Advertisement

Forced Treadmill Running Suppresses Postincisional Pain and Inhibits Upregulation of Substance P and Cytokines in Rat Dorsal Root Ganglion

      Abstract

      Exercise causes a variety of psychophysical effects (eg, alterations in pain sensation). Tissue injury induces mediator releases in the spinal cord resulting in pain hypersensitivity; however, the contribution of the dorsal root ganglion (DRG) is poorly understood. In this study, we tested if forced treadmill running can attenuate postoperative pain and alter substance P (SP) or proinflammatory cytokine level in the DRG by using a rat model of skin/muscle incision and retraction (SMIR). We evaluated mechanical sensitivity to von Frey stimuli (6 and 15 g) and expression of SP, interleukin-1β, and interleukin-6 in the DRG of sham-operated sedentary rats, SMIR sedentary rats, sham-operated rats with forced treadmill running, and SMIR rats with forced treadmill running. At postoperative day 8, trained rats ran for 5 days per week for 4 weeks on a treadmill 70 minutes/d with an intensity of 18 m/min. On postoperative day 6, SMIR sedentary rats displayed a significant mechanical hypersensitivity that persisted until postoperative day 35. By comparison, SMIR-operated rats, which received forced treadmill running, exhibited a quick recovery from mechanical hypersensitivity. SMIR sedentary rats showed an upregulation of SP, interleukin-1β, and interleukin-6 in the DRG at postoperative days 14 and 28, whereas SMIR-operated rats receiving forced treadmill running reversed this upregulation at postoperative day 28. We concluded that forced treadmill running alleviated persistent postincisional pain caused by SMIR surgery. This appears to be protective against postoperative pain, which probably relates to the downturn in excess SP, interleukin-1β, and interleukin-6 in the DRG.

      Perspective

      Controlling the expression of SP, interleukin-6, and interleukin-1β in the DRG can help manage postoperative pain. This finding could potentially help clinicians and physical therapists who seek to examine how exercise may attenuate postsurgical pain and its mechanism.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Barr T.P.
        • Kam S.
        • Khodorova A.
        • Montmayeur J.P.
        • Strichartz G.R.
        New perspectives on the endothelin axis in pain.
        Pharmacol Res. 2011; 63: 532-540
        • Belotto M.F.
        • Magdalon J.
        • Rodrigues H.G.
        • Vinolo M.A.
        • Curi R.
        • Pithon-Curi T.C.
        • Hatanaka E.
        Moderate exercise improves leucocyte function and decreases inflammation in diabetes.
        Clin Exp Immunol. 2010; 162: 237-243
        • Calvino B.
        • Couraud J.Y.
        • Besson J.M.
        Prevaccination with diluted Freund adjuvant prevents the development of chronic pain and transient release of cerebrospinal fluid substance P in adjuvant-induced arthritis in rats.
        Pain. 1994; 58: 211-217
        • Campbell J.N.
        • Meyer R.A.
        Mechanisms of neuropathic pain.
        Neuron. 2006; 52: 77-92
        • Chen B.L.
        • Zhong Y.
        • Huang Y.L.
        • Zeng L.W.
        • Li Y.Q.
        • Yang X.X.
        • Jiang Q.
        • Wang C.H.
        Systematic back muscle exercise after percutaneous vertebroplasty for spinal osteoporotic compression fracture patients: A randomized controlled trial.
        Clin Rehabil. 2012; 26: 483-492
        • Chen Y.W.
        • Hsieh P.L.
        • Chen Y.C.
        • Hung C.H.
        • Cheng J.T.
        Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats.
        Anesth Analg. 2013; 116: 482-490
        • Chen Y.W.
        • Li Y.T.
        • Chen Y.C.
        • Li Z.Y.
        • Hung C.H.
        Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve.
        Anesth Analg. 2012; 114: 1330-1337
        • Chen Y.W.
        • Lin M.F.
        • Chen Y.C.
