Acta Anaesthesiol Scand 2013; 57: 271–277
Printed in Singapore. All rights reserved
New hypothesis of chronic back pain: low pH promotes
nerve ingrowth into damaged intervertebral disks
C. Liang1*, H. Li1*, Y. Tao1, C. Shen1, F. Li1, Z. Shi2, B. Han1 and Q. Chen1
1
Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China and 2Institute of
Orthopedic Research, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
The pathogenesis of low back pain is still elusive. Here, we
proposed a new hypothesis that low pH is a possible cause of the
development and progression of low back pain. We propose that
low pH promotes the production of the inflammatory mediators
and the depletion of proteoglycan in the damaged intervertebral
disk. The inflammation response, evoked by the dorsal root
ganglia, changes the delicate nutrient balance in the nucleus,
resulting in a vicious cycle and leading to choronic back pain.
Our hypothesis may explain many of the available clinical and
L ow back pain (LBP) is one of the leading causes
of morbidity and disability. LBP affects up to
50% to 80% of the population in developed coun-
tries, depending on the operational definition of
LBP and the population studied.1,2 Moreover, the
recurrence rate of LBP amounts to 85%, resulting in
economic loss of approximately 50 to 100 billion
dollars per year in United States.3,4
The effective treatment of LBP is severely ham-
pered due to the poorly understood pathogenesis of
LBP.5 Anatomically, the most common factors asso-
ciated with back pain are degenerative joint disease
and intervertebral disk degeneration (IDD).6 The
intervertebral disk (IVD) is composed of the nucleus
pulposus (NP), the annulus fibrosus (AF), and the
end plates (EPs). The healthy discus is avascular, and
its nutrition depends on diffusion via the AF and the
EP.7,8 However, degenerative disks are often asymp-
tomatic, and the pathobiology of discogenic back
pain remains unclear. It has been proposed that the
degenerative cascade ultimately leads to extensive
structural defects and loss of normal motion
segment function and configuration.9 Therefore, it
appears that degenerative disks become painful
*C.-Z. Liang and H. Li contributed equally to this work and should be
considered co-first authors.
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© 2012 The Acta Anaesthesiologica Scandinavica Foundation
Published by Blackwell Publishing Ltd.
ACTA ANAESTHESIOLOGICA SCANDINAVICA
doi: 10.1111/j.1399-6576.2012.02670.x
Review Article
experimental data on low back pain, thus it may help eluci-
date the pathogenesis of low back pain and improve clinical
management.
Accepted for publication 24 January 2012
© 2012 The Acta Anaesthesiologica Scandinavica Foundation
Published by Blackwell Publishing Ltd.
until the progression of degenerative disks reaches a
certain stage. Moreover, the pain of degenerative
disks is closely related to the individual differences
including pain genetics, degenerative type, disk her-
iation position, intervertebral foraminal form and its
relation with adjacent structure.10 In consideration
of the pathoanatomy of back pain, Calliet11 catego-
rized back pain in terms of dysfunction, instability,
and stabilization.
As most components of the spinal column are
embedded by the nociceptive sensors, several
hypotheses on the pathogenesis of back pain have
focused on the dysfunction of the spinal column
and its components, such as injury and clinical
instability,12,13 spinal column degeneration,14 inferior
facet-tip impingement on the lamina,15 Schmorl’s
nodes,16 and facet joint injury.17 In addition, pain
adaptation and pain–spasm–pain hypotheses have
been proposed,18–20 while Panjabi and Schleip et al.
speculated that subfailure injuries of ligaments
(spinal ligaments, discannulus facet capsules, and
thoracolumbar fascia) may cause chronic back pain
due to muscle control dysfunction.21–23
Several studies have investigated the pain path-
ways and the distribution of nociceptive nerve
endings in healthy and degenerated IVDs.24,25 The
results demonstrated that in healthy adult animals
271
C.-Z. Liang et al.
and human beings, nerves extend no further into
the IVD than the outer third of the AF.8,26–28 Most of
the sensory fibers innervating the IVD are nocicep-
tive and, to a lesser extent, proprioceptive. These
nerves contain putative nociceptive neurotransmit-
ters such as substance P (SP), calcitonin-gene-
