Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage Michael Costigan, Joachim Scholz, and Clifford J. Woolf Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129 Abstract Neuropathic pain is triggered by lesions to the somatosensory nervous system that alter its structure and function so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified. The pain is an expression of maladaptive plasticity within the nociceptive system, a series of changes that constitute a neural disease state. Multiple alterations distributed widely across the nervous system contribute to complex pain phenotypes. These alterations include ectopic generation of action potentials, facilitation and disinhibition of synaptic transmission, loss of synaptic connectivity and formation of new synaptic circuits, and neuroimmune interactions. Although neural lesions are necessary, they are not sufficient to generate neuropathic pain genetic polymorphisms, gender, and age all influence the risk of developing persistent pain. Treatment needs to move from merely suppressing symptoms to a disease-modifying strategy aimed at both preventing maladaptive plasticity and reducing intrinsic risk. Keywords neural plasticity synaptic facilitation disinhibition neuroimmune interaction pain phenotype INTRODUCTION Diseases affecting the somatosensory nervous system can provoke lasting pain in addition to sensory deficits. (See sidebar, Neuropathic Pain Symtoms.) Here we review the neurobiological mechanisms that operate at multiple sites within the nervous system to produce neuropathic hypersensitivity. To understand the nature and specific features of neuropathic pain (defined in Treede et al. 2008), we first compare it with the other pain syndromes: nociceptive, inflammatory, and dysfunctional pain. NOCICEPTIVE PAIN To guard against tissue injury, it is imperative that the body is aware of potentially damaging stimuli. This awareness is achieved by a noxious stimulus-detecting sensory system (Figure 1). Nociceptive pain is an alarm mediated by high-threshold unmyelinated C or thinly Copyright �� 2009 by Annual Reviews. All rights reserved email: mcostigan@partners.org, scholz.joachim@mgh.harvard.edu, cwoolf@partners.org. DISCLOSURE STATEMENTS C.W. is Chairman of the scientific advisory board of Solace Pharmaceuticals, which develops therapies for neuropathic pain and has licensed submitted patents on tetrahydrobiopterin synthesis and polymorphisms in GCH1 from the Massachusetts General Hospital. He is or has been a consultant/advisor to Hydra Biosciences, Pfizer, Abbott, and GlaxoSmithKline and has received research support from Pfizer and GlaxoSmithKline. J.S. is or has been a consultant to Pfizer and receives or has received research support from Pfizer and GlaxoSmithKline. M.C. is a consultant to Solace Pharmaceuticals. NIH Public Access Author Manuscript Annu Rev Neurosci. Author manuscript available in PMC 2010 January 1. Published in final edited form as: Annu Rev Neurosci. 2009 32: 1���32. doi:10.1146/annurev.neuro.051508.135531. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

myelinated A�� primary sensory neurons that feed into nociceptive pathways of the central nervous system (CNS) (Woolf & Ma 2007). These nociceptor neurons express specialized transducer ion channel receptors, mainly transient receptor potential (TRP) channels, tuned to respond to intense thermal or mechanical stimuli as well as exogenous and endogenous chemical mediators (Dhaka et al. 2006). For nociceptive pain to subserve its protective function, the sensation must be so unpleasant that it cannot be ignored. Nociceptive pain occurs in response to noxious stimuli and continues only in the maintained presence of noxious stimuli (Figures1 and 2). It alerts us to external stimuli, such as pinprick or excessive heat, and internal stimuli, such as myocardial ischemia in patients with coronary artery disease. Certain diseases may generate recurrent or ongoing noxious stimuli to produce chronic nociceptive pain. One example is osteoarthritis: Normal weight bearing in the presence of mechanical deformation of the joint may produce sufficient force to activate high-threshold synovial mechanoreceptors (Torres et al. 2006). Loss of nociception, as in hereditary disorders associated with congenital insensitivity to pain (Cox et al. 2006, Indo 2001), leads to repeated injury and inadvertent self mutilation, illustrating the highly adaptive function of nociceptive pain. INFLAMMATORY PAIN This pain occurs in response to tissue injury and the subsequent inflammatory response. Here the imperative shifts from protecting the body against a potentially damaging noxious stimulus to addressing the consequences of damage. To aid healing and repair of the injured body part, the sensory nervous system undergoes a profound change in its