the left ventricle group than the partial occlusion left ventricle group. No animals subjected to partial occlusion showed evidence of infarctions, however, two of the five animals subjected to complete occlusion showed evidence of small infarctions.

The most important finding in this study was the significant improvement obtained from median nerve stimulation to the BK induced reduction in regional function during partial coronary occlusion. MNS produced a positive value with ischemia compared to values before stimulation, in other words, ischemia symptoms were reduced by the EA simulation due to diminished cardiac oxygen demand.

The response of the partial and complete occluded groups to the application of BK to the gallbladder was similar, and both groups evoked a similar improvement in regional function in response to MNS. Therefore, the partial occlusion and complete occlusion groups were combined into a single group and compared with a group that did not receive MNS.

Protocol 2 found that the reduced systolic pressure (reduced afterload) did not significantly change the wall thickening. Therefore, it is likely that significant improvement in regional wall motion during MNS was related to reduced myocardial oxygen demand associated with lowering the blood pressure and not the mechanical effect resulting from reduced afterload.

Pressor or depressor responses evoked from somatic nerve stimulation has been used as an effective treatment method for many years. Low Frequency stimulation (1 to 5 Hz) stimulates A-fibers alone or A and C-fibers and produce a depressor effect, while C-fibers alone produce a pressor effect. In this study both myelinated (A) and unmyelinated (C) fibers were activated by low frequency stimulation to the median nerve. However, the depressor effect was caused by the stimulation of a proportionally larger number of finely myelinated A-fibers. This study produced important new findings in that MNS used as a surrogate for EA significantly improved reflex induced regional cardiac dysfunction induced by increased sympathetic stimulation when there is restricted coronary flow.

Stimulation of the median nerve involves the inhibition of the nucleus arcuatus in the hypothalamus, ventral periaqueduct gray, nucleus raphe obscurus, with a projection to the rostral ventrolateral medulla resulting in decreased cardiac sympathetic drive, vasodilation and reduced blood pressure. Inhibition of the cardiac sympathetic neurons in the ventrolateral medulla is mediated by release of the endorphins serotonin and GABA. This response was activated by the mu and delta-opioid receptors which induced the depressor effects under resting conditions. The kappa-opioid receptors were not activated in this response.

In summary, this study found that MNS used as a surrogate for EA, substantially improved cardiac wall motion during induced diminished myocardial ischemia and a sympathetically mediated increase in cardiac oxygen demand. It also suggested that there was reduced myocardial oxygen demand indicated by improved regional contractile function. The fact that coronary blood flow was unchanged in response to application of BK, although oxygen demands decreased, suggests that maintaining blood flow contributed to the improved supply/demand relationship and reduced myocardial ischemia.

Why this research is important to acupuncture:

There are two main reasons why this research is important to acupuncture. There is a scientific reason that has two components. The first component has been stated several times in this paper. Dr. Li has followed the most rigorous standards of scientific research (i.e., double-blinded, randomized trials) to investigate acupuncture efficacy. The second component is that he has demonstrated the cause and effect relationship between EA and a cardiovascular response. Most important for acupuncture research, is the fact that this study lead to further research which detailed the exact cause and effect relationship of EA on the sympathetic cardiovascular reflex response.

Two related studies followed the 1998 study. The first was in 1999 for which Dr. Li was the principle contributing author in a study titled "Naloxone reverses inhibitory effect of electroacupuncture on sympathetic cardiovascular reflex responses" published in the American Journal of Physiology in, volume 276. This study followed the same protocol as the 1998 study in reversing reflex induced myocardial ischemia by median nerve stimulation, but administered an opioid antagonist, naloxone, to test the hypothesis that the mechanism behind the inhibitory effect is opioid related and occurred in the nucleus paragigantocellularis lateralis (PGL) of the Rostral ventrolateral medulla (rVLM). This study found that microinjections of naloxone into the PGL did block the inhibitory effects of EA on the sympathetic cardiovascular reflex responses. In other words when this opioid antagonist was administered the reflex induced ischemia did not change with the delivery of stimulation to the median nerve.

