Educational Forum with Clinical Studies Current Science and Research

February 16, 2010

Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 8:53 am

Acupuncture: neuropeptide release
produced by electrical stimulation of
different frequencies

Ji-Sheng Han

Neuroscience Research Institute, Peking University, 38 Xue Yuan Road, Beijing 100083, China

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
Neuropeptides play important roles in various aspects of
brain function (e.g. opioid peptides in pain control [1] and
neuropeptide Y (NPY) in appetite modulation [2], among
others). This review discusses evidence that neuropeptides
could be mobilized by peripheral electric stimulation to
benefit human health.
It has been shown that physiological and pathological
conditions can induce release of neuropeptides. Two wellknown
examples are a severe painful stimulus inducing
the release of opioid peptides to ease pain, and sucking of
the nipples promoting the secretion of milk. Oxytocinergic
neurons fire at a very low rate, of ,1 Hz (0.1–2.6 Hz) in
basal conditions, but prolonged sucking by ten or more
pups can bring the firing rate up to 16–50 Hz, followed by
strong milk ejection within 10–12 seconds [3]. This finding
suggests that neuropeptide release could be modulated by
external stimulation.
Clinically, intracranial [4] or intra-spinal [5] electrical
stimulation has been used through neurosurgical procedures
to provide relief for patients suffering from chronic
pain, with a success rate of 50–80% after one year of
treatment. This pain-relief effect could involve the release
of neuropeptides [6], raising the attractive possibility that
non-invasive methods might be used to modulate neuropeptide
release for therapeutic intervention. The question
is, would such an approach be effective and practical?
Frequency-dependent neuropeptide release in vitro
In isolated rat neurohypophyses, field electrical stimulation
induces the release of arginine vasopressin (AVP)
and oxytocin (OT) into the incubation medium. Stimulation
at a frequency such as 15–30 Hz was much more
effective than a lower frequency such as 2–3 Hz in
triggering peptide release [7], and burst stimulation was
more effective than constant-frequency stimulation [8].
Furthermore, in superfused rat spinal cord slices, the
release of the neuropeptide substance P (SP) per pulse of
electrical stimulation was increased by frequencies in the
range of 20–50 Hz, whereas release of the small-molecule
neurotransmitter 5-hydroxytryptamine (5-HT) per pulse
remained constant [9]. Hokfelt proposed that peptide
release requires bursting or high-frequency activities,
whereas individual action potentials firing at a low
frequency will not induce the release of peptides [10,11].
The facilitation of peptide release by high-frequency
stimulation was considered to be due to the lengthening
of the action potential duration, together with the increase
in frequency, leading to an increase in Ca2þ entry and in
the amount of secretion per unit of action potential [12].
This concept has been supported by more recent reports
[13]. However, frequency requirement can vary for
different neuropeptides. In a similar experimental setting,
thyrotropin-releasing hormone (TRH) could be released by
electrical stimulation at a frequency as low as 0.5 and 3 Hz
Frequency-dependent release of CNS opioid peptides by
peripheral electrical stimulation
Peripheral electrical stimulation can be provided via
electrodes placed on the skin (transcutaneous electrical
nerve stimulation, TENS) or via a probe inserted through
skin into the tissue (percutaneous electrical nerve stimulation,
PENS). If the point of stimulation is selected
according to traditional acupuncture therapy, the process
is usually called electroacupuncture (EA). In fact, the
difference between PENS and EA is more hypothetical
than practical. One study compared the analgesic potency
and the underlying neurobiological mechanisms of EA and
TENS, with the acupuncture needles or the skin electrodes
placed at the same ‘acupoints’, and concluded that they
operate through very similar, if not identical, mechanisms
[15]. Thus, the mechanisms of the aforementioned
methods of peripheral stimulation are discussed under
the same heading.