related peptide (CGRP).29–31 Nevertheless, in human
degenerated IVD, as well as in animal models of
IDD, many studies reported that nerve fibers
increased in number and entered granulation tissue
of IVD, the inner layers of the AF and even the
NP,32–35 which is closely related with pain of IVD
origin. However, the mechanisms responsible for
nerve growth and hyperinnervation of the lumbar
IVD have not been fully understood.
A number of experimental evidence supports
the existence of steep gradients in pH through-
out the disk. Steep gradients of lactate were found
in the intervertebral disk of patients with scoliosis
and back pain, consistent with the results calculated
by the diffusion theory.36–38 The nociceptors can be
sensitized by lactate and cytokines, thereby dimin-
ishing their activation threshold.39–42 Recently,
Keshari et al. reported that painful disks are distin-
guishable by an increased ratio of lactate to prote-
oglycan.37 These observations are consistent with
the proposed nociceptor-stimulatory role of lac-
tate.43 On the other hand, acidic pH has a strong
effect on matrix turnover. When the pH decreases to
below 6.7, the matrix anabolism of disk cells will be
inhibited, while the catabolism will remain the
same, consequently, the height of the IVDs will
decrease.44–48 In addition, it is suggested that the
mechanoreceptors embedded in the spinal column
may transduce corrupt signal to neuromuscular
control unit, leading to the fatigue and even the
injury of spinal ligaments and muscles.12,21,49 Based
on these data, painful disks may be triggered to
show obvious pain symptom by low pH microenvi-
ronment caused by lactate accumulation and aggra-
vated by the secondary IDD.
It has been shown that painful disks have a lower
pH than nonpainful disks in humans. In addition,
experimental lowering of the pH in animal models
induced pain-related behaviors and hyperal-
gesia.36–38 Taking together, we proposed a new
hypothesis to explain back pain as described later.
Hypothesis
The hypothesis proposes the following sequential
steps for the development of back pain (Fig. 1):
272
1. Under some certain conditions such as nutri-
tional disturbance, cartilage EP calcification, and
sudden ischemia or cumulative microischemia,
gradually decreases of pH of the IVDs.50,51
2. The low pH promotes the production of inflam-
matory mediators and the depletion of the
proteoglycan. Several studies demonstrated that
acid-exposed esophageal mucosa released SP,
CGRP, platelet-activating factor, and interleukin
(IL)-8 partly via activating acid-sensitive vanil-
loid receptors.52–54 An acidic pH environment
could increase the release of pro-inflammatory
cytokines, cathepsin B, and prostaglandin E2 in
osteoblasts or cells found at the bone–implant
interface.55–57 In addition, acidic pH stimulates the
productions of the angiogenic CXC chemokine
and IL-8 in human adult mesenchymal stem
cells.58 Moreover, tissue acidosis does occur in
inflammatory joint disease, lumbar radiculopa-
thy, and cancer-associated bone pain.59–61 These
factors may be involved in the mechanism of
nerve ingrowth.
3. The pro-inflammatory cytokines may trigger IVD
cells, mastocytes, and macrophages to secrete
neurotrophins, in particular, nerve growth factor
(NGF), which regulate the density and distribu-
tion of sensory and sympathetic nerve fibers in
peripheral tissues. Consequently, extensive nerve
ingrowth occurs in the damaged IVDs. Moreover,
increased level of NGF and the breakdown of the
IVD aggrecans induce tropomyosin receptor
kinase A (TrkA)-expressing neurons to produce
peptides such as SP and CGRP that mediate pain.
4. Nerve ingrowth into damaged IVDs mediates the
signal transduction from the redundant nocicep-
tors embedded in the IVDs to the DRGs (the pain
control unit).
5. This inflammation response changes the delicate
nutrient balance in the NP, resulting in dimin-
ished oxygen diffusion, increased local lactate
concentration, and decreased pH inside the
discus.
6. The deteriorated microenvironment of IVD pro-
motes the production of more inflammatory
cytokines that stimulate DRGs throughout noci-
ceptors, therefore forming a vicious cycle.
7. Consequently, chronic back pain may develop
over time.
The normal IVD is innervated by a continuous
network of sensory and sympathetic perivascular
interlacing nerve fibers. The nerve plexus as of
the ligamentum longitudinale anterius (LLA) and
 New hypothesis of chronic back pain

