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
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 well-known
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 Ca2+
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
[14].
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