J Manipulative Physiol Ther. 2016 (Jan); 39 (1): 42–53 ~ FULL TEXT
Xue-Jun Song, MD, PhD, Xue-Jun Song, PhD Xue-Jun Song, Zhi-Jiang Huang, PhD,
William B. Song, Xue-Song Song, MD, PhD, Arlan F. Fuhr, DC, Anthony L. Rosner, PhD,
Harrison Ndtan, PhD, Ronald L. Rupert, DC
Parker Research Institute,
OBJECTIVES: The purpose of this study was to investigate roles of the anti-inflammatory cytokine interleukin (IL) 10 and the proinflammatory cytokines IL-1β and tumor necrosis factor α (TNF-α) in spinal manipulation-induced analgesic effects of neuropathic and postoperative pain.
METHODS: Neuropathic and postoperative pain were mimicked by chronic compression of dorsal root ganglion (DRG) (CCD) and decompression (de-CCD) in adult, male, Sprague-Dawley rats. Behavioral pain after CCD and de-CCD was determined by the increased thermal and mechanical hypersensitivity of the affected hindpaw. Hematoxylin and eosin staining, whole-cell patch clamp electrophysiological recordings, immunohistochemistry, and enzyme-linked immunosorbent assay were used to examine the neural inflammation, neural excitability, and expression of c-Fos and PKC as well as levels of IL-1β, TNF-α, and IL-10 in blood plasma, DRG, or the spinal cord. We used the activator adjusting instrument, a chiropractic spinal manipulative therapy tool, to deliver force to the spinous processes of L5 and L6.
RESULTS: After CCD and de-CCD treatments, the animals exhibited behavioral and neurochemical signs of neuropathic pain manifested as mechanical allodynia and thermal hyperalgesia, DRG inflammation, DRG neuron hyperexcitability, induction of c-Fos, and the increased expression of PKCγ in the spinal cord as well as increased level of IL-1β and TNF-α in DRG and the spinal cord. Repetitive Activator-assisted spinal manipulative therapy significantly reduced simulated neuropathic and postoperative pain, inhibited or reversed the neurochemical alterations, and increased the anti-inflammatory IL-10 in the spinal cord.
CONCLUSION: These findings show that spinal manipulation may activate the endogenous anti-inflammatory cytokine IL-10 in the spinal cord and thus has the potential to alleviate neuropathic and postoperative pain.
KEYWORDS: Ganglia; Interleukin-10; Interleukin-1beta; Nervous System; Pain; Spinal; Spinal manipulation; Trauma
From the FULL TEXT Article:
Injury and inflammation to the nerve and tissues within or adjacent to the lumbar intervertebral foramen (IVF) can cause a series of pathologic changes, which may contribute to the pathogenesis of chronic low back pain. [1–6] After injury or inflammation, chemical factors (eg, cytokines, nerve growth factors, inflammatory mediators) release, activate, or change the properties of the dorsal root ganglion (DRG) neurons within the IVF and spinal dorsal horn neurons. These changes may contribute to chronic pain. [4, 5, 7–11] To better understand the mechanisms of low back pain due to nerve injury and IVF inflammation, we previously developed an animal model of chronic compression of DRG (CCD) [4, 12] and an IVF inflammation model produced by in vivo delivery of inflammatory mediators into the IVF at L5. [13–15] Rats with CCD or IVF inflammation at L4 and/or L5 exhibited measurable pain and hyperalgesia, and the affected DRG neurons became more excitable. Mechanisms underlying chronic pain remain elusive, and the effective clinical approaches for reliving chronic pain are very limited.
