Neuroinflammation and the generation of neuropathic pain
2013; Elsevier BV; Volume: 111; Issue: 1 Linguagem: Inglês
10.1093/bja/aet128
ISSN1471-6771
Autores Tópico(s)Anesthesia and Pain Management
ResumoSummaryInflammation is the process by which an organism responds to tissue injury involving both immune cell recruitment and mediator release. Diverse causes of neuropathic pain are associated with excessive inflammation in both the peripheral and central nervous system which may contribute to the initiation and maintenance of persistent pain. Chemical mediators, such as cytokines, chemokines, and lipid mediators, released during an inflammatory response have the undesired effect of sensitizing and stimulating nociceptors, their central synaptic targets or both. These changes can promote long-term maladaptive plasticity resulting in persistent neuropathic pain. This review aims to provide an overview of inflammatory mechanisms at differing levels of the sensory neuroaxis with a focus on neuropathic pain. We will compare and contrast neuropathic pain states such as traumatic nerve injury which is associated with a vigorous inflammatory response and chemotherapy induced pain in which the inflammatory response is much more modest. Targeting excessive inflammation in neuropathic pain provides potential therapeutic opportunities and we will discuss some of the opportunities but also the clinical challenges in such an approach. Inflammation is the process by which an organism responds to tissue injury involving both immune cell recruitment and mediator release. Diverse causes of neuropathic pain are associated with excessive inflammation in both the peripheral and central nervous system which may contribute to the initiation and maintenance of persistent pain. Chemical mediators, such as cytokines, chemokines, and lipid mediators, released during an inflammatory response have the undesired effect of sensitizing and stimulating nociceptors, their central synaptic targets or both. These changes can promote long-term maladaptive plasticity resulting in persistent neuropathic pain. This review aims to provide an overview of inflammatory mechanisms at differing levels of the sensory neuroaxis with a focus on neuropathic pain. We will compare and contrast neuropathic pain states such as traumatic nerve injury which is associated with a vigorous inflammatory response and chemotherapy induced pain in which the inflammatory response is much more modest. Targeting excessive inflammation in neuropathic pain provides potential therapeutic opportunities and we will discuss some of the opportunities but also the clinical challenges in such an approach. Editor's key points•There is increasing evidence of the role of inflammatory processes in neuropathic pain.•Peripheral inflammatory mediators can sensitize the nervous system, both peripherally, and centrally.•Central glial cells may enhance excitability within the spinal cord and alter central processing.•Understanding these processes better may lead to potentially novel therapeutic targets for neuropathic pain. •There is increasing evidence of the role of inflammatory processes in neuropathic pain.•Peripheral inflammatory mediators can sensitize the nervous system, both peripherally, and centrally.•Central glial cells may enhance excitability within the spinal cord and alter central processing.•Understanding these processes better may lead to potentially novel therapeutic targets for neuropathic pain. Inflammation is the process by which an organism responds to tissue injury and involves both immune cell recruitment and mediator release. It is an attempt to remove the injurious stimulus and initiate healing. The inflammatory response consists of a pro-inflammatory phase in which any pathogens are removed, damaged cells and debris cleared, and the local homeostasis restored. After this, there is a phase of resolution in which there is local tissue repair and the potentially damaging effects of a continued inflammatory response are dissipated.1Medzhitov R Origin and physiological roles of inflammation.Nature. 