To facilitate the release of opioid peptides in the CNS,
one can use manual acupuncture [16] or EA [17]
stimulation. The parameters of the latter can be precisely
Corresponding author: Ji-Sheng Han ( characterized. It was interesting to note that analgesia
Opinion TRENDS in Neurosciences Vol.26 No.1 January 2003 17 0166-2236/02/$ – see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S0166-2236(02)00006-1
induced by low-frequency (4 Hz) stimulation, but not that
induced by high-frequency (200 Hz) stimulation, can be
reversed by low doses of the opioid antagonist naloxone
[17], suggesting that low-frequency stimulation can
increase the release of opioid peptides in the CNS. By
changing the dose of naloxone or using various opioid
receptor subtype-specific antagonists, we were able to
show that analgesia induced by either low- or highfrequency
stimulation are both mediated by opioid peptides
[18,19]. The difference was that the former was
mediated by m and/or d opioid receptors, whereas the latter
was mediated by k opioid receptors [20]. These results
suggest that different kinds of opioid peptides are released
under these different conditions.
Direct evidence comes from our study using radioimmunoassay
of spinal perfusates from the rat [21],
showing that 2 Hz peripheral stimulation produces a
significant increase in the content of enkephalin-like
immunoreactivity (IR) but not in that of dynorphin IR,
whereas 100 Hz increases dynorphin IR but not enkephalin
IR. In a follow-up double-blind study, in collaboration
with Lars Terenius of the Karolinska Institute (Stockholm,
Sweden), the results obtained in rats were fully confirmed
in humans [22]. These studies suggest that (1) the
principle proposed by Hokfelt in 1991 [11] might have to
be revised, and (2) to support our hypothesis, more
evidence, obtained using different approaches, is needed.
To test whether analgesia induced by stimulation at 2
and 100 Hz are mediated differentially in the spinal cord
by enkephalin and dynorphin, respectively, we performed
an antibody microinjection study. Our idea was that
binding of an opioid peptide molecule to its antibody to
form a large protein complex would hinder its approach to
the receptor, resulting in a loss of its biological function.
Indeed, intrathecal injection of enkephalin antiserum
resulted in a dramatic decrease in the efficacy of 2 Hz
EA analgesia. This effect of antiserum diminished as the
EA frequency was increased to 128 Hz. By contrast,
dynorphin antiserum produced an equally dramatic
decrease in the analgesic effect produced by 128 Hz
EA, but this effect diminished gradually with
decreasing frequency, reaching zero at 4 Hz [23]
(Fig. 1). A similar approach was used to study the
possible effect of b-endorphin in mediating EA
analgesia. Injection of b-endorphin antiserum into
rat periaqueductal grey matter resulted in an 88%
decrease of analgesia at 2 Hz EA and a 61% decrease in
analgesia at 15 Hz EA, with no blockade of the analgesic
effect of 100 Hz EA [24].
Another example is endomorphin, a small peptide
composed of only four amino acid residues that has been
recognized as an endogenous opioid peptide with highly
selective affinity for the m-opioid receptors [25]. Antibodies
against endomorphin injected into the cerebral ventricle
[26] or the spinal subarachnoid space [27] dose-dependently
reduced the analgesia induced by 2 Hz EA stimulation, but
not that induced by 100 Hz EA stimulation. This result is
very similar to that obtained with the other two agonists
of m and d receptor already mentioned, enkephalin and
b-endorphin. Taken together, these studies support the
proposition that, although high-frequency stimulation is
preferable for the release of many CNS peptides, it should
not be taken as a gold standard in determining the
parameters of electrical stimulation for activating a
specific neuropeptide for either experimental or therapeutic
Putative neural pathways mediating low- and
high-frequency electroacupuncture-induced analgesia
The afferent impulses induced by acupuncture have been
characterized to be mainly transmitted by Ab and Ad fibres
[28]. Wang and colleagues have conducted a series of
experiments to analyze the possible neural pathways
responsible for the frequency-specific release of different
kinds of opioid peptides in rat CNS [29] (Fig. 2). Lesion of
the arcuate nuclei of the hypothalamus abolished analgesia
induced by low-frequency EA but not that induced by
high-frequency EA, whereas selective lesion of the parabrachial
nuclei of the brainstem attenuated the effects of
high-frequency EA but not those of low-frequency EA. The
periaqueductal grey matter is a common element for both
of the descending pain inhibitory systems. These findings
have been partially supported by subsequent morphological
studies using fos gene expression as marker of brain
activation in the rat [30], and functional magnetic
resonance imaging (fMRI) study in human volunteers
(W.T. Zhang, et al., unpublished).