Spinal manipulative therapy (SMT) has been recognized as an effective approach for reliving certain chronic pain and used for treating patients with chronic pain syndromes such as low back pain. [16–18] Mechanisms underlying the clinical effects of SMT are poorly understood but are thought to be related to mechanical, neurophysiologic, and reflexogenic processes. [16–20] In addition to traditional manual SMT, instruments such as the activator adjusting instrument (AAI) have been used to produce spinal mobilization.  The AAI was developed to precisely control the speed, force, and direction of the adjustive thrust to produce a safe, reliable, and controlled force for manipulation of osseous spinal structures. [22, 23] Activator evolved in response to currently knowledge in biomechanical and neurophysiologic categories of investigation. [21, 24, 25] We have previously demonstrated the treatment effects of SMT as performed using the AAI (Activator-assisted spinal manipulative therapy [ASMT]) on pain and hyperalgesia produced by DRG inflammation using the IVF inflammation model in adult rats with outcomes being assessed through behavioral, electrophysiological, pathologic, molecular biological approaches.  However, the mechanisms underlying the ASMT-induced analgesic effects remain unknown.
The purpose of this study was to examine the possible mechanisms that may underlie ASMT-induced analgesic effect using a small animal model of CCD and relief of CCD (decompression of CCD [de-CCD]). This study investigated if repetitive ASMT could suppress neuropathic pain after CCD and the postoperative pain after de-CCD, reduce the increased excitability of CCD and de-CCD DRG neurons, attenuate the DRG inflammation, and inhibit induction of c-Fos and expression of PKC in the spinal dorsal horn.
This research is believed to be the first demonstration that the endogenous anti-inflammatory cytokine IL-10 in the spinal cord was activated and contributed to spinal manipulation-induced analgesia. The present study demonstrated that spinal manipulation mimicked by repetitive ASMT reduced neuropathic pain induced by primary sensory neuron injury (DRG compression) and the postoperative pain after decompression of the previously compressed sensory neurons; ASMT-induced increased level of the endogenous anti-inflammatory cytokines IL-10 in the spinal cord as well as the decreased proinflammatory cytokine IL-1β may contribute to ASMT-induced analgesic effects. The major findings are 4–fold: (i) repetitive ASMT significantly suppressed the mechanical allodynia and thermal hyperalgesia after CCD/de-CCD treatment; (ii) repetitive ASMT significantly alleviated CCD/de-CCD DRG neuron inflammation; (iii) repetitive ASMT significantly reduced the increased excitability of the nociceptive DRG neurons after CCD/de-CCD; (iv) repetitive ASMT inhibited induction of c-Fos gene and expression of PKCγ in the spinal cord after CCD/de-CCD; (v) repetitive ASMT significantly increased the anti-inflammatory cytokines IL-10 in the spinal cord as well as reducing CCD-induced increased proinflammatory cytokines IL-1β in DRG. These findings provide evidence supporting a new mechanism that underlies ASMT-induced analgesia in certain neuropathic and postoperative painful conditions.
Low back pain, in pathogenesis and etiology, may involve neuropathic and inflammatory pain and continues to be a major challenge in clinic. This study provides evidence that repetitive spinal manipulation may be an effective approach for treating certain low back pain due to temporary, reversible sensory neuron injury and/or IVF inflammation. Such analgesic effects may be mediated by spinal manipulation–induced reduction of the nerve tissue inflammation and the proinflammatory cytokine IL-1β in DRG and the great increase of the endogenous anti-inflammatory cytokine IL-10 in the spinal cord. This study demonstrates a unique mechanism underlying spinal manipulation–induced relief of chronic pain comparing to the regular analgesics. Spinal manipulation relieves pain through activating the endogenous anti-inflammatory and analgesic systems, but not by suppressing the specific molecular targets that may be responsible for the painful conditions. We know that pathogenesis and etiology of various chronic painful conditions including low back pain are complex and remain elusive, although it is thought that the low back pain may involve in neuropathic and inflammatory mechanisms. Furthermore, mechanisms that underlie the neuropathic and inflammatory pain are also unclear. There is no any single or a couple of specific molecules that could perfectly be responsible for and be the targets for treating low back pain. However, certain techniques and therapies such as spinal manipulation are a good choice, and they are ready for use in clinic to relieve certain chronic painful conditions.