2008; 454: 428-435doi:10.1038/nature07201Crossref PubMed Scopus (1728) Google Scholar 2Serhan CN Chiang N Van Dyke TE Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.Nat Rev Immunol. 2008; 8: 349-361doi:10.1038/nri2294Crossref PubMed Scopus (1319) Google Scholar Several cell types mediate the immune response with temporally distinct contributions. The immune response is recruited and mediated via the release of a range of chemical mediators, many of which have similar effects. These mediators can be classified into seven subgroups, listed in Table 1 along with some examples from each group.1Medzhitov R Origin and physiological roles of inflammation.Nature. 2008; 454: 428-435doi:10.1038/nature07201Crossref PubMed Scopus (1728) Google ScholarTable 1Examples of inflammatory mediators of the immune response shown to have a role in the generation of behavioural hypersensitivity after peripheral nerve injuryMediator classExampleCell typesActionVasoactive aminesHistamine 5-HTMast cells,117Galli SJ Nakae S Tsai M Mast cells in the development of adaptive immune responses.Nat Immunol. 2005; 6: 135-142doi:10.1038/ni1158Crossref PubMed Scopus (809) Google Scholar sensory nerve terminals118Julius D Basbaum AI Molecular mechanisms of nociception.Nature. 2001; 413: 203-210doi:10.1038/35093019Crossref PubMed Scopus (1460) Google ScholarIncreased vascular permeability1Medzhitov R Origin and physiological roles of inflammation.Nature. 2008; 454: 428-435doi:10.1038/nature07201Crossref PubMed Scopus (1728) Google Scholar Direct nociceptive action on sensory terminals14Smith FM Haskelberg H Tracey DJ Moalem-Taylor G Role of histamine H3 and H4 receptors in mechanical hyperalgesia following peripheral nerve injury.Neuroimmunomodulation. 2007; 14: 317-325doi:10.1159/000125048Crossref PubMed Scopus (0) Google Scholar 118Julius D Basbaum AI Molecular mechanisms of nociception.Nature. 2001; 413: 203-210doi:10.1038/35093019Crossref PubMed Scopus (1460) Google ScholarVasoactive peptidesSubstance P BradykininMast cells,117Galli SJ Nakae S Tsai M Mast cells in the development of adaptive immune responses.Nat Immunol. 2005; 6: 135-142doi:10.1038/ni1158Crossref PubMed Scopus (809) Google Scholar sensory nerve terminals118Julius D Basbaum AI Molecular mechanisms of nociception.Nature. 2001; 413: 203-210doi:10.1038/35093019Crossref PubMed Scopus (1460) Google Scholar Mast cells117Galli SJ Nakae S Tsai M Mast cells in the development of adaptive immune responses.Nat Immunol. 2005; 6: 135-142doi:10.1038/ni1158Crossref PubMed Scopus (809) Google ScholarIncreased vascular permeability1Medzhitov R Origin and physiological roles of inflammation.Nature. 2008; 454: 428-435doi:10.1038/nature07201Crossref PubMed Scopus (1728) Google Scholar Direct nociceptive action on sensory terminals (SP and BK), modulation of TRPV1 channel kinetics (BK)21Gonzalez HL Carmichael N Dostrovsky JO Charlton MP Evaluation of the time course of plasma extravasation in the skin by digital image analysis.J Pain. 2005; 6: 681-688doi:10.1016/j.jpain.2005.06.004Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar 119Katanosaka K Banik RK Giron R Higashi T Tominaga M Mizumura K Contribution of TRPV1 to the bradykinin-evoked nociceptive behavior and excitation of cutaneous sensory neurons.Neurosci Res. 2008; 62: 168-175doi:10.1016/j.neures.2008.08.004Crossref PubMed Scopus (0) Google ScholarFragments of complement componentComplement C3a Complement C5aProteins synthesized in the liver. Receptors expressed in mast cells, T cells, macrophages, and microglia120Carroll MC The complement system in regulation of adaptive immunity.Nat Immunol. 2004; 5: 981-986doi:10.1038/ni1113Crossref PubMed Scopus (602) Google ScholarInduce mast cell degranulation120Carroll MC The complement system in regulation of adaptive immunity.Nat Immunol. 2004; 5: 981-986doi:10.1038/ni1113Crossref PubMed Scopus (602) Google Scholar Chemotactic for neutrophils, lymphocytes, macrophages, and microglia120Carroll MC The complement system in regulation of adaptive immunity.Nat Immunol. 2004; 5: 981-986doi:10.1038/ni1113Crossref PubMed Scopus (602) Google Scholar intrathecal administration induces cold hypersensitivity121Griffin RS Costigan M Brenner GJ et al.Complement induction in spinal cord microglia results in anaphylatoxin C5a-mediated pain hypersensitivity.J Neurosci. 