Abstract
Pain is a common presenting and often persistent symptom for children with rheumatological disease. Pain is not clearly related to disease severity in children with inflammatory juvenile idiopathic arthritis, and presentations of non-inflammatory musculoskeletal pain are common but there is limited evidence to guide management. Pain assessment must extend beyond measures of pain severity to more fully evaluate characteristics of pain, functional impact and psychosocial effects and family interactions. Evaluation of mechanisms of joint pain in adults has identified potential treatment targets, but additional studies are required as the acute and long-term impacts of pain and injury change during postnatal development. Genotyping, sensory evaluation and neuroimaging may better characterize chronic musculoskeletal pain, identify high-risk groups and/or provide additional outcome measures to monitor disease and treatment progress. An integrated approach to management is required to effectively select and target interventions, reduce pain and disability and improve long-term outcome.
Introduction
Significant neurodevelopmental changes in nociceptive processing occur from infancy through to adolescence that impact on the nature and degree of response to pain and can also influence the pharmacodynamic profile of analgesic agents. Due to the enhanced plasticity of the developing nervous system, there is potential for pain and injury in early-life pain to produce long-term changes in sensitivity that are not seen following the same insult at older ages . As a result, the ability to extrapolate data obtained from studies in adults may be limited, and the presentation and pathophysiology of diseases associated with chronic pain in paediatric populations differ from those seen in adults. There is a need to increase the quality and quantity of evidence to inform paediatric pain management. Outcome measures that extend beyond isolated measures of pain intensity to more fully characterize pain and its impact are required, with detailed assessment incorporating age- and disease-appropriate measures of activity, sleep and mood and sensory function. An integrated and interdisciplinary approach to management of chronic musculoskeletal pain in children is required to effectively select and target interventions, reduce pain and disability and improve long-term outcomes . In this review, data from studies in children and adolescents with inflammatory (e.g., juvenile inflammatory arthritis JIA) or non-inflammatory conditions will be used to illustrate the need for more comprehensive understanding of chronic musculoskeletal pain.
Pain mechanisms
A mechanism-based approach to pain diagnosis and management has been advocated for many years and is also relevant to rheumatological conditions . Laboratory models of inflammatory arthritis and osteoarthritis (OA) have been essential for investigating underlying mechanisms and for identifying and assessing potential analgesic targets . However, it is clear from studies in young animals that acute and long-term responses to noxious stimuli, peripheral inflammation and nerve or visceral injury change throughout postnatal development . Further evaluation of specific age-dependent effects in developmental models of musculoskeletal pain and joint inflammation is warranted .
Peripheral nociceptive pathways and sensitization
Peripheral nociceptive pathways sense and transduce noxious stimuli into electrical signals that are transmitted to the central nervous system and synapse in the spinal dorsal horn (see Table 1 for definitions and taxonomy). The joint capsule, ligaments, synovium, periosteum and subchondral bone are densely innervated with peripheral nociceptors. Nociceptors respond to noxious mechanical, thermal or chemical stimuli via a range of receptors, and depolarization results in action potential generation and propagation in peripheral myelinated Aδ fibres and unmyelinated C fibres. In addition, release of neuropeptides (substance P and calcitonin gene-related peptide, CGRP) from peripheral afferent nerves contributes to the inflammatory response (neurogenic inflammation) . In the presence of tissue injury and inflammation, nociceptors in muscle and joint become sensitized, particularly to mechanical stimuli . This state of peripheral sensitization has been specifically identified in electrophysiology recordings of afferent nerves from inflamed joints and is characterized by a reduction in the threshold for activation, an enhanced response to suprathreshold stimuli, and recruitment of previously ‘silent’ nociceptors . Mediators released from tissue injury and/or the inflamed synovium contribute to sensitization, including pro-inflammatory chemokines and cytokines (e.g., tumour necrosis factor-alpha, TNF-α; interleukin-1, IL-1; IL-6; IL-17), prostaglandins (e.g., PGE 2 ), neuropeptides (e.g., vasoactive intestinal peptide (VIP) from inflamed synovium) and growth factors (e.g., nerve growth factor (NGF) from articular cartilage, meniscus and synovium) . Enhanced sensitivity can occur within minutes via phosphorylation and changes in gating properties of ion channels, or over more prolonged periods (e.g., changes in expression of receptors and ion channels) .