Inflammatory response after inflammation or nerve injury such as DRG compression in this study plays essential roles in behavioral hyperalgesia and hyperexcitability of DRG neurons in inflammatory as well as in neuropathic painful conditions. [7–11, 16–18] Dorsal root ganglion neuron injury and inflammation are the main reasons for low back pain and similar painful conditions in other regions. After injury and/or inflammation to the primary sensory neuron within the DRG, the chemical factors such as cytokines, nerve growth factors, inflammatory mediators, and other substances release and activate and/or change the properties of DRG neurons and spinal dorsal horn neurons as well as increase their excitability and, therefore, contribute to pain and/or hyperalgesia. [4, 5, 7–11, 16] In the present study, CCD treatment produces a chronic compression as well as inflammation on the DRG and the constituents within the IVF (ie, DRG, nerve root, blood and lymph vessels) and may produce ischemia and compromise the delivery of oxygen and nutrients. Our study shows that ASMT can significantly alleviate the symptoms and shorten the duration of mechanical allodynia and thermal hyperalgesia, DRG inflammation, as well as DRG nociceptive neuron hyperexcitability caused by CCD and the followed postoperative pain (de-CCD treatment).
There are several possibilities of the mechanisms of action for spinal manipulation. For example, (i) the increased movement of the affected intervertebral joints (facets) and the coupled spinal motion may contribute to the effect of spinal manipulation via improving the blood and nutrition supplement to the DRG within the affected IVF;  (ii) Spinal manipulation may “normalize” articular afferent input to the central nervous system with subsequent recovery of muscle tone, joint mobility, and sympathetic activity.  It was hypothesized that a chiropractic lumbar thrust could produce sufficient force to coactivate all of the mechanically sensitive receptor types,  and SMT made with the Activator is thought to accomplish the same task.  Activator SMT may have the capacity to coactivate type III, high-threshold mechanoreceptors. Both type III and IV receptors in diarthrodial joints as well as type II in paravertebral muscles and tendons are responsive to vertebral displacement;  (iii) Spinal manipulation may activate the receptors in the spinal cord and some of the ascending and descending signaling pathways that involve in pain modulation.  Studies have shown that certain cytokines and chemokines are involved in normal subjects and patients with neck pain and soft tissue injury, with or without spinal manipulation therapy. [37–40] In the present study, we found that ASMT can activate the endogenous anti-inflammatory cytokine IL-10 in the spinal cord. This finding provides a new mechanism for understanding the treatment effects of spinal manipulation using ASMT.
The importance of specificity as it relates to the force that is applied to the spinal segment(s) is another important question. Specific SMT with certain forces is important, but it is difficult to determine the “correct” force in practice. Here, we examined applying ASMTs in 2 different forces, ASMT-1 and ASMT-2, representing the SMT force setting at 1 and 2 of the Activator III, respectively, whereas the other parameters in the 2 protocols were kept the same. The results show that ASMT-1 and ASMT-2 result in similar analgesic effect on thermal hyperalgesia and mechanical allodynia after CCD/de-CCD (see description in the first paragraph in Results) and on alterations of the inflammatory cytokines IL-1β and TNF-α as well as the anti-inflammatory cytokines IL-10 (see Fig 5). Thus, with the experimental protocols in this study, the ASMT with forces at setting 1 and setting 2 of the Activator does not produce significantly different results, suggesting that the force at setting 1 may satisfy the minimal or maximal force requirement, in addition to other parameters, to achieve the treatment effects detected. A further study is needed to systematically examine ASMT with a larger range of force settings to determine the specificity of force use in spinal manipulation.
Further studies are needed to identify possible roles of the newly identified molecular targets such as ephrinB-EphB receptor [41–44] and WNT signaling [45, 46], that are important in production and maintenance of neuropathic and cancer pain in spinal manipulation–induced analgesia. In addition, a series of quantitative studies on the Activator settings including forces, frequencies, and others need to be conducted in more details. Furthermore, it is time to conduct clinical translational studies in patients; thus, the scientific findings in this current and our previous studies [4, 13, 15] focusing on the spinal manipulation and low back pain may be translated to improving clinical care of the patients with similar painful conditions.