2007; 27: 8699-8708doi:10.1523/JNEUROSCI.2018-07.2007Crossref PubMed Scopus (0) Google ScholarLipid mediatorsprostaglandin E2 (PGE2), prostaglandin I2 (PGI2)All cell types capable122Kalinski P Regulation of immune responses by prostaglandin E2.J Immunol. 2012; 188: 21-28doi:10.4049/jimmunol.1101029Crossref PubMed Scopus (439) Google ScholarVasodilatation, indirect recruitment of immune response (via increased production of chemoattractants), mast cell degranulation122Kalinski P Regulation of immune responses by prostaglandin E2.J Immunol. 2012; 188: 21-28doi:10.4049/jimmunol.1101029Crossref PubMed Scopus (439) Google Scholar Promotion of synthesis of lipoxins and resolvins2Serhan CN Chiang N Van Dyke TE Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.Nat Rev Immunol. 2008; 8: 349-361doi:10.1038/nri2294Crossref PubMed Scopus (1319) Google Scholar Direct nociceptive action on sensory terminals24Taiwo YO Levine JD Prostaglandin effects after elimination of indirect hyperalgesic mechanisms in the skin of the rat.Brain Res. 1989; 492: 397-399doi:10.1016/0006-8993(89)90928-1Crossref PubMed Google Scholar 117Galli SJ Nakae S Tsai M Mast cells in the development of adaptive immune responses.Nat Immunol. 2005; 6: 135-142doi:10.1038/ni1158Crossref PubMed Scopus (809) Google ScholarLipoxins ResolvinsAll cell types capable2Serhan CN Chiang N Van Dyke TE Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.Nat Rev Immunol. 2008; 8: 349-361doi:10.1038/nri2294Crossref PubMed Scopus (1319) Google ScholarStop neutrophil and mast cell infiltration, activate macrophage phagocytosis of apoptotic cells, promote the departure of phagocytes from inflammation site2Serhan CN Chiang N Van Dyke TE Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators.Nat Rev Immunol. 2008; 8: 349-361doi:10.1038/nri2294Crossref PubMed Scopus (1319) Google Scholar Indirectly antinociceptive: intrathecal Resolvin E1 prevents peripheral nerve injury-induced microgliosis,107Xu ZZ Berta T Ji RR Resolvin E1 inhibits neuropathic pain and spinal cord microglial activation following peripheral nerve injury.J Neuroimmune Pharmacol. 2012; 8: 37-41Crossref PubMed Scopus (33) Google Scholar intrathecal LipoxinA(4) prevents behavioural hypersensitivity in chronic compression of DRG model of neuropathic pain123Sun T Yu E Yu L Luo J Li H Fu Z LipoxinA(4) induced antinociception and decreased expression of NF-kappaB and pro-inflammatory cytokines after chronic dorsal root ganglia compression in rats.Eur J Pain. 2012; 16: 18-27doi:10.1016/j.ejpain.2011.05.005Crossref PubMed Google ScholarCytokinesIL-1β TNF-α IL-6Schwann cells, mast cells, neutrophils, lymphocytes, macrophages, microglia, and astrocytes1Medzhitov R Origin and physiological roles of inflammation.Nature. 2008; 454: 428-435doi:10.1038/nature07201Crossref PubMed Scopus (1728) Google Scholar 15Kumar V Sharma A Neutrophils: Cinderella of innate immune system.Int Immunopharmacol. 2010; 10: 1325-1334doi:10.1016/j.intimp.2010.08.012Crossref PubMed Scopus (159) Google Scholar 117Galli SJ Nakae S Tsai M Mast cells in the development of adaptive immune responses.Nat Immunol. 2005; 6: 135-142doi:10.1038/ni1158Crossref PubMed Scopus (809) Google Scholar 124Hanisch UK Kettenmann H Microglia: active sensor and versatile effector cells in the normal and pathologic brain.Nat Neurosci. 2007; 10: 1387-1394doi:10.1038/nn1997Crossref PubMed Scopus (1724) Google Scholar 125Hald A Spinal astrogliosis in pain models: cause and effects.Cell Mol Neurobiol. 2009; 29: 609-619doi:10.1007/s10571-009-9390-6Crossref PubMed Scopus (0) Google ScholarEffects on transcription via NFκB, p38, JNK pathways IL-1β: wide variety of functions, including effects on appetite, sleep, and body temperature127Ren K Torres R Role of interleukin-1beta during pain and inflammation.Brain Res Rev. 2009; 60: 57-64doi:10.1016/j.brainresrev.2008.12.020Crossref PubMed Scopus (145) Google Scholar Indirect nociceptive actions via promotion of synthesis of inflammatory mediators130Subang MC Richardson PM Influence of injury and cytokines on synthesis of monocyte chemoattractant protein-1 mRNA in peripheral nervous tissue.Eur J Neurosci. 