| Term | Definition | Note |
|---|---|---|
| Pain | An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. | The inability to communicate verbally does not negate the possibility that an individual is experiencing pain and is in need of appropriate pain-relieving treatment. In pre-verbal children, composite scales incorporating behavioural and physiological responses may be viewed as a form of pain ‘report’. |
| Nociception | The neural process of encoding noxious stimuli. | Consequences of encoding may be autonomic (e.g., elevated blood pressure) or behavioural (motor withdrawal reflex or more complex nocifensive behaviour). |
| Nociceptor | A high-threshold sensory receptor of the peripheral somatosensory nervous system that is capable of transducing and encoding noxious stimuli. | |
| Peripheral sensitization | Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields. | Sensitization can include a drop in threshold and an increase in suprathreshold response. Spontaneous discharges and increases in receptive field size may also occur. This is a neurophysiological term. |
| Central sensitization | Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input. | Clinically, sensitization may only be indirectly inferred from phenomena such as hyperalgesia or allodynia. |
| Hyperalgesia | Increased pain from a stimulus that normally provokes pain. | This may be the consequence of peripheral or central sensitization, or both. |
| Allodynia | Pain due to a stimulus that does not normally provoke pain. | Touch, light pressure or moderate cold or warmth evokes pain when applied to apparently normal skin. |
| Nociceptive pain | Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors. | Pain is occurring with a normally functioning somatosensory nervous system |
| Neuropathic pain | Pain caused by a lesion or disease of the somatosensory nervous system. | Neuropathic pain is a clinical description (and not a diagnosis) which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. |
Receptors involved in peripheral nociception and sensitization following joint inflammation/injury include, but are not limited to, the following:
- i)
transient receptor protein (TRP) channels comprise a family of non-selective cation channels that transduce thermal and chemical stimuli. The TRPV 1 receptor is expressed by nociceptive fibres in joints, and levels increase following inflammation . TRPV 1 is directly activated by capsaicin, noxious heat >43 °C and low pH in inflamed tissue, and indirectly sensitized by inflammatory mediators such as bradykinin, PGE 2 and NGF . TRPA 1 is activated by cold temperatures, bradykinin and pungent chemicals (e.g., mustard oil), and may also contribute to joint inflammatory pain ( Table 2 ).
Table 2
Examples of nociceptor receptors and channels.
Receptor/Channel
Activation
Arthritic pain
TRPV1
- •
Noxious heat
- •
Low pH
- •
Capsaicin
- •
Sensitized by BK, PGE2, NGF
- •
Increased expression
- •
Contributes to thermal hyperalgesia
TRPA1
- •
Mechanical stimuli
- •
Cold and chemicals
- •
Contributes to mechanical hyperalgesia
ASICs
- •
Hydrogen ions: low pH in inflamed tissue
- •
Contributes to peripheral sensitization
PAR2, PAR 4
- •
Enzymatic cleavage of receptor by proteinases
- •
Elevated proteinases in synovial fluid
- •
Contribute to peripheral sensitization
Na v 1.7, Na v 1.8
- •
Voltage gated sodium channels
- •
Increased expression
- •
Increased excitability
CB2
- •
Endogenous cannabinoids
- •
Increased expression in synovium and spinal cord
- •
Agonist reduces pro-inflammatory cytokine release and reduces pain
TRP, transient receptor potential; ASIC, acid-sensing ion channel; PAR, protease-activated receptor; Na v , voltage-gated sodium channel; CB, cannabinoid.
- •
- ii)
Acid-sensing ion channels (ASICs) are activated by low extracellular pH during inflammation, and may have a particular role in ischaemic pain in skeletal muscle .
