Acupuncture: A novel hypothesis for the involvement of purinergic signalling

Geoffrey Burnstock

Autonomic Neuroscience Centre, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK

a r t i c l e i n f o

Article history:

Received 14 May 2009

Accepted 15 May 2009

Available online xxxx

s u m m a r y

The hypothesis is summarised schematically in Fig. 1.

It is proposed that mechanical deformation of the skin by needles and application of heat or electrical

current leads to release of large amounts of ATP from keratinocytes, fibroblasts and other cells in skin; the

ATP then occupies specific receptor subtypes expressed on sensory nerve endings in the skin and tongue;

the sensory nerves send impulses through ganglia to the spinal cord, the brain stem, hypothalamus and

higher centres; the brain stem and hypothalamus contain neurons that control autonomic functions,

including cardiovascular, gastrointestinal, respiratory, urinogenital and musculo-skeletal activity.

Impulses generated in sensory fibres in the skin connect with interneurons to modulate (either inhibition

or facilitation) the activities of the motoneurons in the brain stem and hypothalamus to change autonomic

functions; specifically activated sensory nerves, via interneurons, also inhibit the neural pathways

to the pain centres in the cortex.

Background to purinergic signalling

ATP has been well established as an intracellular energy source

for many years. However, in 1972 the concept of purinergic signalling

was introduced, proposing that ATP also acts as an extracellular

signalling molecule

the next 20 years, but when the receptors for ATP and its breakdown

product adenosine were cloned and characterised in the

early 1990s, the concept was accepted and purinergic signalling

is now a rapidly expanding field (see

are being developed to treat a variety of diseases. For example,

clopidogrel, an antagonist to the G protein-coupled receptor subtype

on platelets that mediates aggregation, is a widely used drug

against stroke and thrombosis (it made US$8.6 billion in 2007).

Clinical trials for other purinergic agents are in progress for bladder

incontinence, dry eye, cystic fibrosis, osteoporosis, pain and cancer

(see

Supporting evidence

ATP release

While large amounts of ATP are released from damaged or dying

cells, it has become clear that ATP transport from many cells

in response to mechanical deformation, hypoxia, heat and electrical

currents is a physiological event, which occurs without damage

to the cells. For example, changes in blood flow results in shear

stress releasing ATP from endothelial cells leading to vasodilation

via nitric oxide

the bladder and ureter leading to stimulation of suburothelial sensory

nerves and from epithelial cells of the airways

evidence for release of ATP from keratinocytes in response to

mechanical stimulation

cells

ATP receptors on sensory neurons

Implicit in purinergic signalling is the presence of specific

receptors for purines. Two families of purine receptors were recognised

in 1978, P1 receptors for adenosine and P2 receptors for ATP.

Two families of P2 receptors were proposed in 1985 and the molecular

structure and second messenger agents involved discovered in

the 1990s. Seven P2X ligand-gated ion channel receptor subtypes

and eight P2Y G protein-coupled receptor subtypes are currently

established (see

receptors were cloned in 1995 and shown to be located almost

exclusively on sensory nerve endings

These receptors have been shown with immunohistochemistry

to be located on nerve endings in the skin and are particularly

abundant in the tongue also used for acupuncture

recording from an isolated tongue-nerve preparation showed

increased activity in the lingual nerves supplying the tongue

during mechanical stimulation of the tongue that was mimicked

by ATP and attenuated with P2X

distension of the ureter led to release of substantial amounts

of ATP and evoked a discharge in the suburothelial sensory nerves

that was mimicked by ATP and reduced by 2

ATP, a potent P2X

(see

0306-9877/$ - see front matter

doi:10.1016/j.mehy.2009.05.031

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Medical Hypotheses xxx (2009) xxx–xxx

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ARTICLE IN PRESS

Please cite this article in press as: Burnstock G. Acupuncture: A novel hypothesis for the involvement of purinergic signalling. Med Hypotheses (2009),

doi:10.1016/j.mehy.2009.05.031