In March 2001, Dr. Li was the principle contributing author in a third related study titled "Rostral ventrolateral medullary opioid receptor subtypes in the inhibitor effect of electroacupuncture on reflex autonomic response in cats" which was published in the Journal of Autonomic Neuroscience: Basic & Clinical. In this study, Dr. Li used the same BK application to the gallbladder to increase arterial blood pressure and isolated the specific opioid receptor subtypes and neurotransmitters activated with EA causing the depressor response. This study concluded that a significant portion of the EA inhibitory pressor response was activated by endogenous neurotransmitters for mu and delta opioid receptor, beta endorphins and enkephalins in the rostral ventrolateral medulla (rVLM). This is a very important finding in that it specifically identifies the neurotransmitter, opioids, and area of the brain involved in the inhibitory cardiovascular response when performing EA treatment in clinical practice. It also took his 1998 study on the mechanism of action one step further and gave us a complete picture of what is happening in the body, not only answering the question of how it works but pinpointing the centers of the brain and chemicals involved.

The second reason why this research is important is because it has application to acupuncture practice. This is what evidence-based medicine is all about; adapting proven principles of treatment to applied clinical practice. As I stated before, Dr. Li has already authored and published two follow up studies on this topic which has not only reinforced his findings but have taken it further in isolating the specific opioid receptor subtypes and neurotransmitters involved in the sympathetically triggered response of reversing reflex induced myocardial ischemia.

Dr. Li has found a way to simulate angina or restricted coronary blood flow which can be brought on by stress, exercise, inflammatory conditions of the abdominal organs, or surgical manipulation of the biliary tract and reproduced the physiological condition in cats by the application of BK to the gallbladder. He was able to simulate a clinical EA treatment of acupoint Neiguan or PC6 by direct stimulation to the median nerve. Dr. Li explained the underlying mechanism of action behind the efficacy of EA to PC6 in improving angina and other cardiovascular conditions such as ischemia. Dr. Li demonstrated how the physiological mechanisms underlying the sympathetically mediated diminished regional myocardial ischemia worked in a scientifically acceptable model acceptable to the highest western medical standards of research. This study was followed by his 1999 study in which he found that this response was opioid related or sympathetically mediated. These findings have led to a further deeper understanding by identifying the specific opioids and neurotransmitters underlying this sympathetically mediated mechanism in a follow up study published in March 2001. Through his valuable research he was able explain exactly what is going on inside the body when an acupuncturist uses electroacupuncture on PC6 to treat many common cardiovascular problems such as angina.

Concluding remarks:

The world of western medical science is full of skeptics concerning acupuncture as an effective therapeutic medical treatment. Dr. Peng Li�s contributions and legacy will be in how he helped pioneer the path for future acupuncture research. His work clearly demonstrated the mechanism by which the action of acupuncture can be traced in the cardiovascular or neurovascular system. He has also pioneered the study of EA efficacy compared to acupuncture. Dr. Li has demonstrated the efficacy of EA and stated his belief that EA is the most effective form in clinical practice. In this respect, he is a pioneer in evidence-based medicine applied to acupuncture. His work is the foundational research that alleviates the western medical skepticism and helps clear the path that will deliver acupuncture into mainstream medicine.

References:

• Peng Li, Teng-A-Looi, Pitsillides, Koullis F., Rendig, Stephen V., MS, Pan, Jui-Lin, MD, PhD, Longhurst, John C., MD, PhD, Reversal of Reflex-Induced Myocardial Ischemia by Median Nerve Stimulation: A Feline Model of Electroacupucture, Circulation. 1998;97:1186-1194
• Chao, Dong M., Peng, Li, Shen, Lin L., Longhurst, John C., Tjen-A-Looi, Stephanie, Pitsillides, Koullis F., Naloxone reverses inhibitory effect of electroacupuncture on sympathetic cardiovascular reflex, response, American Journal of Physiology, 1999, 276:H2127-H2134
• Peng Li, Teng-A-Looi, Stephanie Tjen, Longhurst, John C., Rostral ventrolateral medullary opioid receptor subtypes in the inhibitory effect of electroacupuncture on reflex autonomic response in cats, Autonomic Neuroscience: Basic & Clinical, March 2001