The limitations for this study may include at least 2–fold: (i) The force settings reading in the AAI are obviously not the actual forces applied to the spinal processes in the experimental animals. The actual forces applied to the spinal processes using AAI should be measured. (ii) The results showed that ASMT significantly increased level of the anti-inflammatory cytokine IL-10 in the spinal cord and reduced level of proinflammatory cytokine IL-1β in DRG. It was not identified which of these 2 alterations is more important or both are equally important to the ASMT-induced analgesia.
Our results showed that repetitive ASMT significantly suppressed neuropathic pain after CCD and the postoperative pain after de-CCD, reduced the increased excitability of CCD and de-CCD DRG neurons, attenuated the DRG inflammation, and inhibited induction of c-Fos and expression of PKC in the spinal dorsal horn. Most interestingly, ASMT significantly increased level of the anti-inflammatory cytokine IL-10 in the spinal cord and reduced level of IL-1β in DRG in CCD and de-CCD rats. These results suggest that ASMT may attenuate neuropathic pain through, at least partly, activating the endogenous anti-inflammatory cytokines IL-10.
The pathophysiology of damaged peripheral nerves.
in: PD Wall, R Melzack (Eds.)
Text Book of Pain. 3rd ed.
Churchill Livingstone, London; 1994: 79–100
Brisby, H, Olmarker, K, Larsson, K, Nutu, M, and Rydevik, B.
Proinflammatory cytokines in cerebrospinal fluid and serum in patients with disc herniation and sciatica.
Eur Spine J. 2002; 11: 62–66
Song, XJ, Zhang, JM, Hu, SJ, and LaMotte, RH.
Somata of nerve-injured neurons exhibit enhanced responses to inflammatory mediators.
Pain. 2003; 104: 701–709
Song, XJ, Xu, DS, Vizcarra, C, and Rupert, RL.
Onset and recovery of hyperalgesia and hyperexcitability of sensory neurons following intervertebral foramen volume reduction and restoration.
J Manipulative Physiol Ther. 2003; 26: 426–436
Neumann, S, Doubell, TP, Leslie, T, and Woolf, CJ.
Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons.
Nature. 1996; 384: 360–364
Cui, JG, Holmin, S, Mathiesen, T, Meyerson, BA, and Linderoth, B.
Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy.
Pain. 2000; 88: 239–248
Wagner, R and Myers, RR.
Endoneurial injection of TNF-alpha produces neuropathic pain behaviors.
Neuroreport. 1996; 7: 103–111
Waxman, SG, Kocsis, JD, and Black, JA.
Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is reexpressed following axotomy.
J Neurophysiol. 1994; 72: 466–470
Song, XJ, Hu, SJ, Greenquist, K, and LaMotte, RH.
Mechanical and thermal cutaneous hyperalgesia and ectopic neuronal discharge in rats with chronically compressed dorsal root ganglia.
J Neurophysiol. 1999; 82: 3347–3358
Song, XJ, Vizcarra, C, Xu, DS, Rupert, RL, and Wong, ZN.
Hyperalgesia and neural excitability following injuries to the peripheral and central branches of axon and somata of dorsal root ganglion neurons.
J Neurophysiol. 2003; 89: 2185–2193
Song, XJ, Wang, ZB, Gan, Q, and Walters, ET.
cAMP and cGMP pathways contribute to expression of hyperalgesia and sensory neuron hyperexcitability following dorsal root ganglion compression in the rat.
J Neurophysiol. 2006; 95: 479–492
Song, XJ, Hu, SJ, Greenquist, KW, Zhang, JM, and LaMotte, RH.
Mechanical and thermal hyperalgesia and ectopic neuronal discharge after chronic compression of dorsal root ganglia.
J Neurophysiol. 1999; 82: 3347–3358
Song, XJ, Gan, Q, Wang, ZB, and Rupert, RL.