        • Hung C.H.
        • Tzeng J.I.
        • Wang J.J.
        Exercise training attenuates postoperative pain and expression of cytokines and N-methyl-d-aspartate receptor subunit 1 in rats.
        Reg Anesth Pain Med. 2013; 38: 282-288
        • Coleman M.A.
        • Garland Jr., T.
        • Marler C.A.
        • Newton S.S.
        • Swallow J.G.
        • Carter P.A.
        Glucocorticoid response to forced exercise in laboratory house mice (Mus domesticus).
        Physiol Behav. 1998; 63: 279-285
        • Cooper D.M.
        • Nemet D.
        • Galassetti P.
        Exercise, stress, and inflammation in the growing child: From the bench to the playground.
        Curr Opin Pediatr. 2004; 16: 286-292
        • De Koninck Y.
        • Henry J.L.
        Substance P-mediated slow excitatory postsynaptic potential elicited in dorsal horn neurons in vivo by noxious stimulation.
        Proc Natl Acad Sci U S A. 1991; 88: 11344-11348
        • Flatters S.J.
        Characterization of a model of persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR).
        Pain. 2008; 135: 119-130
        • Gencay-Can A.
        • Gunendi Z.
        • Suleyman Can S.
        • Sepici V.
        • Ceviker N.
        The effects of early aerobic exercise after single-level lumbar microdiscectomy: A prospective, controlled trial.
        Eur J Phys Rehabil Med. 2010; 46: 489-496
        • Gerner P.
        Postthoracotomy pain management problems.
        Anesth Clin. 2008; 26 (vii): 355-367
        • Guo W.
        • Wang H.
        • Watanabe M.
        • Shimizu K.
        • Zou S.
        • LaGraize S.C.
        • Wei F.
        • Dubner R.
        • Ren K.
        Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain.
        J Neurosci. 2007; 27: 6006-6018
        • Huang L.
        • Wang C.F.
        • Serhan C.N.
        • Strichartz G.
        Enduring prevention and transient reduction of postoperative pain by intrathecal resolvin D1.
        Pain. 2011; 152: 557-565
        • Ilkjaer S.
        • Bach L.F.
        • Nielsen P.A.
        • Wernberg M.
        • Dahl J.B.
        Effect of preoperative oral dextromethorphan on immediate and late postoperative pain and hyperalgesia after total abdominal hysterectomy.
        Pain. 2000; 86: 19-24
        • Kangrga I.
        • Randic M.
        Tachykinins and calcitonin gene-related peptide enhance release of endogenous glutamate and aspartate from the rat spinal dorsal horn slice.
        J Neurosci. 1990; 10: 2026-2038
        • Kehlet H.
        • Jensen T.S.
        • Woolf C.J.
        Persistent postsurgical pain: Risk factors and prevention.
        Lancet. 2006; 367: 1618-1625
        • Kelly D.J.
        • Ahmad M.
        • Brull S.J.
        Preemptive analgesia I: Physiological pathways and pharmacological modalities.
        Can J Anaesth. 2001; 48: 1000-1010
        • Khodorova A.
        • Montmayeur J.P.
        • Strichartz G.
        Endothelin receptors and pain.
        J Pain. 2009; 10: 4-28
        • Loram L.C.
        • Themistocleous A.C.
        • Fick L.G.
        • Kamerman P.R.
        The time course of inflammatory cytokine secretion in a rat model of postoperative pain does not coincide with the onset of mechanical hyperalgesia.
        Can J Physiol Pharmacol. 2007; 85: 613-620
        • Ma W.
        • Bisby M.A.
        Increase of preprotachykinin mRNA and substance P immunoreactivity in spared dorsal root ganglion neurons following partial sciatic nerve injury.
        Eur J Neurosci. 1998; 10: 2388-2399
        • MacLean D.B.
        Adrenocorticotropin-adrenal regulation of transported substance P in the vagus nerve of the rat.