Optimization of peripheral electrical stimulation for
maximal release of central opioid peptides
From the research already mentioned, stimulation at a
single frequency, whether low or high, would not be
sufficient to trigger the full release of all four kinds of
opioid peptide together. To elicit the maximal release of all
four, two models have been considered. Model A involves
stimulation at low (2 Hz) and high (100 Hz) frequencies
alternately (referred to as ‘2/100’), optimally spaced so that
Fig. 1. Antibody-microinjection study investigating the roles played by spinal metenkephalin
and dynorphin A in mediating the analgesic effects that are induced by
electroacupuncture (EA) of different frequencies. Rats were given intrathecal injection
of normal rabbit serum (NRS) or antisera against either met-enkephalin (Enk
AS, red) or dynorphin A (Dyn AS, blue), 30 minutes before the administration of
EA. The analgesic effect was measured by the percentage change of tail-flick
latency (data were normalized with NRS control group as 100%). The analgesic
effects of low- or high-frequency EA were blocked by Enk AS or Dyn AS, respectively.
Modified, with permission, from Ref. [23].
TRENDS in Neurosciences
Dyn AS
Enk AS
n = 13 or 14 rats
Analgesic effect of EA (%)
2 4 8 16 32 64 128
Frequency of EA (Hz)
18 Opinion TRENDS in Neurosciences Vol.26 No.1 January 2003
the residual effect produced by the low frequency
stimulation could overlap with that produced by the
high frequency and, therefore, elicit an synergistic effect
[31]. Model B involves stimulation at 2 and 100 Hz
simultaneously (referred to as ‘2 þ 100’) applied at
different parts of the body, in which case all four kinds of
opioid peptide might be released simultaneously (Fig. 3).
Model A has been tested carefully [32], showing that
automatic shifting between low- and high-frequency
stimulation for three seconds each (i.e. 2/100 stimulation)
did, indeed, produce a simultaneous activation of the
enkephalin and dynorphin systems, inducing a much more
potent analgesic effect than that induced by a constant
frequency stimulation.
Formodel B (2 þ 100), two possibilities exist. One (B1) is
that the brain is capable of clearly distinguishing two
different frequencies of stimulation (2 Hz versus 100 Hz)
and induces the two efferent systems to work simultaneously.
The other (B2) is that two different signals
(2 and 100 Hz), coming from two different sites, merge in
the reticular formation of the brainstem so that they are
received as a stimulation of 102 Hz, which is indistinguishable
from a stimulation of 100 Hz.Model B2 is supported by
at least three observations [33]. First, an increase of the
content of dynorphin IR in the spinal fluid (representing an
increase in release of the dynorphin peptide) was observed
in both the 2/100 and 2 þ 100 modes, yet an increase of
the release of endomorphin IR was observed only in rats
treated with 2/100 mode. Second, intrathecal injection of k
opioid-receptor antagonist norbinaltorphimide (Nor-BNI)
suppressed the analgesic effect of both the 2/100 and
2 þ 100 modes, whereas the m opioid-receptor antagonist
D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP) produced
a selective blockade of the analgesia only in the 2/100
mode. Third, these results have been validated by the
antibody microinjection experiment. Taken together, the 2/
100 mode seems to activate both the m/d and k opioid
systems to induce a synergistic analgesic effect,whereas the
2 þ 100 mode activates only the k opioid system. In
accordance with this hypothesis, the analgesic effect
induced by 2/100 Hz was significantly stronger than that
induced by 2 þ 100 Hz [33]. A recent study using molecular
biology has supported the concept that endogenously
released dynorphin does indeed possesses a strong antinociceptive
effect in the spinal cord [34].
Clinical verification of laboratory findings
The findings obtained in experimental animals have since
been confirmed in humans in clinical practice. White et al.
Fig. 3. Possible mechanisms for the analgesic effects of acupuncture. (a) Opioid
peptides and opioid receptors involved in analgesia elicited by electroacupuncture
of different frequencies. Opioids and receptors involved at 2 Hz are in red, those
involved at 100 Hz, in blue. At 15 Hz, there is a partial involvement of components
involved at both of the other two frequencies (purple). Abbreviations: Dyn, dynorphin
A; b-End, b-endorphin; Em, endomorphin; Enk, enkephalins. Simultaneous
activation of all three types of opioid receptor elicits a synergistic analgesic effect.