2001; 13: 521-528doi:10.1046/j.1460-9568.2001.01425.xCrossref PubMed Scopus (0) Google Scholar Direct actions sensitizing nociceptors27Binshtok AM Wang H Zimmermann K et al.Nociceptors are interleukin-1beta sensors.J Neurosci. 2008; 28: 14062-14073doi:10.1523/JNEUROSCI.3795-08.2008Crossref PubMed Scopus (233) Google Scholar 95Kawasaki Y Zhang L Cheng JK Ji RR Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord.J Neurosci. 2008; 28: 5189-5194doi:10.1523/JNEUROSCI.3338-07.2008Crossref PubMed Scopus (489) Google Scholar 126Leung L Cahill CM TNF-alpha and neuropathic pain–a review.J Neuroinflammation. 2010; 7: 27doi:10.1186/1742-2094-7-27Crossref PubMed Scopus (0) Google Scholar, 127Ren K Torres R Role of interleukin-1beta during pain and inflammation.Brain Res Rev. 2009; 60: 57-64doi:10.1016/j.brainresrev.2008.12.020Crossref PubMed Scopus (145) Google Scholar, 128Oka T Aou S Hori T Intracerebroventricular injection of interleukin-1 beta enhances nociceptive neuronal responses of the trigeminal nucleus caudalis in rats.Brain Res. 1994; 656: 236-244doi:10.1016/0006-8993(94)91466-4Crossref PubMed Scopus (0) Google Scholar TNF-α enhances excitatory currents, IL-6 reduces inhibitory currents, IL-1β enhances excitatory currents and reduces inhibitory currents. IL-1β directly sensitizes TRPV1 receptorsChemokinesMCP-1 (CCL2)Schwann cells, neutrophils, mast cells, macrophages, microglia, astrocytes, and neuron15Kumar V Sharma A Neutrophils: Cinderella of innate immune system.Int Immunopharmacol. 2010; 10: 1325-1334doi:10.1016/j.intimp.2010.08.012Crossref PubMed Scopus (159) Google Scholar 117Galli SJ Nakae S Tsai M Mast cells in the development of adaptive immune responses.Nat Immunol. 2005; 6: 135-142doi:10.1038/ni1158Crossref PubMed Scopus (809) Google Scholar 129Flugel A Hager G Horvat A et al.Neuronal MCP-1 expression in response to remote nerve injury.J Cereb Blood flow Metab. 2001; 21: 69-76doi:10.1097/00004647-200101000-00009Crossref PubMed Google Scholar, 130Subang MC Richardson PM Influence of injury and cytokines on synthesis of monocyte chemoattractant protein-1 mRNA in peripheral nervous tissue.Eur J Neurosci. 2001; 13: 521-528doi:10.1046/j.1460-9568.2001.01425.xCrossref PubMed Scopus (0) Google Scholar, 131Gao YJ Zhang L Samad OA et al.JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain.J Neurosci. 2009; 29: 4096-4108doi:10.1523/JNEUROSCI.3623-08.2009Crossref PubMed Scopus (281) Google ScholarRecruitment of monocytes Indirect nociceptive action: activation of microglia after peripheral nerve injury,132Thacker MA Clark AK Bishop T et al.CCL2 is a key mediator of microglia activation in neuropathic pain states.Eur J Pain. 2009; 13: 263-272doi:10.1016/j.ejpain.2008.04.017Crossref PubMed Scopus (0) Google Scholar 133Abbadie C Lindia JA Cumiskey AM et al.Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2.Proc Natl Acad Sci USA. 2003; 100: 7947-7952doi:10.1073/pnas.1331358100Crossref PubMed Scopus (398) Google Scholar and disruption of blood–spinal cord barrier58Echeverry S Shi XQ Rivest S Zhang J Peripheral nerve injury alters blood-spinal cord barrier functional and molecular integrity through a selective inflammatory pathway.J Neurosci. 2011; 31: 10819-10828doi:10.1523/JNEUROSCI.1642-11.2011Crossref PubMed Scopus (100) Google ScholarFractalkine (CX3CL1)Neurons.134Kiguchi N Kobayashi Y Kishioka S Chemokines and cytokines in neuroinflammation leading to neuropathic pain.Curr Opin Pharmacol. 2012; 12: 55-61doi:10.1016/j.coph.2011.10.007Crossref PubMed Scopus (0) Google Scholar Receptors predominantly on macrophages and microgliaIndirect nociceptive action via microglial activation97Clark AK Yip PK Malcangio M The liberation of fractalkine in the dorsal horn requires microglial cathepsin S.J Neurosci. 2009; 29: 6945-6954doi:10.1523/JNEUROSCI.0828-09.2009Crossref PubMed Scopus (101) Google Scholar 135Clark AK Yip PK Grist J et al.Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain.Proc Natl Acad Sci USA. 2007; 104: 10655-10660doi:10.1073/pnas.0610811104Crossref PubMed Scopus (259) Google ScholarProteolytic enzymesMMP-9Schwann cells, neutrophils, and neurons136Kawasaki Y Xu ZZ Wang X et al.Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain.Nat Med. 2008; 14: 331-336doi:10.1038/nm1723Crossref PubMed Scopus (0) Google Scholar 137Shubayev VI Angert M Dolkas J Campana WM Palenscar K Myers RR TNFalpha-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve.Mol Cell Neurosci. 2006; 31: 407-415doi:10.1016/j.mcn.2005.10.011Crossref PubMed Scopus (0) Google ScholarDegradation of myelin basic protein, macrophage recruitment137Shubayev VI Angert M Dolkas J Campana WM Palenscar K Myers RR TNFalpha-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve.Mol Cell Neurosci. 2006; 31: 407-415doi:10.1016/j.mcn.2005.10.011Crossref PubMed Scopus (0) Google Scholar 138Kobayashi H Chattopadhyay S Kato K et al.MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage.Mol Cell Neurosci. 2008; 39: 619-627doi:10.1016/j.mcn.2008.08.008Crossref PubMed Scopus (0) Google Scholar Indirect nociceptive actions via degradation of myelin,138Kobayashi H Chattopadhyay S Kato K et al.MMPs initiate Schwann cell-mediated MBP degradation and mechanical nociception after nerve damage.Mol Cell Neurosci. 2008; 39: 619-627doi:10.1016/j.mcn.2008.08.008Crossref PubMed Scopus (0) Google Scholar and cleavage of pro-IL-1β136Kawasaki Y Xu ZZ Wang X et al.Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain.Nat Med. 2008; 14: 331-336doi:10.1038/nm1723Crossref PubMed Scopus (0) Google ScholarCathepsin SMacrophages, microglia135Clark AK Yip PK Grist J et al.Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain.Proc Natl Acad Sci USA. 2007; 104: 10655-10660doi:10.1073/pnas.0610811104Crossref PubMed Scopus (259) Google Scholar 139Liuzzo JP Petanceska SS Devi LA Neurotrophic factors regulate cathepsin S in macrophages and microglia: a role in the degradation of myelin basic protein and amyloid beta peptide.Mol Med. 1999; 5: 334-343PubMed Google ScholarIndirect nociceptive action via cleavage of membrane-bound fractalkine, which in turn activates microglia and macrophages140Barclay J Clark AK Ganju P et al.Role of the cysteine protease cathepsin S in neuropathic hyperalgesia.Pain. 2007; 130: 225-234doi:10.1016/j.pain.2006.11.017Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Open table in a new tab Inflammation is a key biological process and, consequently, its role is not restricted to mounting a response to infection; inflammatory processes play a key role in diverse disease states such as cancer biology and diabetes. It is increasingly recognized that the immune system interacts with the sensory nervous system contributing to persistent pain states.3Calvo M Dawes JM Bennett DL The role of the immune system in the generation of neuropathic pain.Lancet Neurol. 2012; 11: 629-642doi:10.1016/S1474-4422(12)70134-5Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 4Scholz J Woolf CJ The neuropathic pain triad: neurons, immune cells and glia.Nat Neurosci. 2007; 10: 1361-1368doi:10.1038/nn1992Crossref PubMed Scopus (900) Google Scholar, 5Marchand F Perretti M McMahon SB Role of the immune system in chronic pain.Nat Rev Neurosci. 2005; 6: 521-532doi:10.1038/nrn1700Crossref PubMed Scopus (678) Google Scholar Inflammation is a well-established cause of nociceptive pain whether attributable to autoimmunity (e.g. rheumatoid arthritis) or chemical mediators (e.g. gout). Neuropathic pain is distinct from nociceptive pain, arising as a consequence of a lesion or disease of the somatosensory system.6Treede RD Jensen TS Campbell JN et al.Neuropathic pain: redefinition and a grading system for clinical and research purposes.Neurology. 2008; 70: 1630-1635doi:10.1212/01.wnl.0000282763.29778.59Crossref PubMed Scopus (1304) Google Scholar In certain cases, this lesion may be attributable to an aberrant immune response resulting in excessive neuroinflammation of the peripheral (e.g. Guillain–Barré syndrome) or central (e.g. multiple sclerosis) nervous system. Both of these conditions are associated with a high prevalence of neuropathic pain.7Solaro C Brichetto G Amato MP et al.The prevalence of pain in multiple sclerosis: a multicenter cross-sectional study.Neurology. 