Hyperalgesia and hyperexcitability of sensory neurons induced by local application of inflammatory mediators: an animal model of acute lumbar intervertebral foramen inflammation.
Soc Neurosci Abstr. 2004; 30
Song, XJ, Gan, Q, Wang, ZB, and Rupert, RL.
Lumbar intervertebral foramen inflammation-induced hyperalgesia and hyperexcitability of sensory neurons in the rat.
FASEB J. 2004; 1616
Song, XJ, Gan, Q, Cao, JL, Wang, ZB, and Rupert, RL.
Spinal Manipulation Reduces Pain and Hyperalgesia After
Lumbar Intervertebral Foramen Inflammation in the Rat
J Manipulative Physiol Ther. 2006 (Jan); 29 (1): 5–13
Kizhakkeveettil, A, Rose, K, and Kadar, GE.
Integrative therapies for low back pain that include complementary and alternative medicine care: a systematic review.
Glob Adv Health Med. 2014; 3: 49–64
Peterson, CK, Humphreys, BK, Vollenweider, R, Kressig, M, and Nussbaumer, R.
Outcomes for chronic neck and low back pain patients after manipulation under anesthesia: a prospective cohort study.
J Manipulative Physiol Ther. 2014; 37: 377–382
Kolberg, C, Horst, A, Moraes, MS et al.
Peripheral oxidative stress blood markers in patients with chronic back or neck pain treated with high-velocity, low-amplitude manipulation.
J Manipulative Physiol Ther. 2015; 38: 119–129
Bronfort, G, Haas, M, and Evans, R.
The clinical effectiveness of spinal manipulation for musculoskeletal conditions.
in: S Haldeman (Ed.)
Principle and Practice of Chiropractic. 3rd ed.
McGraw Hill, New York; 2005: 147–165
The treatment of headache, neurologic, and non-musculoskeletal disorders by spinal manipulation.
in: S Haldeman (Ed.)
Principle and Practice of Chiropractic. 3rd ed.
McGraw Hill, New York; 2005: 167–182
Fuhr, AW and Menke, JM.
Activator methods chiropractic technique.
Top Clin Chiropr. 2002; 9: 30–43
The activator story: development of a new concept in chiropractic.
Chiropr J Austr. 1994; 24: 28–32
Osterbauer, P, Fuhr, AW, and Keller, TS.
Description and analysis of activator methods chiropractic technique, advances in chiropractic.
1995; 2: 471–520
Fuhr, AW and Smith, DB.
Accuracy of piezoelectric accelerometers measuring displacement of a spinal adjusting instrument.
J Manipulative Physiol Ther. 1986; 9: 15–21
Smith, DB, Fuhr, AW, and Davis, BP.
Skin accelerometer displacement and relative bone movement of adjacent vertebrae in response to chiropractic percussion thrusts.
J Manipulative Physiol Ther. 1989; 12: 26–37
Song, XJ, Zheng, JH, Cao, JL, Liu, WT, Song, XS, and Huang, ZJ.
EphrinB-EphB receptor signaling contributes to neuropathic pain by regulating neural excitability and spinal synaptic plasticity in rats.
Pain. 2008; 139: 168–180
Wang, ZB, Gan, Q, Rupert, RL, Zeng, YM, and Song, XJ.
Thiamine, pyridoxine, cyanocobalamin and their combination inhibit thermal, but not mechanical hyperalgesia in rats with primary sensory neuron injury.
Pain. 2005; 114: 266–277
Song, XS, Huang, ZJ, and Song, XJ.
Thiamine suppresses thermal hyperalgesia, inhibits hyperexcitability, and lessens alterations of sodium currents in injured, dorsal root ganglion neurons in rats.
Anesthesiology. 2009; 110: 387–400
Zheng, JH, Walters, ET, and Song, XJ.
Dissociation of dorsal root ganglion neurons induces hyperexcitability that is maintained by increased responsiveness to cAMP and cGMP.
J Neurophysiol. 2007; 97: 15–25
Huang, ZJ, Li, HC, Cowan, AA, Liu, S, Zhang, YK, and Song, XJ.
