Introduction

The word pain shares its etymological origin with the words punishment and penalty. Some terms relating to pain states are defined in Box 1. Although an unpleasant sensation, nociceptive pain serves a fundamental evolutionary function to warn that bodily harm has occurred or is imminent. This warning signal occurs in parallel with tactile and proprioceptive sensations; if alarm and motor withdrawal are appropriate responses, it is important to know which body parts to withdraw. The sensory threshold for interoceptive monitoring is usually high enough that distinctions can be made between stimuli that are benign and those that are sufficiently harmful to require a protective response. Nonetheless, pain can occur spontaneously (in the absence of evocative stimuli) or result from hypersensitivity to a stimulus. The perception of pain is the result of neural integration and processing of sensory information that is generally initiated in the periphery and transferred centrally to the cortex—although in neuropathic states this process can occur in reverse.

Rheumatoid arthritis (RA) is a chronic inflammatory condition in which joint pain is a common clinical manifestation. Rheumatologic pain presents a special challenge, in that joints are densely innervated. Our maintenance of balance and the normal use of our hands and limbs are dependent upon the sensory input we receive from our joints. This innervation, however, also includes the presence of nociceptors surrounding the joint. Thus, any joint pathology, whether acute or chronic, can produce severe pain resulting from sensitization of primary afferent nociceptive neurons.

In this article we review the molecular pathways involved in the pain signaling that occurs in response to noxious stimuli. We also present information on how pain signaling processes become recruited and co-opted in the production of inflammatory and rheumatic pain. We limit our examination of pathologic pain to inflammatory and rheumatic pain states (since to address neuropathic pain is beyond the scope of this article) and consider possibilities for pharmacotherapeutic intervention in relation to these states.

Nociceptive pain

For the perception of pain to serve its evolutionarily adaptive function, thermal, mechanical and chemical stimuli need to be recognized as potentially dangerous. Transduction—translation of noxious stimuli into electrochemical activity—begins with the depolarization of the peripheral terminals of high-threshold primary sensory neurons, with the resulting action potentials (APs) conducted to the central nervous system (CNS) by the axons of primary afferent sensory neurons. Secondary projection neurons in the dorsal horn transmit information to the brainstem and thalamus, which relay the signal to the cortex, hypothalamus and limbic system. Transmission of the pain signal is modulated at all levels of the nervous system by inhibitory and excitatory interneurons1,2 (Figure 1).

Figure 1: The nociceptive pain pathway.
figure 1

Activation of peripheral pain receptors (also called nociceptors) by noxious stimuli generates signals that travel to the dorsal horn of the spinal cord via the dorsal root ganglion. From the dorsal horn, the signals are carried along the ascending pain pathway or the spinothalamic tract to the thalamus and the cortex. Pain can be controlled by pain-inhibiting and pain-facilitating neurons. Descending signals originating in supraspinal centers can modulate activity in the dorsal horn by controlling spinal pain transmission. Abbreviation: CNS, central nervous system.

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Stimulation of primary sensory neurons

Axons of primary afferent neurons produce APs in response to thermal, mechanical and chemical stimuli that conduct sensory information from the peripheral terminal to the CNS. These axons are classified into three major groups, primarily according to their conduction velocity and major activating stimuli, although all subtypes have multiple sensory functions. First, rapidly conducting (>30 m/s), myelinated Aβ fibers have a low threshold of response, mainly conduct innocuous tactile stimuli (e.g., mild mechanical and thermal cues) and are involved in reflex responses. The two other subtypes, Aδ and C fibers, are primarily nociceptors and have a higher threshold of activation, which means they principally respond to stimuli of sufficient intensity that tissue damage might ensue. The Aδ fibers are thinly myelinated and C fibers are unmyelinated, leading to moderate (2–30 m/s) and slow (≤2 m/s) conduction, respectively, and together they constitute the majority of sensory neurons in the peripheral nervous system. Given the functional diversity and polymodal nature of nociceptors, each subtype is not restricted to conducting a certain quality of pain.3

Highly specialized ion channels expressed on primary afferent neurons mediate APs. Information regarding the onset, intensity and location of the stimulus is transferred to the CNS via the firing frequency and duration of the AP in the activated fibers. Responses to thermal stimuli involve thermosensitive cation channels, particularly members of the transient receptor potential (TRP) family, which perceive changes in temperature and extracellular pH and the presence of vanilloid ligands, such as capsaicin and mustard oil.4 The thermosensitive TRP family constitutes an interface with the environment and includes a number of diverse channels, each with a distinct thermal threshold and a different set of chemical activators (Table 1).