- iii)
Purinergic receptors comprise a P 2 X family of ionotropic channels and a P 2 Y family of G-protein-coupled receptors. Adenosine triphosphate (ATP) opens P 2 X channels and mediates pain in contracting muscles or inflammatory states .
- iv)
Proteinase-activated receptors (PAR2 and PAR4) are expressed in joint primary afferent nerve endings. Rather than being a ligand-gated receptor, proteinases (such as mast cell tryptase) cleave specific PARs and this alters nociceptive signalling and contributes to sensitization.
- v)
Voltage-gated sodium (Na v ) channels are essential for the generation and propagation of action potentials. Subtypes of Na v channels vary in their structure, kinetics, distribution and sensitivity to tetrodotoxin. Nociceptive neurons express mainly Na v 1.7, Na v 1.8 and Na v 1.9, and these channels modulate excitability (‘set the gain’) and have important roles in both pain sensitivity and specific disease states . Channel expression and activity are increased following peripheral tissue inflammation and in joint afferents from Complete Freund’s Adjuvant (CFA) inflamed knees .
- vi)
Effects of endogenous cannabinoids (CBs) are mediated by CB1 and CB2 receptors , and atypical receptors such as the orphan receptor GPR55 . In the periphery, a CB1 agonist reduces mechanosensitivity of afferents from control and arthritic knees, whereas a CB2 agonist reduced joint afferent firing in controls, but potentiated firing in OA knee joint mechanoreceptors .
Developmental changes: Nociceptors are responsive to noxious mechanical, thermal and chemical stimuli after birth, and peripheral sensitization has been demonstrated from young ages in laboratory and clinical studies . Age-related changes in receptor function and distribution and in firing frequency can alter sensitivity to different stimuli. TRPV 1 messenger RNA (mRNA) is present in the afferent cell body in the dorsal root ganglion (DRG) and peripheral TRPV 1 receptors are functional in early life although the density of TRPV 1 -positive nerve terminals in cutaneous tissue is initially less than in adults . Levels of TRPA 1 mRNA are low in DRG neurons at birth , but peripherally applied TRPA 1 agonists (e.g., mustard oil) produce peripheral sensitization in neonatal rodents . In early development, a higher proportion of DRG neurons express P2X 3 receptors, and P2X 3 agonists evoke increased behavioural responses . Na v 1.8 and Na v 1.9 are expressed on C-fibres at birth and reach adult levels by postnatal day 7 (P7) . Hindpaw injection of inflammatory agents such as carrageenan or CFA produce robust acute inflammatory responses in neonatal rodents, and depending on the type and volume of material injected also produce long-term changes in structure and function, including persistent neurotrophin-dependent hyperinnervation in wounded tissue .
Spinal cord and ascending pathways
Nociceptive primary afferent neurons synapse in the dorsal horn of the spinal cord form local circuits with inhibitory and excitatory interneurons, connect to wide dynamic range neurons in deeper laminae and provide input to a number of ascending projection pathways. Ongoing input in afferent nerves from skin, joint and/or muscle can lead to central sensitization, with a reduction in threshold, spontaneous activity and enlargement of the receptive field of dorsal horn neurons. Changes in the threshold, kinetics and distribution of glutamate (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA; and N-methyl- d -aspartate, NMDA) receptors increase membrane excitability and produce synaptic facilitation; and disinhibition due to reduced actions of inhibitory gamma-aminobutyric acid (GABA) and glycine further increases sensitivity . Joint inflammation triggers central sensitization via multiple transmitters and signalling pathways, including IL-6, TNF-α and endocannabinoids . Clinically, this is manifest as sensitivity extending beyond the area of injured peripheral tissue .