        Endocrinology. 1987; 121: 1540-1547
        • Mantyh P.W.
        Neurobiology of substance P and the NK1 receptor.
        J Clin Psychiatry. 2002; 63: 6-10
        • Navarro X.
        • Vivo M.
        • Valero-Cabre A.
        Neural plasticity after peripheral nerve injury and regeneration.
        Prog Neurobiol. 2007; 82: 163-201
        • Obata K.
        • Noguchi K.
        Contribution of primary sensory neurons and spinal glial cells to pathomechanisms of neuropathic pain.
        Shinkei Kenkyu no Shinpo. 2008; 60 ([in Japanese]): 483-492
        • Papanicolaou D.A.
        • Petrides J.S.
        • Tsigos C.
        • Bina S.
        • Kalogeras K.T.
        • Wilder R.
        • Gold P.W.
        • Deuster P.A.
        • Chrousos G.P.
        Exercise stimulates interleukin-6 secretion: Inhibition by glucocorticoids and correlation with catecholamines.
        Am J Physiol. 1996; 271: E601-E605
        • Papanicolaou D.A.
        • Tsigos C.
        • Oldfield E.H.
        • Chrousos G.P.
        Acute glucocorticoid deficiency is associated with plasma elevations of interleukin-6: Does the latter participate in the symptomatology of the steroid withdrawal syndrome and adrenal insufficiency?.
        J Clin Endocrinol Metab. 1996; 81: 2303-2306
        • Pinto-Ribeiro F.
        • Almeida A.
        • Pego J.M.
        • Cerqueira J.
        • Sousa N.
        Chronic unpredictable stress inhibits nociception in male rats.
        Neurosci Lett. 2004; 359: 73-76
        • Pinto-Ribeiro F.
        • Moreira V.
        • Pego J.M.
        • Leao P.
        • Almeida A.
        • Sousa N.
        Antinociception induced by chronic glucocorticoid treatment is correlated to local modulation of spinal neurotransmitter content.
        Molecular pain. 2009; 5: 41
      1. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines.
        Arthritis Rheum. 2000; 43: 1905-1915
        • Reeve J.
        • Stiller K.
        • Nicol K.
        • McPherson K.M.
        • Birch P.
        • Gordon I.R.
        • Denehy L.
        A postoperative shoulder exercise program improves function and decreases pain following open thoracotomy: A randomised trial.
        J Physiother. 2010; 56: 245-252
        • Richmond C.E.
        • Bromley L.M.
        • Woolf C.J.
        Preoperative morphine pre-empts postoperative pain.
        Lancet. 1993; 342: 73-75
        • Robertson K.
        • Adolfsson P.
        • Riddell M.C.
        • Scheiner G.
        • Hanas R.
        Exercise in children and adolescents with diabetes.
        Pediatr Diabetes. 2008; 9: 65-77
        • Rodriguez M.N.
        • Gomez-Pan A.
        • Arilla E.
        Decrease in number of somatostatin receptors in rat brain after adrenalectomy: Normalization after glucocorticoid replacement.
        Endocrinology. 1988; 123: 1147-1152
        • Rokugo T.
        • Takeuchi T.
        • Ito H.
        A histochemical study of substance P in the rat spinal cord: Effect of transcutaneous electrical nerve stimulation.
        J Nippon Med Sch. 2002; 69: 428-433
        • Sah D.W.
        • Ossipo M.H.
        • Porreca F.
        Neurotrophic factors as novel therapeutics for neuropathic pain.
        Nat Rev Drug Discov. 2003; 2: 460-472
        • Sahbaie P.
        • Shi X.
        • Guo T.Z.
        • Qiao Y.
        • Yeomans D.C.
        • Kingery W.S.
        • Clark J.D.
        Role of substance P signaling in enhanced nociceptive sensitization and local cytokine production after incision.
        Pain. 2009; 145: 341-349
        • Sluka K.A.
        • Westlund K.N.