Table 1 Mammalian sensory transient receptor potential channels.
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Intense mechanical stimulation, such as a pinch or pinprick, brings about activation of a specific subpopulation of primary afferent terminals known as high-threshold mechanoreceptors. Among the ion channels implicated in mechanoreceptor function are members of the degenerin epithelial sodium channel (ENaC) family,5,6 and the acid-sensing ion channel (ASIC) family, of which ASIC3 has been implicated in the perception of noxious mechanical stimulation in mammals.7 ASICs also have a part in sensing the tissue damage that results in the release of protons from injured cells. For instance, ASIC3 mediates the intense pain associated with cardiac ischemia.8 Tissue damage also results in the release of high concentrations of ATP, which can act on ligand-gated purinergic P2X2 and P2X3 channels and the P2Y2 receptor to activate nociceptors.9 A range of nociceptors involved in high-threshold transduction10 display combinative properties in their functioning; for example, perception of a single stimulus, such as heat, requires multiple transduction mechanisms, while some sensory proteins participate in multiple perceptual modalities, such as temperature and touch.11

Sensory conduction

Voltage-gated sodium channels (VGSCs) are critical for the initiation of APs in the peripheral terminals of nociceptors and conduction along axons in peripheral nerves to the spinal cord. VGSCs are proteins composed of a large α subunit and two smaller β subunits. Of the nine mammalian α subunits (Nav1.1–1.9), six are expressed by primary sensory neurons—tetrodotoxin (TTX)-sensitive Nav1.1, Nav1.2, Nav1.6 and Nav1.7 and the TTX-resistant Nav1.812 and Nav1.9.13 These last two are expressed almost exclusively by dorsal root ganglion neurons.

VGSCs allow sodium ion influx in response to local membrane depolarization, such as the potential generated in the peripheral terminals of nociceptors.14 Different roles have been attributed to each sodium channel in influencing neuronal excitability, often associated with expression in specific subclasses of dorsal root ganglion neurons. Thus, Nav1.8 might be the major contributor to AP upstroke and repetitive firing in small neurons, whereas activation of Nav1.7 produces ramp current and amplifies small depolarizing stimuli.15

VGSCs are highly expressed on the primary afferent neurons that innervate joints. Hyperalgesia can result from abnormal or inappropriate spontaneous activity of these VGSCs, changes in channel expression, the influence of channel auxiliary subunits,15,16 edema, or the presence of inflammatory mediators in the synovial fluid. VGSCs in the resting state open in response to depolarizing stimuli. Subsequent conformational changes render the channel inactive, preventing further influx of sodium ions; inactivation modulates the duration of the AP. When the channel becomes hyperpolarized it returns to the resting (closed) state (Figure 2).

Figure 2: Functional states of nociceptor sodium channels in sensory conductance.
figure 2

A closed sodium channel opens in response to depolarization, allowing influx of sodium molecules. Inactivation occurs when the pore is blocked by a cytoplasmic portion of the channel, which modulates the duration of the AP. Many clinically useful drugs show affinity for the inactivated state of the channel, substantially retarding the recovery of the channel from inactivation or increasing the stability of the inactivated state. Depending on the channel selectivity (and the cell-type specificity) of the inactivation or the pore blockade that is achieved, the clinical result can be analgesia, anesthesia or paralysis. Abbreviations: AP, action potential; C, closed; I, inactive; O, open.

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The state of VGSCs (open, closed or inactive) affects the ability of compounds to block these channels' action; an affinity for the inactive rather than the closed state has been reported for many clinically useful agents.17,18 Naturally occurring mutations of the SCN9A gene, which encodes Nav1.7, link the sodium channel to human pain disorders. Gain-of-function mutations result in hyperexcitability of dorsal root ganglion neurons, leading to severe pain, whereas loss-of-function mutations produce insensitivity to pain.19,20 The absence of other discernable effects of human SCN9A mutations make this channel a very attractive therapeutic target. Accordingly, Nav1.7-selective channel blockers are in preclinical development. For arthritis pain, the nonselective sodium channel blocker lidocaine is commonly used as a topical analgesic patch applied directly to the affected knee, but the resulting nonselective sodium-channel blockade produces a reduced perception of tactile sensory stimuli. The selective prevention of depolarization in pain-transmitting neurons, therefore, seems possible only through state-dependent blockade of specific subsets of VGSCs.