Note that simultaneous receptor activation does not necessarily mean that the
opioids are released simultaneously – it could be that the residual presence of one
opioid overlaps with newly induced release of another. (b) Model for the synergistic
analgesic effect produced by alternating low and high frequency stimulation
(referred to as model A in the text). Stimulation at 2 Hz facilitates the release of
enkephalin (red); that at 100 Hz stimulates the release of dynorphin (blue). The
overlapping areas (purple) indicate the synergistic interaction between the two
peptides. Modified, with permission, from Ref. [32].
TRENDS in Neurosciences
Frequency of electrical
stimulation (Hz)
Opioid peptides
Opioid receptors
Physiological effects
Em, Enk, β-End
2 15 100
Peptide released in CNS
Enk Dyn Enk + Dyn
2 Hz 100 Hz 100 Hz
0 3 6 9 12 15
2 Hz
Time (s)
Fig. 2. Neural pathways mediating the analgesic effect elicited by low-frequency
(2 Hz, red) or high-frequency (100 Hz, blue) electroacupuncture stimulation.
Abbreviations: DHN, dorsal horn neuron of the spinal cord; Dyn, Dynorphin A;
b-End, b-endorphin; Enk, enkephalin; PAG, periaqueductal grey matter. Modified,
with permission, from Ref. [23].
TRENDS in Neurosciences
Enk Dyn
Parabrachial nucleus
Arcuate nucleus of
2 Hz
100 Hz
Opinion TRENDS in Neurosciences Vol.26 No.1 January 2003 19
at the University of Texas Southwestern Medical Center
(TX, USA) performed a series of studies to determine
whether peripheral electrical stimulation of the alternating-
frequency mode would produce a significantly stronger
analgesic effect than that produced by stimulation of fixed
frequency in various clinical settings. Observations on
the post-operative requirement of opioid analgesics [35]
revealed that the alternating-mode stimulation reduced
morphine requirement by 53%, whereas a constant low
(2 Hz) or constant high (100 Hz) frequency produced only a
32 or 35% decrease, respectively. Ghoname et al. [36] made
similar observations in patients with chronic lower-back
pain and found that the alternating mode of stimulation
was the most effective in decreasing pain, increasing
physical activity and improving the quality of sleep (when
compared with the pure low- and pure high-frequency
stimulation). Because the alternating mode produced a
more potent analgesic effect, it was used as a standard
mode of stimulation for further studies searching for the
optimal intensity [37] and optimal stimulation duration
[38]. Thus, controlled clinical studies performed in the past
six years using peripheral electrical stimulation for
the control of various forms of acute [35,37] and chronic
[36,38,39] pain have elegantly replicated what we have
found in animal studies over the past two decades.
Results obtained in EA-induced analgesia have been
applied to the treatment of heroin addiction with considerable
success. The withdrawal syndrome observed in
rats dependent on morphine can be effectively suppressed
by 100 Hz EA, which accelerates the release of dynorphin
in the spinal cord [40,41]. By contrast, morphine-induced
conditioned-place preference (CPP), an experimental
model simulating the craving of heroin addicts, can be
successfully suppressed by 2 Hz EA but not 100 Hz EA
[42,43]. This effect can be blocked by a small dose of
naloxone, indicating the involvement of endogenous opioid
peptides interacting with m and d opioid receptors [42,43].
As would thus be expected, in clinical practice the
alternating mode of stimulation has shown strong therapeutic
effects for both physical and psychological dependence
in heroin addicts [44,45].
Responses of other neuropeptides to peripheral
electrical stimulation
Orphanin FQ (OFQ, also known as nociceptin) [46,47] is
another opiate-related neuropeptide that modulates nociception.