Projection neurons in the spinal dorsal horn are concentrated in lamina I, scattered through deeper laminae and relay to several brain areas ( Fig. 1 ). Briefly, inputs to spinothalamic tracts ascend via the ventral posterolateral thalamus to the primary somatosensory cortex and signal the sensory-discriminative aspects of pain. Ascending spinoparabrachial pathways to the lateral parabrachial area project to forebrain areas such as the amygdala and hypothalamus, and are involved in emotional and autonomic components of pain. Projections to the nucleus of the solitary tract mediate cardio-respiratory responses to pain, and those to the periaqueductal grey (PAG) link to other brainstem areas and descending modulatory pathways . Using neuroimaging techniques, specific patterns of increased brain activity in response to noxious stimulation or different pain states have been identified that include the thalamus, hippocampus and amygdala, in addition to the somatosensory and other cortical regions (insula, anterior cingulate and posterior parietal) .
Developmental changes: Dorsal horn neurons have low thresholds and large peripheral receptive fields, and there is a relative excess of excitatory responses and delayed development of inhibitory mechanisms in developing spinal pathways . Maturation is activity dependent and can be altered by excess nociceptive input during critical periods . Transcription of voltage-gated sodium and potassium channels in the superficial dorsal horn vary in a subtype-specific and age-dependent manner and can influence efficacy of analgesics targeting these sites . Projections to higher centres are functional following birth, as noxious stimuli produce electroencephalogram (EEG) and blood flow changes indicative of activity in the somatosensory cortex even in preterm-born neonates .
Descending modulation of pain
Descending pathways that relay in brainstem nuclei, particularly the PAG and rostral ventromedial medulla (RVM), can facilitate or inhibit nociceptive transmission in the spinal cord, with the balance depending on the transmitters and receptors involved and the type and duration of injury . Descending opioidergic and noradrenergic pathways have inhibitory actions, whereas serotonin (5-HT) has bidirectional effects with inhibition via 5-HT 1 and facilitation via 5-HT 2 and 5-HT 3 receptors. Altered descending modulatory pathways contribute to central sensitization and may have important roles in chronic pain states, such as fibromyalgia. The anterior cingulate cortex, amygdalae and hypothalamus relay via these brainstem nuclei, providing a neural pathway for the influence of cognitive and emotional factors on pain experience .
Developmental changes: Descending pathways in early life are predominantly facilitatory, and endogenous inhibitory mechanisms are slow to mature . As a result, endogenous inhibitory mechanisms may be less effective throughout childhood and early adolescence . In addition, the balance of descending control may be influenced by early pain exposure. Using quantitative sensory testing (QST) generalized decreases in pain sensitivity but increased sensitization with a sustained thermal stimulus have been identified in children born preterm requiring intensive care , and threshold changes were more marked in those who also required surgery suggesting that the degree of tissue injury may have an impact .
Neuroimmune interactions
The sensitivity of nociceptive pathways is mediated not only by alterations in neuron-to-neuron signalling, as additional interactions between neurons and glial cells also have a significant impact . In peripheral nervous system sensory ganglia (dorsal root and trigeminal ganglia), satellite glial cells that surround and communicate with neuronal cell bodies and macrophages form a network that modulates pain sensitivity . In adult rodents, macrophage infiltration in the DRG following antigen-induced arthritis or surgical destabilization to model OA correlated with increased sensitivity and the onset of pain behaviour . In the spinal cord, afferent nerve terminals release not only neurotransmitters that activate receptors on the post-synaptic neuron but also factors such as ATP and chemokines that increase reactivity of nearby microglia and astrocytes. Subsequent release of inflammatory mediators and signalling molecules from glial cells modulate synaptic transmission, and this feedback loop can further enhance pain sensitivity. Upregulation of microglial and astrocytic markers in the spinal cord that are suggestive of increased reactivity have been documented in a number of pain models, including joint arthritis .
Developmental changes: The impact of neuro-glial signalling is influenced by age and type of injury. Spinal microglia can be primed by neonatal surgical injury and contribute to enhanced sensitivity following injury in later life. However, when compared to adult animals, peripheral nerve injury initially produces less glial response and minimal hyperalgesia in young animals . The role of neuroglial signalling following arthritis at different postnatal ages has not been evaluated.