Transmission and central integration of nociceptive information

Action potentials generated in primary afferent neurons induce neurotransmitter release in the central axon terminals of the dorsal horn of the spinal cord. Like most neurons in the CNS, Aδ and C fiber nociceptors use glutamate as their fast neurotransmitter. Glutamate binds to ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptors, as well as to metabotropic glutamate receptors expressed in the dorsal horn. AMPA receptors produce fast excitatory postsynaptic potentials that signal the onset, intensity, duration and location of peripheral noxious stimulation. More-intense or sustained activation of C fiber nociceptors also results in the release of neuropeptide neuromodulators, such as substance P and the calcitonin-gene-related peptide (CGRP), which produce slow synaptic potentials via the neurokinin 1 receptor (NK1R) and the CGRP-1 and CGRP-2 receptors, respectively. The presence of these peptides enables considerable use-dependent functional plasticity in the control of pain transmission, since their release typically follows high-intensity stimulation.21

Presynaptic voltage-gated calcium channels, such as CaV2.2, contribute substantially to controlling neurotransmitter release from synaptic vesicles in the dorsal horn. Neurotransmitter release is also regulated by presynaptic inhibition produced by the neurotransmitter γ-aminobutyric acid (GABA) acting on GABAA ion channels and GABAB receptors. Other presynaptic inhibitory receptors include the cannabinoid receptor 1 (CB1) and the three opioid receptors µ, δ and κ. GABA also induces postsynaptic inhibition in dorsal horn neurons comparable to that caused by the neurotransmitter glycine.22 Each of the elements involved in the regulation of spinal neurotransmitter release constitute potential targets for pain pharmacotherapy.

Nociceptive signals reach the brain via spinal projections to the brainstem, hypothalamus, thalamus and ventral forebrain (Figure 3). Two major ascending pathways, the lateral and the medial spinothalamic tracts, convey nociceptive signals from the dorsal horn to the thalamus. The majority of these neurons project into the contralateral thalamus. Direct spinobulbar terminations are concentrated in the parabrachial nucleus, midbrain periaqueductal gray, reticular formation and catecholaminergic nuclei of the brainstem. Functional imaging studies in humans show that pain can activate the primary and secondary somatosensory cortex, the insula, the anterior cingulate gyrus and the prefrontal cortices.23,24 The sensory-discriminative component of pain, including determination of the location and intensity of the noxious stimulus, is rooted in the primary somatosensory cortex, whereas the type of the stimulus (e.g. thermal versus mechanical) and other cognitive aspects of pain perception are discerned in the secondary somatosensory cortex. The affective–motivational component of pain is processed by the limbic system. Pain affect, such as the displeasure and suffering associated with pain, seems to be integrated in the anterior cingulate cortex, while the insula is involved in the emotional aversion and autonomic reaction to the pain-evoking stimulus.23,25 The role of the prefrontal cortex in integrating pain stimuli seems to span sensory–discriminative and affective–motivational components. Only certain kinds of pain (e.g. cutaneous, but not esophageal) stimulate activity in the prefrontal cortex, but when such prefrontal activity is present, fear and depression seem to be the main experiences that accompany pain perceptions.26

Figure 3: Depiction of some of the brain regions involved in ascending and descending pathways and pain signal processing.
figure 3

Ascending pathways convey signals from the dorsal horn to the central nervous system, primarily via the thalamus, with connections to additional regions including the parabrachial nucleus and periaqueductal gray. Part of the central integration of pain sensations is the activation of regions including the somatosensory cortex, insula and prefrontal cortex. Descending signals from the frontal cortex, insula, amygdala and hypothalamus converge on the periaqueductal gray prior to modulation of activity in the spinal dorsal horn.

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The descending modulatory pathway (Figure 3) of the spinal processing of nociceptive input is relayed through the periaqueductal gray, which integrates input from multiple sources, including the frontal cortex, insula, amygdala, hypothalamus and brainstem nuclei. Unlike the ascending pathways, these pathways only indirectly project to the dorsal horn, via the rostral ventromedial medulla (RVM) and the pontomesencephalic noradrenergic nuclei. Descending serotonergic RVM input modulates nociceptive processing in the spinal cord.27,28