2004; 63: 919-921doi:10.1212/01.WNL.0000137047.85868.D6Crossref PubMed Google Scholar 8Ruts L Drenthen J Jongen JL et al.Pain in Guillain-Barre syndrome: a long-term follow-up study.Neurology. 2010; 75: 1439-1447doi:10.1212/WNL.0b013e3181f88345Crossref PubMed Scopus (0) Google Scholar In addition, many diverse causes of neuropathic pain (e.g. traumatic neuropathy and spinal cord injury) are in themselves associated with excessive inflammation which may be involved in both the initiation and maintenance of persistent pain. This review provides an overview of inflammatory mechanisms at differing levels of the sensory neuroaxis shown to play a role in persistent pain states, with a focus on neuropathic pain. Although the inflammatory response is likely to differ depending on the physiological situation, an overview of the stages of an inflammatory response is illustrated in Figure 1. Damage to the peripheral nerve leads to a local inflammatory response which contributes to the generation of behavioural hypersensitivity. The first cells to react to damage of the nerve are Schwann cells and resident immune cells such as mast cells and macrophages. An as yet unspecified signal from damaged axons results in activation of the extracellular signal-related (ERK) mitogen-activated protein kinase (MAP) kinase signalling pathway in Schwann cells; this is one of the earliest events triggering the expression of inflammatory mediators and recruiting immune cells to the damaged nerve.9Napoli I Noon LA Ribeiro S et al.A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo.Neuron. 2012; 73: 729-742doi:10.1016/j.neuron.2011.11.031Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Myelinating Schwann cells dedifferentiate and begin the process of degrading the myelin sheath at the site of injury, a necessary prerequisite for regeneration.10Allodi I Udina E Navarro X Specificity of peripheral nerve regeneration: interactions at the axon level.Prog Neurobiol. 2012; 98: 16-37doi:10.1016/j.pneurobio.2012.05.005Crossref PubMed Scopus (136) Google Scholar Resident mast cells degranulate releasing inflammatory mediators, including histamine, serotonin, nerve growth factor, and leukotrienes, which can sensitize nociceptors and also contribute to the recruitment of neutrophils, the first cells to infiltrate damaged tissue.11Perkins NM Tracey DJ Hyperalgesia due to nerve injury: role of neutrophils.Neuroscience. 2000; 101: 745-757doi:10.1016/S0306-4522(00)00396-1Crossref PubMed Scopus (123) Google Scholar, 12Zuo Y Perkins NM Tracey DJ Geczy CL Inflammation and hyperalgesia induced by nerve injury in the rat: a key role of mast cells.Pain. 2003; 105: 467-479doi:10.1016/S0304-3959(03)00261-6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 13Kim CF Moalem-Taylor G Detailed characterization of neuro-immune responses following neuropathic injury in mice.Brain Res. 2011; 1405: 95-108doi:10.1016/j.brainres.2011.06.022Crossref PubMed Scopus (50) Google Scholar, 14Smith FM Haskelberg H Tracey DJ Moalem-Taylor G Role of histamine H3 and H4 receptors in mechanical hyperalgesia following peripheral nerve injury.Neuroimmunomodulation. 2007; 14: 317-325doi:10.1159/000125048Crossref PubMed Scopus (0) Google Scholar Mast cell stabilization with sodium cromoglycate reduces the infiltration of neutrophils to the injured nerve and suppresses the development of thermal and mechanical hypersensitivity, highlighting the importance of the early immune response in the neuropathic pain development.12Zuo Y Perkins NM Tracey DJ Geczy CL Inflammation and hyperalgesia induced by nerve injury in the rat: a key role of mast cells.Pain. 2003; 105: 467-479doi:10.1016/S0304-3959(03)00261-6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Similarly, using an anti-neutrophil antibody to deplete circulating neutrophils at the time of injury has been shown to significantly attenuate subsequent behavioural hypersensitivity.11Perkins NM Tracey DJ Hyperalgesia due to nerve injury: role of neutrophils.Neuroscience. 