responsiveness normally innocuous stimuli now produce pain and responses to noxious stimuli are both exaggerated and prolonged (Juhl et al. 2008) (Figure 1). Heightened sensitivity occurs within the inflamed area and in contiguous noninflamed areas as a result of plasticity in peripheral nociceptors and central nociceptive pathways (Huang et al. 2006, Hucho & Levine 2007, Woolf & Salter 2000). Because the pain system after inflammation is sensitized, it no longer acts just as a detector for noxious stimuli but can be activated also by low-threshold innocuous inputs (Figures1 and 2). Ablation of a specific set of nociceptor neurons, those expressing the tetrodotoxin-resistant sodium channel Nav1.8, eliminates inflammatory pain but leaves neuropathic pain intact, indicating a fundamental difference in the neuronal pathways responsible for these pain states (Abrahamsen et al. 2008). Typically, inflammatory pain disappears after resolution of the initial tissue injury. However, in chronic disorders such as rheumatoid arthritis the pain persists for as long as inflammation is active (Michaud et al. 2007). MECHANISMS COMMON TO DIFFERENT CHRONIC PAIN STATES Although inflammatory, dysfunctional, and neuropathic pain are distinct in terms of their etiology and clinical features (Figure 1), they have some mechanisms in common. NEUROPATHIC PAIN SYMPTOMS Imagine an excruciating pain every time clothes touch your skin, spontaneous burning that feels like boiling water, bursts of ���pins and needles��� in your feet when you walk, a continuous crushing pain after an amputation as if your phantom foot is being squeezed, a band of searing pain around your body at the level at which you have lost all sensation after a spinal cord injury. These are just some of the devastating symptoms patients with neuropathic pain may experience. Costigan et al. Page 2 Annu Rev Neurosci. Author manuscript available in PMC 2010 January 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Immune Mediator Detection Nociceptors respond directly to cytokines, chemokines, and other inflammatory mediators produced in inflamed tissues (Binshtok et al. 2008). Interleukin-1�� (IL1��), tumor necrosis factor (TNF), bradykinin, and nerve growth factor elicit action potential discharge by increasing sodium and calcium currents at the nociceptor peripheral terminal. After neural damage, these same inflammatory mediators are produced by peripheral immune cells and microglia in the spinal cord and contribute to neuropathic pain by activating nociceptive neurons. Peripheral Sensitization Inflammatory mediators activate intracellular signal transduction pathways in the nociceptor terminal, prompting an increase in the production, transport, and membrane insertion of transducer channels and voltage-gated ion channels. The threshold for activation is reduced and membrane excitability increases (Figure 2). A reduction in thermal and mechanical pain thresholds also occurs in some patients with peripheral nerve lesions, which might reflect nociceptor sensitization owing to increased membrane excitability without inflammation (irritable nociceptors) (Fields et al. 1998). Central Sensitization Central sensitization, a form of use-dependent synaptic plasticity, is a major pathophysiological mechanism common to inflammatory, neuropathic, and dysfunctional pain (Figure 2). Activity generated by nociceptors during inflammation produces rapid-onset homo- and heterosynaptic facilitation in the dorsal horn of the spinal cord. In neuropathic pain, ongoing activity originating in injured nerves is the trigger for central sensitization. In dysfunctional pain, the trigger is unclear. Central sensitization resembles activity-dependent synaptic plasticity in the cortex with involvement of various synaptic modulators and excitatory amino acids, alterations in ion channel kinetics and properties, increased density of ionotropic receptors, and activation of kinases pre- and post-synaptically. The increase in synaptic strength enables previously subthreshold inputs to activate nociceptive neurons, reducing their threshold, enhancing their responsiveness, and expanding their receptive fields. Homosynaptic facilitation of nociceptor inputs in the spinal cord is a form of long-term potentiation (LTP). For heterosynaptic facilitation, the initial input that triggers nociceptor activation is different from the facilitated input. Low-threshold afferents convert to pain drivers, and input outside the injury site is recruited. DYSFUNCTIONAL PAIN The remaining two major pain states, neuropathic pain and a group of clinical syndromes that can best be called dysfunctional pain, are maladaptive in the sense that the pain neither protects nor supports healing and repair (Figure 1). Instead, these pain syndromes are caused by a malfunction of