Several endogenous substances modulate transmission of nociceptive signals. The opioid and endocannabinoid systems are active in the brain, spinal cord and peripheral terminals.29 Opioid receptors are highly expressed on central neurons and engage the naturally occurring endorphin ligands. Although the cannabinoid receptors 1 and 2 (CB1 and CB2) have traditionally been termed central and peripheral, respectively, the distribution of each is more varied than the terms suggest. Agonists of CB1 have central and peripheral sites of action, while central CB2, especially its induced expression in response to injury, has been recognized as contributing to the analgesic qualities of cannabinoid ligands.30 Although endocannabinoids are mostly nonselective endogenous ligands, selective CB2 agonists are emerging as a therapeutic opportunity in pain, owing to their low risk of adverse effects compared with agonists of CB1.31

The noradrenergic system has a role in the descending pathway of nociceptive inhibition. The primary receptor for norepinephrine in the spinal cord is the α2 adrenergic receptor, which acts similarly to opioid receptors in inhibiting presynaptic vesicle release and postsynaptic hyperpolarization. Serotonergic descending input provides control (both inhibition and facilitation) of dorsal horn nociceptive function.32 Selective serotonin (5-hydroxytryptamine) reuptake inhibitors (SSRIs) increase synaptic serotonin levels, but have limited analgesic action compared with norepinephrine and serotonin dual-uptake inhibitors, such as tricyclic antidepressants, which have demonstrated efficacy against neuropathic pain.33

Chronic inflammatory pain

Inflammatory pain occurs as part of the normal response to tissue damage, including that caused by noxious stimuli. Tissue damage can cause physiologic changes to primary sensory and dorsal horn neurons. The alterations in the primary sensory neurons are characterized by a reduction in the transduction threshold and an increase in the response of the peripheral terminals of nociceptors—a phenomenon termed peripheral sensitization. Peripheral inflammation results in increased membrane excitability and synaptic efficacy in the dorsal horn, termed central sensitization.34

Tissue damage leads to the production and release of inflammatory mediators, including cytokines, chemokines, growth factors, kinins, prostanoids and nerve growth factor (NGF).35 These factors sensitize the nerve terminal, enabling low-intensity stimuli that would not normally be perceived as painful to cause pain via the nociceptive pathway. Among the nociceptor sensitizers that have so far been identified are activin, a member of the transforming growth factor (TGF) β family,36 cytokines such as tumor necrosis factor (TNF),37 chemokines such as CCL3,38 regulatory peptides such as the prokineticins,39 and inflammatory proteases such as mast cell tryptase and trypsins.40,41 The large number of these sensitizers, many of which can act in parallel as part of an inflammatory syndrome, limits the therapeutic potential of disrupting any one signal transduction pathway.

Among the multiple intracellular signaling systems that have been implicated in inflammatory receptor-mediated signaling, kinases seem to have a critical role. Calcium-dependent protein kinase C (PKC),42 cyclic-AMP-dependent protein kinase A (PKA),43 phosphoinositide 3 (PI3) kinase,44 mitogen-activated protein (MAP) kinases such as p38 and extracellular signal-regulated kinase (ERK),37,45 and Jun kinase46 are all components of second messenger cascades for pain. Among the substrates for these kinases are sodium channels, TRP family channels and receptors expressed in sensory neurons (Figure 4). TRPV1 and TRPA1 in nociceptors contribute to peripheral sensitization.47,48,49

Figure 4: The role of phosphorylation in TRPV1 signal transduction.
figure 4

Direct activation of the TRPV1 can be induced by heat, acidity, endogenous ligands, such as endocannabinoids, or exogenous ligands, such as capsaicin. Because TRPV1 serves as a substrate for cyclic-AMP-dependent PKA, PKC, and CamKII, any stimulus that promotes activity of these enzymes can bring about indirect activation of TRPV1 through the reversal of receptor desensitization. PIP2 interacts with TRPV1 near its C-terminus, and has been proposed to inhibit TRPV1 signaling and PLC cleavage to relieve TRPV1 from this inhibition. In addition, dephosphorylation, such as by calcineurin, can promote desensitization. Abbreviations: 2AG, 2-arachadonoylglycerol; CamKII, calcium–calmodulin-dependent protein kinase II; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; P, phosphate; PKA, protein kinase A; PIP, phosphatidylinositol bisphosphate; PKC, protein kinase C: PLC, phospholipase C; TRP, transient receptor potential.