2000; 101: 745-757doi:10.1016/S0306-4522(00)00396-1Crossref PubMed Scopus (123) Google Scholar Neutrophil infiltration to the site of injury is acute, peaking within the first few hours after injury and declining after 3 days, though levels remain elevated. Neutrophils release mediators capable of sensitizing nociceptors, and recruiting macrophages and T cells to the injury site.15Kumar V Sharma A Neutrophils: Cinderella of innate immune system.Int Immunopharmacol. 2010; 10: 1325-1334doi:10.1016/j.intimp.2010.08.012Crossref PubMed Scopus (159) Google Scholar 16Moalem G Xu K Yu L T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats.Neuroscience. 2004; 129: 767-777doi:10.1016/j.neuroscience.2004.08.035Crossref PubMed Scopus (140) Google Scholar Recruited infiltrating macrophages join the resident macrophages and, along with Schwann cells, take part in the phagocytosis of degenerating axons and myelin sheaths. In addition to this function, they secrete a myriad of pro-inflammatory cytokines/chemokines, and lipid mediators.17Nathan CF Secretory products of macrophages.J Clin Invest. 1987; 79: 319-326doi:10.1172/JCI112815Crossref PubMed Google Scholar Depletion of the circulating population of macrophages via the administration of liposomes containing clodronate reduces behavioural hypersensitivity after peripheral nerve injury.18Liu T van Rooijen N Tracey DJ Depletion of macrophages reduces axonal degeneration and hyperalgesia following nerve injury.Pain. 2000; 86: 25-32doi:10.1016/S0304-3959(99)00306-1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar T cells are characterized by the expression of surface molecules and broadly grouped into T-helper cells or cytotoxic T cells. T-helper cells, dependent on their class, release pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-17, and also anti-inflammatory cytokines such as IL-4 and IL-10.19Palmer MT Weaver CT Autoimmunity: increasing suspects in the CD4+ T cell lineup.Nat Immunol. 2010; 11: 36-40doi:10.1038/ni.1802Crossref PubMed Scopus (0) Google Scholar (For expansion of the abbreviations used in this article, please see the Appendix.) In addition to the release of inflammatory mediators from infiltrating immune cells, the sensory nerve terminals release neuropeptides such as Substance P and Calcitonin Gene Related Peptide (CGRP) upon antidromic conduction of impulses. These vasoactive peptides enhance the immune response by increasing vascular permeability and also directly interact with immune cells such as Langerhan's cells and macrophages.20Torii H Hosoi J Beissert S et al.Regulation of cytokine expression in macrophages and the Langerhans cell-like line XS52 by calcitonin gene-related peptide.J Leukoc Biol. 1997; 61: 216-223Crossref PubMed Scopus (0) Google Scholar Additionally, they may feedback and sensitize primary afferent neurons.21Gonzalez HL Carmichael N Dostrovsky JO Charlton MP Evaluation of the time course of plasma extravasation in the skin by digital image analysis.J Pain. 2005; 6: 681-688doi:10.1016/j.jpain.2005.06.004Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The chemical mediators released by various cells of the peripheral immune response after nerve injury have the undesired effect of sensitizing and stimulating nociceptors. In the short term, this is necessary to alert the individual of damage and promote rest. However, in the case of neuropathic pain, this can promote long-term deleterious plastic changes. Table 1 lists some examples of inflammatory mediators of the immune response shown to have a role in the generation of behavioural hypersensitivity after peripheral nerve injury. The change in the local chemical milieu brought about by the inflammatory response not only has actions on damaged, degenerating neurons, but also on the neighbouring uninjured afferents sharing the same innervation territory. As a result, these ‘spared’ fibres exhibit spontaneous activity, an important driver of neuropathic pain.22Ma C Shu Y Zheng Z et al.Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons.J Neurophysiol. 2003; 89: 1588-1602doi:10.1152/jn.00855.2002Crossref PubMed Scopus (0) Google Scholar 23Wu G Ringkamp M Murinson BB et al.Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents.J Neurosci. 2002; 22: 7746-7753Crossref PubMed Google Scholar The actio
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