Fig. 1. Schematic representation of the sequential steps for the development of LBP. Low pH promotes the production of the inflammatory
mediators and the depletion of proteoglycan. Consequently, nerve ingrowth into damaged intervertebral disks may mediate the signaling
from the nociceptors embedded in the intervertebral disks to the dorsal root ganglia (DRG). DRG has difficulty in interpreting these
inflammation signals, which destroy the delicate nutrient balance in the nucleus. More deteriorated microenvironments of intervertebral
disk produce more inflammatory cytokines, establishing a vicious cycle.

the nerve plexus of the ligamentum longitudinale
posterius (LLP) account for innervating the corre-
sponding segments ventrally and dorsally, res-
pectively. The sensory innervation of the IVD occurs
via branches of the truncus sympathicus.62 The
ventral and lateral sides of the IVD are supplied
by branches of the rami communicantes, direct
branches of the truncus sympathicus, and the LLA
nerve plexus62 (Fig. 2). Therefore, discogenic pain
may be regarded as a visceral pain due to its neural
pathway.
The innervation of degenerated IVD is different
from the normal IVD (Fig. 3). The extensive inner-
vation of disks from patients with discogenic pain
has been reported.24,33,63,64 Moreover, immunoreac-
tivity to sensory nerve structures (SP) has been dem-
onstrated in the annulus fibrosus, extending into the
inner layers, and even reaching up to the NP.24,65
Yoshizawa et al.66 found nerve structures in the
outer fibrocartilagenous layers of the AF on interver-
tebral disk tissue obtained from patients undergoing
surgery for LBP.
In general, our hypothesis is that pH changes are
the possible causes of LBP and antacid therapy may
retard the progression of LBP by improving the pH
microclimate of painful disk.
Discussion
The most common cause of chronic severe LBP is
thought to be related to lumbar IVDs. Some reports
manifest that painful disks have increased density of
pain-transmitting neurons (nociceptors) at the EP
and outer AF.33,67,68 Data from other experiments
prove how nociceptors can be sensitized by lactate
and cytokines, thereby diminishing their activation
threshold.39–41 Based on these data, painful disks may
be triggered to show obvious pain symptom by low
pH microenvironment caused by lactate accumula-
tion. Therefore, the pathologic mechanism of LBP is
thought to be due to sensory nerve ingrowth into
the inner layer of AF and/or NP in the IVD.
It is possible that nerve ingrowth is induced as a
consequence of the depletion of the proteoglycan

273
C.-Z. Liang et al.

Fig. 2. Schematic representation of the innervation of the normal intervertebral disk (IVD). The ventral and lateral sides of the IVD are
supplied by branches of the rami communicantes, direct branches of the truncus sympathicus, and the ligamentum longitudinale anterius
and ligamentum longitudinale posterius nerve plexus. In healthy adult animals and human beings, nerves extend no further into the IVD
than the outer third of the annulus fibrosus.

and aggrecan after the degeneration of the lumbar
IVDs.69–75 Actually, in animal disk degeneration
models, nerve ingrowth was induced accompanied
by the depletion of proteoglycan.71 Other studies
revealed that inflammation condition71,75 and
inflammatory mediators76 in the disk may promote
nerve ingrowth into the disk.
As the largest avascular tissue in the body, IVD
appears to acquire most of its energy by glycolysis.
Thus, there are steep gradients in the concentration
of lactate metabolites from periphery to the center of
the disk, according to the diffusion theory.77 It has
been shown that the pH in degenerated disks was
lower than in normal intervertebral disk.36,78 Fur-
thermore, the pH of the intervertebral disk tissue
may shift to even more acidity as herniation devel-
ops.46 Interestingly, acidity greatly reduced the levels
of tissue inhibitors of metalloproteinases (TIMPs) in
NP cells, without significant direct effect on MMP
activity.79,80 These data suggest that acidity increases
the activity of matrix metalloproteinases (MMPs)
through reducing the level of TIMPs. Therefore, in
our hypothesis, we speculate that low pH increases
the activity of MMPs, which then cause the inflam-
mation and the degeration of the disk.
There are limitations to our hypothesis. LBP is a
complicated process, and a single hypothesis can
not explain all the clinical and pathological aspects
of LBP. Our hypothesis does not exclude any other
mechanism for low back pain, and maybe a comple-
ment, to hypotheses such as subfailure injuries of
spinal ligaments,21 instability,12,49 and pain.18,19
Conclusion
This hypothesis aims to explain the possible patho-
logic process of pH changes during the develop-
ment and progression of LBP. We propose that low
pH promotes the production of the inflammatory
mediators and the depletion of proteoglycan in the

274

Fig. 3. Schematic representation of the innervation of the injured intervertebral disk (IVD). The innervation of IVD is more extensive.
Sensory nerve structures have been demonstrated in the annulus fibrosus, extending into the inner layers of annulus fibrosus, and even
reaching up to nucleus pulposus.
damaged IVDs. The inflammation response, evoked
by the DRG, changes the delicate nutrient balance in
4.
the nucleus, resulting in a vicious cycle and leading
to choronic back pain.
5.
Acknowledgement
6.
This study was partly supported by grants from the National
Nature Science Foundation of China (No. 81171756), the Science
and Technology Planning Project of Zhejiang Province (No. 7.
2009C33093), and the Natural Science Foundation of Zhejiang
Province (No. Y206257). In revising this manuscript, the authors
wish to thank Prof Xiangming Chen (Department of Anesthesi- 8.
ology, Second Affiliated Hospital, Zhejiang University) for his
helpful advice. 9.
Conflicts of interest: No conflict of interests reported.
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Address:
Qi-xin Chen
Department of Orthopedic Surgery, 2nd Affiliated Hospital,
School of Medicine
Zhejiang University
88 Jie Fang Road
Hangzhou 310009
Zhejiang
China
e-mail:zrcqx@zju.edu.cn
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