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Although interaction between TRPV1 and phosphatidylinositol-4,5-bisphosphate (PIP2) has been demonstrated, the role of the latter molecule in modulating TRPV1 function remains controversial.50 Kinase-mediated phosphorylation and other post-translational modifications also alter the kinetics and activation threshold of the VGSCs Nav1.7, Nav1.8 and Nav1.9, contributing to peripheral sensitization and pain hypersensitivity.51,52,53 Second-order sensory neurons in the dorsal horn respond to noxious nociceptive input with an increase in excitability that outlasts the stimulus, leading to central sensitization. As in peripheral sensitization, intracellular kinases are activated during central sensitization, leading to modification of ion channel and receptor function. NMDA receptor phosphorylation leads to an increased level of receptor distribution in the synaptic membrane and an increased level of the receptor's responsiveness to glutamate.54

Activity-dependent changes in the dorsal horn that constitute acute or immediate central sensitization are induced within minutes and typically last for a few hours or less. In addition, transcription-dependent changes are initiated that produce alterations in the excitability of spinal cord neurons, which can last several days or more. Changes in gene expression include the upregulation of dynorphin,55 cyclo-oxygenase (COX) 2,56 and both neurokinin-1 receptor (NK1R) and its ligand, substance P.57 An increase in prostanoid production in dorsal horn neurons, due to induction of COX2, mediates an increase in neurotransmitter release, depolarization of spinal neurons and blockade of glycine receptors.58 Inhibition of centrally induced COX2 produces analgesia, suggesting that improved central penetration of NSAIDs and COX2 inhibitors would add to their efficacy in inflammatory pain therapy.35

Pain in rheumatic diseases

Clinical manifestations of rheumatic joint pain

Despite extensive innervation, normal, mobile joints are not perceived as painful. With age, sensations of joint movement, such as stiffness (most common) and/or pain, become increasingly perceptible. These sensations might arise independently of pathology, but a wide range of manifestations are also related to rheumatic conditions. By comparing the clinical presentations of different rheumatic diseases, the complexity of the somesthetic experience in differing pathologies can be elucidated, thereby illustrating the unclear boundaries between inflammatory and neuropathic pain states. Some examples are provided below.

Podagra (gout-like pain in the first toe) is one of the most painful forms of arthritis; patients cannot bear for their toe to be touched, the joint throbs and all the cardinal features of inflammation are evident, with pain typically burning, piercing or crushing in character. Patients with acute podagra can be fearful, withdrawn and emotionally labile. The spread of inflammation within the foot, away from the site of uric acid crystal deposition, mimics complex regional pain syndrome, which is considered a neuropathic state.59

Acute Charcot arthropathy bears some resemblance to distal symmetric neuropathy or the sensorimotor neuropathy that occurs in diabetes mellitus. The latter condition is associated with substantial neuropeptide release. After levels of neuropeptides subside, repair remains poor, causing complications such as foot ulceration that can lead to limb loss and even death.60 By contrast, acute diabetic Charcot denervation arthropathy almost always presents with signs of inflammation, distinctively characterized by unilateral swelling, increase in local skin temperature, joint effusion and bone resorption in a relatively insensate foot. Foot fractures and bone dislocations are a risk in Charcot arthropathy, and pain occurs in most patients. Periodic deep burning pain with temperature intolerance might supervene, in which a critical temperature between 32–36 °C can provoke a neuropathic pain crisis.61 This condition mimics primary erythromelalgia.

Patients with inflammation due to RA might have a plethora of somesthetic experiences, including pain, fatigue and stiffness.62 Symptoms are, however, often overlooked during consultations because the emphasis is on the suppression of inflammation, the idea being that if the inflammation is treated, the pain will treat itself. In RA, the superficial synovium denervates in the presence of chronic inflammation,63 which might explain why inflamed rheumatoid joints are generally painless when fully supported. This denervation, although beneficial to the patient's pain state in the short term, can lead to neuropathic processes and central pains in the long term.

Irrespective of their pain state, RA patients experience stiff joints and feel fatigued. A familiar complaint of rheumatoid patients is that joints feel disproportionately swollen compared with their visual appearance. Capsular nerve stimulation and synovial denervation can create sensations of swelling in joints, such as the metacarpals. Whether the stiffness typical of RA is centrally mediated remains unknown, although its presence as part of phantom sensations experienced by patients with RA who have had limbs amputated supports this theory. The most characteristic rheumatoid pain, which occurs in relation to movement, is probably derived from the capsule and enthesis, centrally sensitized by inflammatory mediators.