Neuropathic pain
Neuropathic pain is the result of a lesion or disease of the somatosensory nervous system . Although peripheral mechanisms differ from inflammatory pain, spontaneous activity and enhanced sensitivity of damaged afferent nerves can also produce central sensitization. Histological changes in joint afferents and in nerve fibre density have been identified in adult models of OA, and neuropathic pain arising from these damaged peripheral nerves may contribute to the overall pain experience .
Developmental changes: Laboratory models of peripheral nerve injury produce minimal hyperalgesia in young animals. Similarly, neuropathic pain is less frequently reported when surgery or trauma occur at younger ages (<6 years), but a number of diseases (e.g., erythromelalgia, Fabry’s disease) and treatments (e.g., chemotherapy) can also produce neuropathic pain in children. The presentation of neuropathic pain differs from inflammatory pain. Pain may be paroxysmal and episodic with no clear precipitating factor. Typical sensory descriptors include stabbing, pins and needles, shooting, piercing and electric shocks. Altered sensory symptoms and signs can range from sensory loss to marked allodynia. Treatment is largely extrapolated from adult practice to include anti-convulsants and/or low-dose anti-depressants with actions on descending noradrenergic mechanisms (see recent reviews for further details) . Nerve damage has not been assessed in developmental joint injury models.
Pain mechanisms
A mechanism-based approach to pain diagnosis and management has been advocated for many years and is also relevant to rheumatological conditions . Laboratory models of inflammatory arthritis and osteoarthritis (OA) have been essential for investigating underlying mechanisms and for identifying and assessing potential analgesic targets . However, it is clear from studies in young animals that acute and long-term responses to noxious stimuli, peripheral inflammation and nerve or visceral injury change throughout postnatal development . Further evaluation of specific age-dependent effects in developmental models of musculoskeletal pain and joint inflammation is warranted .
Peripheral nociceptive pathways and sensitization
Peripheral nociceptive pathways sense and transduce noxious stimuli into electrical signals that are transmitted to the central nervous system and synapse in the spinal dorsal horn (see Table 1 for definitions and taxonomy). The joint capsule, ligaments, synovium, periosteum and subchondral bone are densely innervated with peripheral nociceptors. Nociceptors respond to noxious mechanical, thermal or chemical stimuli via a range of receptors, and depolarization results in action potential generation and propagation in peripheral myelinated Aδ fibres and unmyelinated C fibres. In addition, release of neuropeptides (substance P and calcitonin gene-related peptide, CGRP) from peripheral afferent nerves contributes to the inflammatory response (neurogenic inflammation) . In the presence of tissue injury and inflammation, nociceptors in muscle and joint become sensitized, particularly to mechanical stimuli . This state of peripheral sensitization has been specifically identified in electrophysiology recordings of afferent nerves from inflamed joints and is characterized by a reduction in the threshold for activation, an enhanced response to suprathreshold stimuli, and recruitment of previously ‘silent’ nociceptors . Mediators released from tissue injury and/or the inflamed synovium contribute to sensitization, including pro-inflammatory chemokines and cytokines (e.g., tumour necrosis factor-alpha, TNF-α; interleukin-1, IL-1; IL-6; IL-17), prostaglandins (e.g., PGE 2 ), neuropeptides (e.g., vasoactive intestinal peptide (VIP) from inflamed synovium) and growth factors (e.g., nerve growth factor (NGF) from articular cartilage, meniscus and synovium) . Enhanced sensitivity can occur within minutes via phosphorylation and changes in gating properties of ion channels, or over more prolonged periods (e.g., changes in expression of receptors and ion channels) .