Chronic compression or acute dissociation of dorsal root ganglion induces cAMP-dependent neuronal hyperexcitability through activation of PAR2.
Pain. 2012; 153: 1426–1437
Huang, ZJ, Li, HC, Liu, S, and Song, XJ.
Activation of cGMP-PKG signaling pathway contributes to neuronal hyperexcitability and hyperalgesia after in vivo prolonged compression or in vitro acute dissociation of dorsal root ganglion in rats.
Sheng Li Xue Bao. 2012; 64: 563–576
Three neurophysiological theories on the chiropractic subluxation.
in: MI Gatterman (Ed.)
Foundation of Chiropractic Subluxation,
St. Louis, Mosby; 1995
In vivo transient vibration assessment of the normal human thoracolumbar spine.
J Manipulative Physiol Ther. 2000; 23: 521–530
A speculative argument for the coactivation of diverse somatic receptor populations by forceful chiropractic adjustments.
Man Med. 1987; 3: 1–14
Nathan, M and Keller, TS.
Measurement and analysis of the in vivo posteroanterior impulse response of the human thoracolumbar spine: a feasibility study.
J Manipulative Physiol Ther. 1994; 17: 431–441
The audible release associated with joint manipulation.
J Manipulative Physiol Ther. 1995; 18: 155–164
Cao, TV, Hicks, MR, Campbell, D, and Standley, PR.
Dosed myofascial release in three-dimensional bioengineered tendons: effects on human fibroblast hyperplasia, hypertrophy, and cytokine secretion.
J Manipulative Physiol Ther. 2013; 36: 513–521
Eagan, TS, Meltzer, KR, and Standley, PR.
Importance of strain direction in regulating human fibroblast proliferation and cytokine secretion: a useful in vitro model for soft tissue injury and manual medicine treatments.
J Manipulative Physiol Ther. 2007; 30: 584–592
Teodorczyk-Injeyan, JA, Injeyan, HS, and Ruegg, R.
Spinal Manipulative Therapy Reduces Inflammatory Cytokines but Not
Substance P Production in Normal Subjects
J Manipulative Physiol Ther 2006 (Jan); 29 (1): 14–21
Teodorczyk-Injeyan, JA, Triano, JJ, McGregor, M, Woodhouse, L, and Injeyan, HS.
Elevated Production of Inflammatory Mediators Including Nociceptive
Chemokines in Patients With Neck Pain: A Cross-Sectional Evaluation
J Manipulative Physiol Ther. 2011 (Oct); 34 (8): 498–505
Liu, S, Liu, YP, Song, WB, and Song, XJ.
EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord.
Pain. 2013; 154: 2823–2835
Liu, S, Liu, WT, Liu, YP, Dong, HL, Henkemeyer, M, and Song, XJ.
Blocking EphB1 receptor forward signaling in spinal cord relieves bone cancer pain and rescues analgesic effect of morphine treatment in rodents.
Cancer Res. 2011; 71: 4392–4402
Song, XJ, Cao, JL, Li, HC, Song, XS, and Xiong, LZ.
Upregulation and redistribution of ephrin1B-EphB1 receptor signaling in dorsal root ganglion and spinal dorsal horn after nerve injury and dorsal rhizotomy.
Eur J Pain. 2008; 12: 1031–1039
Han, Y, Song, XS, Liu, WT, Henkemeyer, M, and Song, XJ.
Targeted mutation of EphB1 receptor prevents development of neuropathic hyperalgesia and physical dependence on morphine in mice.
Mol Pain. 2008; 4: 60
Zhang, YK, Huang, ZJ, Liu, S, Liu, YP, Song, AA, and Song, XJ.
WNT signaling underlies the pathogenesis of neuropathic pain in rodents.
J Clin Invest. 2013; 123: 2268–2286
Liu, S, Liu, YP, Huang, ZJ et al.
Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats.
Pain. 2015; 156: 2572–2584
Return to the SPINAL PAIN MANAGEMENT Page