        Behavioral and immunohistochemical changes in an experimental arthritis model in rats.
        Pain. 1993; 55: 367-377
        • Smith G.D.
        • Harmar A.J.
        • McQueen D.S.
        • Seckl J.R.
        Increase in substance P and CGRP, but not somatostatin content of innervating dorsal root ganglia in adjuvant monoarthritis in the rat.
        Neurosci Lett. 1992; 137: 257-260
        • Smith G.D.
        • Seckl J.R.
        • Sheward W.J.
        • Bennie J.G.
        • Carroll S.M.
        • Dick H.
        • Harmar A.J.
        Effect of adrenalectomy and dexamethasone on neuropeptide content of dorsal root ganglia in the rat.
        Brain Res. 1991; 564: 27-30
        • Stubhaug A.
        • Breivik H.
        • Eide P.K.
        • Kreunen M.
        • Foss A.
        Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery.
        Acta Anaesthesiol Scand. 1997; 41: 1124-1132
        • Svensson C.I.
        • Hua X.Y.
        • Protter A.A.
        • Powell H.C.
        • Yaksh T.L.
        Spinal p38 MAP kinase is necessary for NMDA-induced spinal PGE(2) release and thermal hyperalgesia.
        Neuroreport. 2003; 14: 1153-1157
        • Svensson C.I.
        • Marsala M.
        • Westerlund A.
        • Calcutt N.A.
        • Campana W.M.
        • Freshwater J.D.
        • Catalano R.
        • Feng Y.
        • Protter A.A.
        • Scott B.
        • Yaksh T.L.
        Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing.
        J Neurochem. 2003; 86: 1534-1544
        • Thacker M.A.
        • Clark A.K.
        • Marchand F.
        • McMahon S.B.
        Pathophysiology of peripheral neuropathic pain: Immune cells and molecules.
        Anesth Analg. 2007; 105: 838-847
        • Watkins L.R.
        • Maier S.F.
        Glia: A novel drug discovery target for clinical pain.
        Nat Rev Drug Discov. 2003; 2: 973-985
        • Wei T.
        • Li W.W.
        • Guo T.Z.
        • Zhao R.
        • Wang L.
        • Clark D.J.
        • Oaklander A.L.
        • Schmelz M.
        • Kingery W.S.
        Post-junctional facilitation of substance P signaling in a tibia fracture rat model of complex regional pain syndrome type I.
        Pain. 2009; 144: 278-286
        • Wei X.H.
        • Na X.D.
        • Liao G.J.
        • Chen Q.Y.
        • Cui Y.
        • Chen F.Y.
        • Li Y.Y.
        • Zang Y.
        • Liu X.G.
        The up-regulation of IL-6 in DRG and spinal dorsal horn contributes to neuropathic pain following L5 ventral root transection.
        Exp Neurol. 2013; 241: 159-168
        • Wilkerson J.L.
        • Gentry K.R.
        • Dengler E.C.
        • Wallace J.A.
        • Kerwin A.A.
        • Armijo L.M.
        • Kuhn M.N.
        • Thakur G.A.
        • Makriyannis A.
        • Milligan E.D.
        Intrathecal cannabilactone CB(2)R agonist, AM1710, controls pathological pain and restores basal cytokine levels.
        Pain. 2012; 153: 1091-1106
        • You H.J.
        • Lei J.
        • Sui M.Y.
        • Huang L.
        • Tan Y.X.
        • Tjølsen A.
        • Arendt-Nielsen L.
        Endogenous descending modulation: Spatiotemporal effect of dynamic imbalance between descending facilitation and inhibition of nociception.
        J Physiol. 2010; 588: 4177-4188
        • Zimmermann M.
        Ethical guidelines for investigations of experimental pain in conscious animals.
        Pain. 1983; 16: 109-110
        • Zubrzycka M.
        • Janecka A.
        • Substance P.
        Transmitter of nociception (Minireview).
        Endocr Regul. 2000; 34: 195-201