Recent studies describe apparent paradoxical
effects of OFQ on pain modulation – analgesia in the
spinal cord and pronociception (an increase in pain
sensitivity) in the brain [48–52]. Analgesia induced by
100 Hz EA can be potentiated by antibodies to OFQ
injected into the cerebral lateral ventricle and suppressed
by the same antibodies injected into the spinal arachnoid
space [53], suggesting that endogenous OFQ released by
100 Hz EA plays opposite roles in brain and spinal cord.
Cholecystokinin octapeptide (CCK-8) has been recognized
as an anti-opioid peptide in the CNS [54]. The most
effective method for stimulating the release of CCK-8 in
the spinal cord with peripheral stimulation is to use
higher frequencies (15 or 100 Hz), whereas 2 Hz is only
marginally effective [55]. Liu et al. [56] measured the
amount of CCK-8 in rat spinal perfusate as an indicator of
CCK-8 release and found that those rats showing a
significant increase in CCK release during 100 Hz EA
stimulation were low responders (i.e exhibited weak EA
analgesia), whereas rats showing little increase in CCK
release were high responders (i.e. exhibited strong EA
analgesia). Moreover, the speed of response also plays an
important role. It seems that the effect of EA analgesia is
determined by, among other things, the magnitude and the
rapidity of CCK release in the spinal cord in response to
peripheral stimulation. This has been confirmed by the
finding that a rat that is not responsive to 100 Hz EA can
be transformed into a responder by injection of antisense
oligonucleotides to CCK mRNA into the cerebral ventricles,
which suppresses the expression of CCK in the
brain [57]. Furthermore, a responder rat can be changed
into a non-responder by inducing overexpression of CCK in
the brain [58].
Substance P mediates nociception at the first synapse in
the spinal cord. In vivo study revealed that peripheral
stimulation in the 8–100 Hz range elevated the content of
SP in rat spinal perfusate, with maximal effect at 15 Hz
[59]. Similar results were obtained in cats (maximal
release at 20 Hz) [60]. By contrast, 2 Hz peripheral
stimulation produced a 50% decrease in the SP content
of the spinal perfusate [59], possibly owing to the release of
enkepahlin [21], which in turn suppressed the release of
SP [61].
Angiotensin II (AII) is another neuropeptide with antiopioid
activity [62]. The release profile is unique, with a
significant decrease (þ62%, P , 0.01) at 15 Hz and a
significant increase (þ60%, P , 0.05) at 100 Hz [63]. The
decrease of AII release can be reversed by the m-preferring
opioid antagonist naloxone, which changed the 62%
decrease into a 125% increase. These results suggest
that opioid peptides are important modulators affecting
the release of other neuropeptides: 2 Hz EA releases
enkephalin, which activates AII and, thus, a negative
feedback control [63]; 100 Hz EA releases dynorphin,
which activates CCK-8 and, thus, another feedback control
[64]. These can be considered as examples of the finetuning
that is achieved by interactions among peptides.
Last, but not least, is the finding that brain-derived
neurotrophic factor (BDNF) can be released by peripheral
stimulation of 100 Hz bursts, but not by pure low- (1 Hz) or
pure high- (constant 100 Hz) frequency stimulation [65].
This has been verified in primary cultures of hippocampal
neurons, in which high-frequency bursts of stimuli evoke
instantaneous secretion of BDNF together with the
induction of long-term potentiation (LTP) [66]. The ability
of peripheral stimulation to accelerate the release of nerve
growth factors has obvious clinical implications.
Concluding remarks
It has long been a dream to cure diseases by non-invasive
measures that activate self-healing mechanisms, without
using drugs or surgical operations. One recent effort along
these lines was the use of repetitive transcranial magnetic
stimulation(rTMS) to stimulate certainareas of the cerebral
cortex; this has achieved limited success in the treatment
of depression [67]. Evidence presented in the present
20 Opinion TRENDS in Neurosciences Vol.26 No.1 January 2003
review demonstrates that it is possible to facilitate the
release of certain neuropeptides in the CNS by means of
peripheral electrical stimulation. In contrast to magnetic
stimulation, which stimulates the superficial areas of the
brain (i.e. the cortex) [67], peripheral stimulation of the
skin or deeper structures activates various brain structures
and/or the spinal cord via specific neural pathways
(Fig. 2). Any predictions made at this stage should not be
overly optimistic. But the clinical efficacy demonstrated
using frequency-specific parameters to ease post-operative
pain [35,37], lower-back pain [36,38] and diabetic neuropathic
pain [39], and the successful application of 100 Hz
(but not 2 Hz) stimulation for treating muscle spastic pain
of spinal origin [68], certainly hold exciting promise for the
I wish to thank Tomas Hokfelt of the Karolinska Institute and Richard
Morris of the University of Edinburgh for their encouragement in
preparing this article. Special thanks go to many of my colleagues and
friends, at home and abroad, who provided helpful suggestions and
editorial comments. This work was supported by the National Basic
Research Programme (G1999054000), the National Natural Science
Foundation of China (39830160) and a grant from the NIDA/NIH of the
USA (DA 03983).
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