| Term | Definition | Note |
|---|---|---|
| Pain | An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. | The inability to communicate verbally does not negate the possibility that an individual is experiencing pain and is in need of appropriate pain-relieving treatment. In pre-verbal children, composite scales incorporating behavioural and physiological responses may be viewed as a form of pain ‘report’. |
| Nociception | The neural process of encoding noxious stimuli. | Consequences of encoding may be autonomic (e.g., elevated blood pressure) or behavioural (motor withdrawal reflex or more complex nocifensive behaviour). |
| Nociceptor | A high-threshold sensory receptor of the peripheral somatosensory nervous system that is capable of transducing and encoding noxious stimuli. | |
| Peripheral sensitization | Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields. | Sensitization can include a drop in threshold and an increase in suprathreshold response. Spontaneous discharges and increases in receptive field size may also occur. This is a neurophysiological term. |
| Central sensitization | Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input. | Clinically, sensitization may only be indirectly inferred from phenomena such as hyperalgesia or allodynia. |
| Hyperalgesia | Increased pain from a stimulus that normally provokes pain. | This may be the consequence of peripheral or central sensitization, or both. |
| Allodynia | Pain due to a stimulus that does not normally provoke pain. | Touch, light pressure or moderate cold or warmth evokes pain when applied to apparently normal skin. |
| Nociceptive pain | Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors. | Pain is occurring with a normally functioning somatosensory nervous system |
| Neuropathic pain | Pain caused by a lesion or disease of the somatosensory nervous system. | Neuropathic pain is a clinical description (and not a diagnosis) which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. |
Receptors involved in peripheral nociception and sensitization following joint inflammation/injury include, but are not limited to, the following:
- i)
transient receptor protein (TRP) channels comprise a family of non-selective cation channels that transduce thermal and chemical stimuli. The TRPV 1 receptor is expressed by nociceptive fibres in joints, and levels increase following inflammation . TRPV 1 is directly activated by capsaicin, noxious heat >43 °C and low pH in inflamed tissue, and indirectly sensitized by inflammatory mediators such as bradykinin, PGE 2 and NGF . TRPA 1 is activated by cold temperatures, bradykinin and pungent chemicals (e.g., mustard oil), and may also contribute to joint inflammatory pain ( Table 2 ).
Table 2
Examples of nociceptor receptors and channels.
Receptor/Channel
Activation
Arthritic pain
TRPV1
- •
Noxious heat
- •
Low pH
- •
Capsaicin
- •
Sensitized by BK, PGE2, NGF
- •
Increased expression
- •
Contributes to thermal hyperalgesia
TRPA1
- •
Mechanical stimuli
- •
Cold and chemicals
- •
Contributes to mechanical hyperalgesia
ASICs
- •
Hydrogen ions: low pH in inflamed tissue
- •
Contributes to peripheral sensitization
PAR2, PAR 4
- •
Enzymatic cleavage of receptor by proteinases
- •
Elevated proteinases in synovial fluid
- •
Contribute to peripheral sensitization
Na v 1.7, Na v 1.8
- •
Voltage gated sodium channels
- •
Increased expression
- •
Increased excitability
CB2
- •
Endogenous cannabinoids
- •
Increased expression in synovium and spinal cord
- •
Agonist reduces pro-inflammatory cytokine release and reduces pain
TRP, transient receptor potential; ASIC, acid-sensing ion channel; PAR, protease-activated receptor; Na v , voltage-gated sodium channel; CB, cannabinoid.
- •
- ii)
Acid-sensing ion channels (ASICs) are activated by low extracellular pH during inflammation, and may have a particular role in ischaemic pain in skeletal muscle .
- iii)
Purinergic receptors comprise a P 2 X family of ionotropic channels and a P 2 Y family of G-protein-coupled receptors. Adenosine triphosphate (ATP) opens P 2 X channels and mediates pain in contracting muscles or inflammatory states .
- iv)
Proteinase-activated receptors (PAR2 and PAR4) are expressed in joint primary afferent nerve endings. Rather than being a ligand-gated receptor, proteinases (such as mast cell tryptase) cleave specific PARs and this alters nociceptive signalling and contributes to sensitization.
- v)
Voltage-gated sodium (Na v ) channels are essential for the generation and propagation of action potentials. Subtypes of Na v channels vary in their structure, kinetics, distribution and sensitivity to tetrodotoxin. Nociceptive neurons express mainly Na v 1.7, Na v 1.8 and Na v 1.9, and these channels modulate excitability (‘set the gain’) and have important roles in both pain sensitivity and specific disease states . Channel expression and activity are increased following peripheral tissue inflammation and in joint afferents from Complete Freund’s Adjuvant (CFA) inflamed knees .
- vi)
Effects of endogenous cannabinoids (CBs) are mediated by CB1 and CB2 receptors , and atypical receptors such as the orphan receptor GPR55 . In the periphery, a CB1 agonist reduces mechanosensitivity of afferents from control and arthritic knees, whereas a CB2 agonist reduced joint afferent firing in controls, but potentiated firing in OA knee joint mechanoreceptors .
Developmental changes: Nociceptors are responsive to noxious mechanical, thermal and chemical stimuli after birth, and peripheral sensitization has been demonstrated from young ages in laboratory and clinical studies . Age-related changes in receptor function and distribution and in firing frequency can alter sensitivity to different stimuli. TRPV 1 messenger RNA (mRNA) is present in the afferent cell body in the dorsal root ganglion (DRG) and peripheral TRPV 1 receptors are functional in early life although the density of TRPV 1 -positive nerve terminals in cutaneous tissue is initially less than in adults . Levels of TRPA 1 mRNA are low in DRG neurons at birth , but peripherally applied TRPA 1 agonists (e.g., mustard oil) produce peripheral sensitization in neonatal rodents . In early development, a higher proportion of DRG neurons express P2X 3 receptors, and P2X 3 agonists evoke increased behavioural responses . Na v 1.8 and Na v 1.9 are expressed on C-fibres at birth and reach adult levels by postnatal day 7 (P7) . Hindpaw injection of inflammatory agents such as carrageenan or CFA produce robust acute inflammatory responses in neonatal rodents, and depending on the type and volume of material injected also produce long-term changes in structure and function, including persistent neurotrophin-dependent hyperinnervation in wounded tissue .
Spinal cord and ascending pathways
Nociceptive primary afferent neurons synapse in the dorsal horn of the spinal cord form local circuits with inhibitory and excitatory interneurons, connect to wide dynamic range neurons in deeper laminae and provide input to a number of ascending projection pathways. Ongoing input in afferent nerves from skin, joint and/or muscle can lead to central sensitization, with a reduction in threshold, spontaneous activity and enlargement of the receptive field of dorsal horn neurons. Changes in the threshold, kinetics and distribution of glutamate (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA; and N-methyl- d -aspartate, NMDA) receptors increase membrane excitability and produce synaptic facilitation; and disinhibition due to reduced actions of inhibitory gamma-aminobutyric acid (GABA) and glycine further increases sensitivity . Joint inflammation triggers central sensitization via multiple transmitters and signalling pathways, including IL-6, TNF-α and endocannabinoids . Clinically, this is manifest as sensitivity extending beyond the area of injured peripheral tissue .
Projection neurons in the spinal dorsal horn are concentrated in lamina I, scattered through deeper laminae and relay to several brain areas ( Fig. 1 ). Briefly, inputs to spinothalamic tracts ascend via the ventral posterolateral thalamus to the primary somatosensory cortex and signal the sensory-discriminative aspects of pain. Ascending spinoparabrachial pathways to the lateral parabrachial area project to forebrain areas such as the amygdala and hypothalamus, and are involved in emotional and autonomic components of pain. Projections to the nucleus of the solitary tract mediate cardio-respiratory responses to pain, and those to the periaqueductal grey (PAG) link to other brainstem areas and descending modulatory pathways . Using neuroimaging techniques, specific patterns of increased brain activity in response to noxious stimulation or different pain states have been identified that include the thalamus, hippocampus and amygdala, in addition to the somatosensory and other cortical regions (insula, anterior cingulate and posterior parietal) .
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