the somatosensory apparatus itself, and this malfunction can be considered a disease in its own right. Dysfunctional pain occurs in situations in which there is no identifiable noxious stimulus nor any detectable inflammation or damage to the nervous system. It is unclear in most cases what causes the manifestation or persistence of dysfunctional pain. In conditions such as fibromyalgia, irritable bowel syndrome, and interstitial cystitis, the pain appears to result from an autonomous amplification of nociceptive signals inside the CNS (Nielsen et al. 2008,Staud & Rodriguez 2006) with a disturbed balance of excitation and inhibition in central circuits (Julien et al. 2005) and altered sensory processing that can be detected by functional imaging (Staud et al. 2008). Dysfunctional pain syndromes share some features of neuropathic pain: temporal summation with a progressive buildup in pain in response to repeated stimuli (windup), spatial diffuseness, and reduced pain thresholds (Staud et al. 2007). Costigan et al. Page 3 Annu Rev Neurosci. Author manuscript available in PMC 2010 January 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Primary erythermalgia and paroxysmal extreme pain disorder, which are caused by gain-of- function mutations in the Nav1.7 voltage-gated sodium channel (Drenth & Waxman 2007), may be considered peripherally mediated dysfunctional pain, but here the molecular causes are known. These mutations are hereditary channelopathies of the peripheral nervous system, which cause pain by ectopic activity of primary sensory neurons due to increased membrane excitability in the absence of axonal lesions or demyelination. NEUROPATHIC PAIN Pain and loss of function are intimately associated with the reaction of the nervous system to neural damage, and both provide important diagnostic clues that such damage has occurred. Peripheral neuropathic pain results from lesions to the peripheral nervous system (PNS) caused by mechanical trauma, metabolic diseases, neurotoxic chemicals, infection, or tumor invasion and involves multiple pathophysiological changes both within the PNS and in the CNS (Dworkin et al. 2003, Woolf & Mannion 1999). Central neuropathic pain most commonly results from spinal cord injury, stroke, or multiple sclerosis (Ducreux et al. 2006). The conventional approach to neuropathic pain has been to classify and treat it on the basis of the underlying disease (Dworkin et al. 2007). However, such an etiological approach does not capture the essential feature of neuropathic pain, which is the manifestation of maladaptive plasticity in the nervous system. The primary disease and the neural damage it causes are only the initiators of a cascade of changes that lead to and sustain neuropathic pain. Although treatment targeted at the primary pathology is obviously essential, understanding the mechanisms responsible for the maladaptive plasticity offers specific therapeutic opportunities to prevent the development of neuropathic hypersensitivity and normalize function in established neuropathic pain. Transformation of Acute Neural Injury to Neuropathic Pain Once neuropathic pain is generated, the sensory hypersensitivity typically persists for prolonged periods, even though the original etiological cause may have long since disappeared, as after nerve trauma. The syndrome can nevertheless progress if the primary disease, such as diabetes mellitus or nerve compression, continues to damage the nervous system. Neuropathic pain is not an inevitable consequence of neural lesions, though. On the contrary, the pain associated with acute neural damage usually transitions to chronic neuropathic pain in a minority of patients. This transition to chronicity is most obvious after surgical nerve lesions where the extent and timing of the lesion are defined (Kehlet et al. 2006). For damage of a relatively small nerve, such as the ilioinguinal nerve during hernia repair, the risk of persistent (more than two years) pain is on the order of ���5% (Kalliomaki et al. 2008), whereas sectioning a large nerve, such as the sciatic nerve or multiple intercostal nerves during thoracotomy, produces sustained neuropathic pain in 30%-60% of patients (Ketz 2008, Maguire et al. 2006). Understanding why one individual develops chronic pain and another with an effectively identical lesion is spared is obviously crucial to developing strategies to abort such transitions. Injury such as brachial avulsion during birth does not produce pain in neonates (Anand & Birch 2002), whereas ���40% of adults develop severe chronic pain when subjected to the same injury (Htut et al. 2006), indicating that neuropathic pain depends in some way on the maturity of the nervous system (Moss et al. 2007). Epidemiological studies on the prevalence of neuropathic pain indicate a high incidence (���5%) (Bouhassira et al. 2008, Dieleman et al. 2008, Torrance et al. 2006). Associated risk factors include gender, age, and anatomical site of the injury. Smaller studies on persistent neuropathic pain after surgery indicate that pain at the time of surgery and the severity of acute postoperative pain increase the incidence of chronic pain (Poleshuck et al. 2006), although it is unclear whether the risk increases because acute postoperative pain was inadequately Costigan et al. Page 4 Annu Rev Neurosci. Author manuscript available in PMC 2010 January 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