Therapeutic considerations

Pain in normal human joints is attributed partly to the dense sensory and sympathetic innervation with which they are bestowed. Nociceptors are located in the capsule, ligaments, menisci, periosteum and subchondral bone.64 In the presence of physical changes, such as tissue edema, or biochemical changes, such as the release of inflammatory mediators, the mechanical threshold required for the activation of nociceptors is lowered, causing even normal movement to be painful.59 Moreover, the nerve damage in diseased joints might result in synovial afferent fibers becoming sensitized to sympathetic activity. Sympathetic adrenergic fibers influence synovial blood flow as well as pain, and unmyelinated C fibers, which are normally inactive, provide a route for pain transmission as well as neurogenic inflammation via neuropeptide release.65

Although it would be an oversimplification to classify RA simply as an inflammatory disease, since complex immune-mediated degenerative processes are at play in this disease,66 pain signaling in RA closely resembles that of inflammatory pain. The inflammatory mediators the cytokines, chemokines, histamine and bradykinin have all been implicated in RA pathology. These mediators also promote central sensitization. Elevated levels of the proinflammatory cytokines interleukin (IL)-6, IL-1, and TNF have been observed in RA joints. IL-6 is believed to have a dual part by initiating the inflammatory process and maintaining the immune response.67 IL-1 and TNF contribute to pain signaling and induce production of the matrix metalloproteinases (MMPs), which have an important role in the etiology of joint destruction.68

Synovial fluid acidification is a biochemical feature of RA. Accordingly, ASICs and TRPV1, molecules capable of detecting local acidification, have been implicated in RA pain transmission. In a model of induced arthritis in rats, however, only modest pH changes were observed,69 raising the question of whether synovial acidification in RA is sufficient to stimulate TRPV1 signaling.70 Most noteworthy among the biochemical changes in joints in RA is increased prostaglandin E2 (PGE2), the production of which is a COX-dependent (particularly COX2) process. This molecule can induce nociceptor firing.

For decades before the discovery of COX, the nonselective COX inhibitor aspirin was used with modest success to treat RA pain; NSAIDs remain a component of RA therapy. Selective COX2 inhibitors have demonstrated efficacy both in trials and clinical practice in the treatment of RA pain,71 with the added benefit of a reduced risk of gastrointestinal adverse effects compared with nonselective COX inhibitors. The discovery of adverse cardiac events in patients treated with the COX2-selective inhibitor rofecoxib, however, has led to the use of all COX2 inhibitors being limited in all clinical contexts.

Meanwhile, pain and other RA symptoms have been found to respond well to immunomodulatory therapies. Antibodies and soluble receptors that target TNF, IL-1β, IL-6 and other immune mediators are now part of the RA therapeutic armamentarium.72,73 Most of the other molecular targets discussed in this Review are still in clinical or preclinical stages of development. If trials are successful, clinicians will certainly welcome the introduction of new pain therapies.

Conclusions

In inflammatory and rheumatic pain states, numerous overlapping molecular and cellular mechanisms are at play. The modifiability and plasticity of the nervous system in pain pathogenesis is becoming increasingly clear; no single mechanistic entity typifies acute or chronic pain, or spontaneous or evoked pain. Elucidation of the molecular mechanisms in the peripheral and central nervous systems responsible for pain perception has yielded a degree of understanding of how current analgesic options work, and, of greater importance, why they often do not work. The complexity of nociceptive signaling pathways implies a wealth of putative therapeutic targets, although how many of these targets will be therapeutically accessible remains to be seen. Irrespective of the molecular target of a pharmacotherapeutic, in clinical studies of novel analgesics, we need to take account of simple clinical observations and manage pain in a broader context. The ultimate goal must be to provide patients with effective pain relief that is free from debilitating side effects.

Molecular and mechanistic studies of pain conditions, often using animal models, are improving our understanding of the neurobiologic mechanisms that drive pain. Demonstrating efficacy in animal models of pain is a necessary step towards developing new pharmacotherapies, but we must recognize the limitations of these methods. In animal models, we can measure biochemical changes, image joint morphology and observe nocifensive behavior, but we cannot make direct assessments of the sensation of pain. In the clinic, therefore, clinicians need to acknowledge, evaluate and treat the pains of rheumatic disease on an individual basis.

Review criteria

We searched for original and Review articles published between 1988 and 2008 on nociception, and inflammatory and rheumatic pain in PubMed. Search terms included “sensory neurons”, “inflammation”, “peripheral sensitization”, “central sensitization”, “rheumatoid disease”, “TRP” and “sodium channels”.