managed or individuals who have a higher inherent susceptibility to developing persistent pain also suffer more intense acute pain. Emotional and cognitive factors influence how patients react to chronic pain (Haythornthwaite et al. 2003), but it is much less certain if these factors contribute to the risk of developing pain. Two interdependent processes appear to be major general contributors to developing neuropathic pain: the balance between compensatory and decompensatory reactions of the nervous system to neural damage, and a genetic background that either enhances or protects an individual from the establishment of neuropathic pain. Many of the changes that occur in response to neural injury are potentially adaptive: removal of cell and myelin debris, changes in receptors that counterbalance the loss of input, other alterations that dampen ion fluxes and metabolic stress after the acute injury, recruitment of antiapoptotic survival strategies to prevent neuronal cell death, induction of axonal growth and sprouting, synaptic remodeling, and remyelination (Benn & Woolf 2004, Cafferty et al. 2008). However, many are clearly maladaptive: abnormal stimulus thresholds and sensitivity, ectopic impulse generation, conduction slowing or block, reduced inhibition, inappropriate connectivity, abortive growth, neuronal loss, and glial scarring. Some of these changes occur early after the initial damage and participate in the induction phase of neuropathic pain, others develop later and help maintain the pain, and in some individuals, there may occasionally be a slow resolution. MECHANISMS OF NEUROPATHIC PAIN Major known mechanisms responsible for peripheral neuropathic pain are represented in Figure 3 (Campbell & Meyer 2006,Finnerup et al. 2007a). Much less is understood aboutthe mechanisms underlying central neuropathic pain (Crown et al. 2008,Detloff et al. 2008,Finnerup et al. 2007b). Ectopic Impulse Generation An important feature of neuropathic pain is pain in the absence of an identifiable stimulus. Spontaneous pain arises as a result of ectopic action potential generation within the nociceptive pathways and does not originate in peripheral terminals in response to a stimulus (Figures 2 and 3). Theoretically, ectopic activity could be generated at any anatomical level proximal to those brain regions that mediate the sensory experience. Compelling evidence for peripheral neuropathic pain, however, points to substantial ectopic activity arising in primary sensory neurons. After peripheral nerve damage, spontaneous activity is generated at multiple sites, including in the neuroma (the site of injury with aborted axon growth), in the cell body of injured dorsal root ganglia (DRG) neurons (Amir et al. 2005), and in neighboring intact afferents (Wu et al. 2002). Spontaneous pain may arise both from ectopic activity in nociceptors (Bostock et al. 2005) and from low-threshold large myelinated afferents (Campbell et al. 1988) due to central sensitization and altered connectivity in the spinal cord (Woolf et al. 1992) (Figure 2). After spinal cord injury, spontaneous pain may result from increases in the intrinsic excitability of second-order neurons (Balasubramanyan et al. 2006,Hains & Waxman 2007). Voltage-gated sodium channels contribute largely to the generation of ectopic activity as indicated by the robust inhibitory effects of local anesthetics, which are nonselective sodium channel blockers (Sheets et al. 2008). DRG neurons express several sodium channels that are either sensitive or resistant to tetrodotoxin (TTX) (Fukuoka et al. 2008). However, which of these channels is responsible for the abnormal generation of action potentials is not entirely clear. Studies using gene knockdown with antisense oligonucleotides support a specific role for the Nav1.3 channel, which is upregulated in DRG neurons after nerve injury (Hains et al. 2003), but knockout of the channel fails to alter neuropathic pain-like behavior or ectopic activity (Nassar et al. 2006). On the other hand, preclinical models cannot directly measure Costigan et al. Page 5 Annu Rev Neurosci. Author manuscript available in PMC 2010 January 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript