Evidence of augmented central pain processing in idiopathic chronic low back pain

OBJECTIVE: For many individuals with chronic low back pain (CLBP), there is no identifiable cause. In other idiopathic chronic pain conditions, sensory testing and functional magnetic resonance imaging (fMRI) have identified the occurrence of generalized increased pain sensitivity, hyperalgesia, and altered brain processing, suggesting central augmentation of pain processing in such conditions. We compared the results of both of these methods as applied to patients with idiopathic CLBP (n = 11), patients with widespread pain (fibromyalgia; n = 16), and healthy control subjects (n = 11). METHODS: Patients with CLBP had low back pain persisting for at least 12 months that was unexplained by MRI/radiographic changes. Experimental pain testing was performed at a neutral site (thumbnail) to assess the pressure-pain threshold in all subjects. For fMRI studies, stimuli of equal pressure (2 kg) and of equal subjective pain intensity (slightly intense pain) were applied to this same site. RESULTS: Despite low numbers of tender points in the CLBP group, experimental pain testing revealed hyperalgesia in this group as well as in the fibromyalgia group; the pressure required to produce slightly intense pain was significantly higher in the controls (5.6 kg) than in the patients with CLBP (3.9 kg) (P = 0.03) or the patients with fibromyalgia (3.5 kg) (P = 0.006). When equal amounts of pressure were applied to the 3 groups, fMRI detected 5 common regions of neuronal activation in pain-related cortical areas in the CLBP and fibromyalgia groups (in the contralateral primary and secondary [S2] somatosensory cortices, inferior parietal lobule, cerebellum, and ipsilateral S2). This same stimulus resulted in only a single activation in controls (in the contralateral S2 somatosensory cortex). When subjects in the 3 groups received stimuli that evoked subjectively equal pain, fMRI revealed common neuronal activations in all 3 groups. CONCLUSION: At equal levels of pressure, patients with CLBP or fibromyalgia experienced significantly more pain and showed more extensive, common patterns of neuronal activation in pain-related cortical areas. When stimuli that elicited equally painful responses were applied (requiring significantly lower pressure in both patient groups as compared with the control group), neuronal activations were similar among the 3 groups. These findings are consistent with the occurrence of augmented central pain processing in patients with idiopathic CLBP.     

Irritable bowel syndrome as a common precipitant of central sensitization

Animal models of neuropathic pain have significantly advanced our knowledge of abnormalities in central pain processing mechanisms in chronic pain disorders. New neuroimaging techniques using functional magnetic resonance imaging and positron emission tomography scanning are beginning to provide insight into cortical participation in the processing of pain. Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders seen by physicians. Visceral hypersensitivity or decreased pain thresholds to distension of the gut is considered to be a biologic marker for IBS and is present in most patients with this gastrointestinal disorder. Patients with IBS also have many extraintestinal symptoms consistent with a central hyperalgesic state. Recent studies suggest that patients with IBS may also have cutaneous hyperalgesia similar to that seen in other chronic pain disorders such as fibromyalgia. This suggests that abnormalities of central nociceptive processing are present in IBS.     

Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI

Objectives

The aim of the present study was to systematically review the literature addressing pain-induced changes in the brain related to central sensitization in patients with fibromyalgia (FM) using specific functional (rs-fMRI and fMRI) and structural (voxel-based morphometry—VBM) brain MRI techniques.

Methods

PubMed and Web of Science were searched for relevant literature using different key word combinations related to FM, brain MRI, and central sensitization. Full-text reports fulfilling the inclusion criteria were assessed on risk of bias and reviewed by two independent reviewers.

Results

From the 61 articles that were identified, 22 met the inclusion criteria and achieved sufficient methodological quality. Overall, eight articles examined structural brain (VBM) changes in patients with FM, showing moderate evidence that central sensitization is correlated with gray matter volume decrease in specific brain regions (mainly anterior cingulate cortex and prefrontal cortex). However, global gray matter volume remains unchanged. A total of 13 articles evaluated brain activity (fMRI) in response to a nociceptive stimulus. Findings suggest a higher but similar pattern of activation of the pain matrix in FM patients compared to controls. There is also evidence of decreased functional connectivity in the descending pain-modulating system in FM patients. Overall, two articles examined intrinsic brain connectivity in FM patients with rs-fMRI. In conclusion, there is moderate evidence for a significant imbalance of the connectivity within the pain network during rest in patients with FM.

Conclusions

The included studies showed a moderate evidence for region-specific changes in gray matter volume, a decreased functional connectivity in the descending pain-modulating system, and an increased activity in the pain matrix related to central sensitization. More research is needed to evaluate the cause–effect relationship.     

Pathophysiologie neuropathischer Schmerzen

Neuropathic pain syndromes are generated by the impairment of nociceptive pathways. Both lesions of the peripheral and central nervous system may cause such pain. There are multifarious damage mechanisms: mechanical, metabolic, toxic or inflammatory injuries lead to biochemical, morphological and physiological changes of the affected neurons. Pathophysiological processes, such as peripheral and central sensitization, as well as degeneration of the inhibitory system, often result in neuropathic pain becoming chronic. These changes may become irreversible with time and persist in spite of the healing of the injured tissue. Neuropathic pain syndromes are clinically characterized by spontaneous pain (ongoing, paroxysms) and evoked types of pain (hyperalgesia, allodynia). An important aim in addition to causal treatment is symptomatic pain therapy, which inhibits the pathophysiological processes of pain.     

Evidence of involvement of central neural mechanisms in generating fibromyalgia pain

Fibromyalgia syndrome (FMS) is characterized by widespread pain, fatigue, sleep abnormalities, and distress. Because FMS lacks consistent evidence of tissue abnormalities, recent investigations have focused on central nervous system mechanisms of pain. Abnormal temporal summation of second pain (wind-up) and central sensitization have been described recently in patients with FMS. Windup and central sensitization, which rely on central pain mechanisms, occur after prolonged C-nociceptor input and depend on activation of nociceptor-specific neurons and wide dynamic range neurons in the dorsal horn of the spinal cord. Other abnormal central pain mechanisms recently detected in patients with FMS include diffuse noxious inhibitory controls. These pain inhibitory mechanisms rely on spinal cord and supraspinal systems involving pain facilitatory and pain inhibitory pathways. Brain-imaging techniques that can detect neuronal activation after nociceptive stimuli have provided additional evidence for abnormal central pain mechanisms in FMS. Brain images have corroborated the augmented reported pain experience of patients with fibromyalgia during experimental pain stimuli. In addition, thalamic activity, which contributes significantly to pain processing, was decreased in fibromyalgia. However, central pain mechanisms of fibromyalgia may not depend exclusively on neuronal activation. Neuroglial activation has been found to play an important role in the induction and maintenance of chronic pain. These findings may have important implications for future research and the treatment of fibromyalgia pain.     

Central sensitization in patients with non-cardiac chest pain: a clinical experimental study

OBJECTIVE: Patients with non-cardiac chest pain (NNCP) suffer from unexplained and often intractable pain which can pose a major clinical problem. The aim of this study was to investigate nociceptive processing in NNCP patients and their response to experimentally acid-induced oesophageal hyperalgesia using a multimodal stimulation protocol. MATERIAL AND METHODS: Ten highly selected patients with NCCP (mean age 43 years, 1 M) were compared with an age- and gender-matched group of 20 healthy subjects. After preconditioning, the distal oesophagus was painfully distended with a balloon using "impedance planimetry". This method assesses the luminal cross-sectional area of the oesophagus based on the electrical impedance of the fluid inside the balloon. The baseline distensions were done before and after pharmacological relaxation of the smooth muscle with 20 mg butylscopolamine. After baseline distensions, a series of up to 10 mechanical stimuli was performed (temporal summation). The stimulations were repeated after sensitization of the oesophagus induced by acid perfusion. The sensory intensities were assessed during the stimulations and the referred pain area was mapped. RESULTS: At baseline distensions, no differences were seen between patients and controls before and after relaxation of the smooth muscles. The patients tolerated fewer repeated distensions than controls (4.8+/-0.5 versus 9.1+/-0.9; p=0.04) and had an increased size of the referred pain areas to the mechanical stimulations (32.9+/-6.2 versus 64.9+/-18.3 cm2; p=0.01). After sensitization with acid, the patients developed hyperalgesia (p<0.001), whereas no significant changes were seen in controls. CONCLUSIONS: NCCP patients showed facilitated central pain mechanisms (temporal summation and visceral hyperalgesia after sensitization). This could be used in the diagnosis and understanding of the symptoms in these patients.     

Supraspinal contributions to hyperalgesia.

Tissue injury is associated with sensitization of nociceptors and subsequent changes in the excitability of central (spinal) neurons, termed central sensitization. Nociceptor sensitization and central sensitization are considered to underlie, respectively, development of primary hyperalgesia and secondary hyperalgesia. Because central sensitization is considered to reflect plasticity at spinal synapses, the spinal cord has been the principal focus of studies of mechanisms of hyperalgesia. Not surprisingly, glutamate, acting at a spinal N-methyl-D-aspartate (NMDA) receptor, has been implicated in development of secondary hyperalgesia associated with somatic, neural, and visceral structures. Downstream of NMDA receptor activation, spinal nitric oxide (NO.), protein kinase C, and other mediators have been implicated in maintaining such hyperalgesia. Accumulating evidence, however, reveals a significant contribution of supraspinal influences to development and maintenance of hyperalgesia. Spinal cord transection prevents development of secondary, but not primary, mechanical and/or thermal hyperalgesia after topical mustard oil application, carrageenan inflammation, or nerve-root ligation. Similarly, inactivation of the rostral ventromedial medulla (RVM) attenuates hyperalgesia and central sensitization in several models of persistent pain. Inhibition of medullary NMDA receptors or NO. generation attenuates somatic and visceral hyperalgesia. In support, topical mustard oil application or colonic inflammation increases expression of NO. synthase in the RVM. These data suggest a prominent role for the RVM in mediating the sensitization of spinal neurons and development of secondary hyperalgesia. Results to date suggest that peripheral injury and persistent input engage spinobulbospinal mechanisms that may be the prepotent contributors to central sensitization and development of secondary hyperalgesia.     

Estrogen increases nociception-evoked brain-derived neurotrophic factor gene expression in the female rat

Chronic pain induces plastic changes in nociceptive sensory pathways, and is often accompanied and exacerbated by depression. Estrogen can influence nociceptive sensory processing, but the molecular mechanisms underlying sex differences in pain remain unclear. Brain-derived neurotrophic factor (BDNF) may orchestrate changes occurring during persistent pain or depression by increasing spinal nociceptive signaling and altering neuronal growth in higher brain structures. This study addressed whether estrogen regulates BDNF gene expression in central systems associated with nociceptive processing and/or affective state, which may in turn influence sex differences in pain sensitivity. Thus, BDNF gene expression was quantified in intact female rats in proestrus and diestrus, and in ovariectomized (OVX) rats with or without 17beta-estradiol (E2) replacement following intraplantar injection of dilute formalin as an inflammatory nociceptive stimulus. Twenty-four hours after formalin injection, central nervous system (CNS) tissues were removed and solution hybridization-nuclease protection assays used to quantify BDNF mRNA levels. Results demonstrated that estrogen replacement increased BDNF mRNA levels in the hippocampus, cortex and spinal cord. Cortical BDNF mRNA levels were significantly decreased by nociception, in the hippocampus this decrease was only evident in estrogen-treated rats. Spinal BDNF expression was robustly increased by nociception. The pain-evoked up-regulation of spinal BDNF gene expression was significantly potentiated by concomitant estrogen treatment. Results demonstrate that BDNF gene expression in certain brain structures is inhibited by inflammatory pain, yet estrogen may enhance central nervous system sensitization associated with sensory processing. Since alterations in BDNF gene expression in higher brain centers may be relevant to cognitive changes that occur in recurrent depression, these results may provide insights into the coincidence of chronic pain and depression.     

Pain in chronic pancreatitis: the role of reorganization in the central nervous system

BACKGROUND & AIMS: In various chronic pain conditions cortical reorganization seems to play a role in the manifestations. The aim of this study was to investigate cortical reorganization in patients with pain caused by chronic pancreatitis. METHODS: Twelve healthy subjects and 10 patients with chronic pancreatitis were included. The esophagus, stomach, and duodenum were stimulated electrically at the pain threshold using a nasal endoscope. The electroencephalogram was recorded from 64 surface electrodes and event-related brain potentials (EPs) were obtained. RESULTS: As compared with healthy subjects, the patient group showed decreased latencies of the early EP components (N1, P < .001; P1, P = .02), which is thought to reflect the exogenous brain pain processing specifically. Source analysis showed that the dipolar activities corresponding to the early EPs were located consistently in the bilateral insula, in the anterior cingulate gyrus, and in the bilateral secondary somatosensory area. The bilateral insular dipoles were localized more medial in the patient group than in the healthy subjects after stimulation of all 3 gut segments (P < .01). There also were changes in the cingulate cortex where the neuronal source was more posterior in patients than in controls to stimulation of the esophagus (P < .05). CONCLUSIONS: The findings indicate that pain in chronic pancreatitis leads to changes in cortical projections of the nociceptive system. Such findings also have been described in somatic pain disorders, among them neuropathic pain. Taken together with the clinical data this suggests a neuropathic component in pancreatic pain, which may influence the approach to treatment.     

Evidence for Shared Pain Mechanisms in Osteoarthritis,Low Back Pain,and Fibromyalgia

Osteoarthritis (OA), low back pain (LBP), and fibromyalgia (FM) are common chronic pain disorders that occur frequently in the general population. They are a significant cause of dysfunction and disability. Why some of these chronic pain disorders remain localized to few body areas (OA and LBP), whereas others become widespread (FM) is unclear at this time. Genetic, environmental, and psychosocial factors likely play an important role. Although patients with OA, LBP, and FM frequently demonstrate abnormalities of muscles, ligaments, or joints, the severity of such changes is only poorly correlated with clinical pain. Importantly, many patients with these chronic pain disorders show signs of central sensitization and abnormal endogenous pain modulation. Nociceptive signaling is actively regulated by the central nervous system to allow adaptive responses after tissue injuries. Thus, abnormal processing of tonic peripheral tissue impulse input likely plays an important role in the pathogenesis of OA, LBP, or FM. Tonic and/or intense afferent nociceptive barrage can result in central sensitization that depends on facilitatory input from brainstem centers via descending pain pathways to the spinal cord. Abnormal endogenous control of these descending pathways can lead to excessive excitability of dorsal horn neurons of the spinal cord and pain. Ineffective endogenous pain control and central sensitization are important features of OA, LBP, and FM patients.     

Pain mechanisms in osteoarthritis: understanding the role of central pain and current approaches to its treatment

In this literature review, the mechanisms underlying pain associated with osteoarthritis (OA) are discussed, along with evidence for the efficacy of medications thought to act centrally to relieve OA pain. We survey the cascade of events from inflammation to activation of nociceptive and neuropathic pathways, to the development and maintenance of central and peripheral sensitization. Preclinical and clinical evidence for the sensitization hypothesis is discussed, along with recently identified genetic variations that may increase sensitivity to pain in patients with OA. Evidence is presented for the efficacy of centrally acting analgesics for OA pain (opioids, antiepileptics, tricyclic antidepressants, and serotonin/norepinephrine receptor inhibitors).     

The influence of the 5-HT3 receptor antagonist tropisetron on pain in fibromyalgia: a functional magnetic resonance imaging pilot study.

OBJECTIVE: Central pain processing is altered in patients with fibromyalgia syndrome (FMS). The serotonin metabolism, especially the 5-HT3 receptor, seems to play an important role. METHODS: We investigated the effect of the local injection of the 5-HT3 receptor antagonist tropisetron on the perception and central processing of pain in FMS patients using painful mechanical stimulation and functional magnetic resonance imaging (fMRI) within the framework of a pre-/posttreatment double-blind design. RESULTS: In the contralateral primary somatosensory cortex, contralateral posterior insula, and anterior cingulate cortex, we found that the activation was significantly reduced after treatment. On average, patients rated the stimulation-induced pain intensity as stronger in the session after treatment compared to before treatment, although the individual data revealed a heterogeneous pattern. All patients showed sensitisation during the painful stimulation, which was not influenced by the treatment. CONCLUSIONS: Both the sensory-discriminative and motivational-affective components of pain as measured by fMRI were altered by tropisetron.     

Polysialic acid-induced plasticity reduces neuropathic insult to the central nervous system

Under chronic conditions of neuropathic pain, nociceptive C terminals are lost from their target region in spinal lamina II, leading to reduced thermal hyperalgesia. This region of the spinal cord expresses high levels of polysialic acid (PSA), a cell surface carbohydrate known to weaken cell-cell interactions and promote plasticity. Experimental removal of PSA from the spinal cord exacerbates hyperalgesia and results in retention of C terminals, whereas it has no effect on plasticity of touch Abeta fibers and allodynia. We propose that expression of PSA at this stress pathway relay point could serve to protect central circuitry from chronic sensory overload.     

Mas-related G-protein–coupled receptors inhibit pathological pain in mice

An important objective of pain research is to identify novel drug targets for the treatment of pathological persistent pain states, such as inflammatory and neuropathic pain. Mas-related G-protein–coupled receptors (Mrgprs) represent a large family of orphan receptors specifically expressed in small-diameter nociceptive primary sensory neurons. To determine the roles of Mrgprs in persistent pathological pain states, we exploited a mouse line in which a chromosomal locus spanning 12 Mrgpr genes was deleted (KO). Initial studies indicated that these KO mice show prolonged mechanical- and thermal-pain hypersensitivity after hind-paw inflammation compared with wild-type littermates. Here, we show that this mutation also enhances the windup response of dorsal-horn wide dynamic-range neurons, an electrophysiological model for the triggering of central pain sensitization. Deletion of the Mrgpr cluster also blocked the analgesic effect of intrathecally applied bovine adrenal medulla peptide 8–22 (BAM 8–22), an MrgprC11 agonist, on both inflammatory heat hyperalgesia and neuropathic mechanical allodynia. Spinal application of bovine adrenal medulla peptide 8–22 also significantly attenuated windup in wild-type mice, an effect eliminated in KO mice. These data suggest that members of the Mrgpr family, in particular MrgprC11, may constitute an endogenous inhibitory mechanism for regulating persistent pain in mice. Agonists for these receptors may, therefore, represent a class of antihyperalgesics for treating persistent pain with minimal side effects because of the highly specific expression of their targets.     

Pain perception and brain evoked potentials in patients with angina despite normal coronary angiograms.

OBJECTIVE: To evaluate the role of nociception in patients with angina despite normal coronary angiograms and to investigate whether any abnormality is confined to visceral or somatosensory perception. METHODS: Perception, pain threshold, and brain evoked potentials to nociceptive electrical stimuli of the oesophageal mucosa and the sternal skin were investigated in 10 patients who had angina but normal coronary angiograms, no other signs of cardiac disease, and normal upper endoscopy. Controls were 10 healthy volunteers. The peaks of the evoked potential signal were designated N for negative deflections and P for positive. Numbers were given to the peaks in order of appearance after the stimulus. The peak to peak amplitudes (P1/N1, N1/P2) were measured in microV. RESULTS: (1) Angina pectoris was provoked in seven patients following continuous oesophageal stimulation. (2) Distant projection of pain occurred after continuous electrical stimulation of the oesophagus in four patients and in no controls. (3) Patients had higher oesophageal pain thresholds (median 16.3 mA v 7.3 mA, P = 0.02) to repeated stimuli than controls, whereas the values did not differ with respect to the skin. There were no intergroup differences in thresholds to single stimuli. (4) Patients had substantially reduced brain evoked potential amplitudes after both single oesophageal (P1/N1, median values: 7.2 microV, controls: 29.0 microV; N1/P2: 16.5 microV, controls: 66.0 microV; P < 0.001 for both) and skin (N1/P2: 13.5 microV; controls: 76.0 microV; P < 0.001) stimuli despite the similar pain thresholds. CONCLUSION: Central nervous system responses to visceral and somatosensory nociceptive input are altered in patients who have angina despite normal coronary angiograms.     

Nociception, pain, and antinociception: current concepts

The physiology of nociception involves a complex interaction of peripheral and central nervous system (CNS) structures, extending from the skin, the viscera and the musculoskeletal tissues to the cerebral cortex. The pathophysiology of chronic pain shows alterations of normal physiological pathways, giving rise to hyperalgesia or allodynia. After integration in the spinal cord, nociceptive information is transferred to thalamic structures before it reaches the somatosensory cortex. Each of these levels of the CNS contain modulatory mechanisms. The two most important systems in modulating nociception and antinociception, the N-methyl-D-aspartate (NMDA) and opioid receptor system, show a close distribution pattern in nearly all CNS regions, and activation of NMDA receptors has been found to contribute to the hyperalgesia associated with nerve injury or inflammation. Apart from substance P (SP), the major facilitatory effect in nociception is exerted by glutamate as the natural activator of NMDA receptors. Stimulation of ionotropic NMDA receptors causes intraneuronal elevation of Ca²⁺ which stimulates nitric oxide synthase (NOS) and the production of nitric oxide (NO). NO as a gaseous molecule diffuses out from the neuron and by action on guanylyl cyclase, NO stimulates in neighboring neurons the formation of cGMP. Depending on the expression of cGMP-controlled ion channels in target neurons, NO may act excitatory or inhibitory. NO has been implicated in the development of hyperexcitability, resulting in hyperalgesia or allodynia, by increasing nociceptive transmitters at their central terminals. Among the three subtypes of opioid receptors, μ- and δ-receptors either inhibit or potentiate NMDA receptor-mediated events, while κ opioids antagonize NMDA receptor-mediated activity. Recently, CRH has been found to act at all levels of the neuraxis to produce analgesia. Modulation of nociception occurs at all levels of the neuraxis, thus, eliciting the multidimensional experience of pain involving sensory-discriminative, affective-motivational, cognitive and locomotor components.     

Nociception, pain, and antinociception: current concepts

Summary The physiology of nociception involves a complex interaction of peripheral and central nervous system (CNS) structures, extending from the skin, the viscera and the musculoskeletal tissues to the cerebral cortex. The pathophysiology of chronic pain shows alterations of normal physiological pathways, giving rise to hyperalgesia or allodynia. After integration in the spinal cord, nociceptive information is transferred to thalamic structures before it reaches the somatosensory cortex. Each of these levels of the CNS contain modulatory mechanisms. The two most important systems in modulating nociception and antinociception, the N-methyl-D-aspartate (NMDA) and opioid receptor system, show a close distribution pattern in nearly all CNS regions, and activation of NMDA receptors has been found to contribute to the hyperalgesia associated with nerve injury or inflammation. Apart from substance P (SP), the major facilitatory effect in nociception is exerted by glutamate as the natural activator of NMDA receptors. Stimulation of ionotropic NMDA receptors causes intraneuronal elevation of Ca²⁺ which stimulates nitric oxide synthase (NOS) and the production of nitric oxide (NO). NO as a gaseous molecule diffuses out from the neuron and by action on guanylyl cyclase, NO stimulates in neighboring neurons the formation of cGMP. Depending on the expression of cGMP-controlled ion channels in target neurons, NO may act excitatory or inhibitory. NO has been implicated in the development of hyperexcitability, resulting in hyperalgesia or allodynia, by increasing nociceptive transmitters at their central terminals. Among the three subtypes of opioid receptors, μ- and δ-receptors either inhibit or potentiate NMDA receptor-mediated events, while κ opioids antagonize NMDA receptor-mediated activity. Recently, CRH has been found to act at all levels of the neuraxis to produce analgesia. Modulation of nociception occurs at all levels of the neuraxis, thus, eliciting the multidimensional experience of pain involving sensory-discriminative, affective-motivational, cognitive and locomotor components.      

The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline

Noradrenaline (NA), a key neurotransmitter of the endogenous pain inhibitory system, acutely inhibits nociceptive transmission (including that mediated by substance P), potentiates opioid analgesia, and underlies part of the antinociceptive effects of the widely prescribed tricyclic antidepressants. Lesions of noradrenergic neurons, however, result in either normal or reduced pain behavior and variable changes in morphine antinociception, undermining the proposed association between noradrenaline (NA) deficiency and chronic pain (hyperalgesia). We used mice lacking the gene coding for dopamine beta-hydroxylase, the enzyme responsible for synthesis of NA from dopamine, to reexamine the consequences of a lack of NA on pain behavior. Here, we show that absence of NA in the central nervous system results in a substance P-mediated chronic hyperalgesia (decreased nociceptive threshold) to thermal, but not mechanical, stimuli and decreased efficacy of morphine. Contrary to studies that show substance P-mediated hyperalgesia requires intense stimuli, we found that even a mild stimulus is sufficient to evoke substance P-dependent hyperalgesia in the NA-deficient mice. Restoring central NA normalized both the nociceptive threshold and morphine efficacy, which is consistent with a tonic inhibitory effect of NA on nociceptive transmission. Unexpectedly, however, antagonists to the substance P receptor (the NK1 receptor) could achieve the same effect as NA replacement. We conclude that when unopposed by NA, substance P acting at the NK1 receptor causes chronic thermal hyperalgesia, and that the reduced opioid efficacy associated with a lack of NA is due to increased NK1-receptor stimulation.     

Central sensitization in patients with non-cardiac chest pain: A clinical experimental study

Objective. Patients with non-cardiac chest pain (NNCP) suffer from unexplained and often intractable pain which can pose a major clinical problem. The aim of this study was to investigate nociceptive processing in NNCP patients and their response to experimentally acid-induced oesophageal hyperalgesia using a multimodal stimulation protocol. Material and methods. Ten highly selected patients with NCCP (mean age 43?years, 1?M) were compared with an age- and gender-matched group of 20 healthy subjects. After preconditioning, the distal oesophagus was painfully distended with a balloon using “impedance planimetry”. This method assesses the luminal cross-sectional area of the oesophagus based on the electrical impedance of the fluid inside the balloon. The baseline distensions were done before and after pharmacological relaxation of the smooth muscle with 20?mg butylscopolamine. After baseline distensions, a series of up to 10 mechanical stimuli was performed (temporal summation). The stimulations were repeated after sensitization of the oesophagus induced by acid perfusion. The sensory intensities were assessed during the stimulations and the referred pain area was mapped. Results. At baseline distensions, no differences were seen between patients and controls before and after relaxation of the smooth muscles. The patients tolerated fewer repeated distensions than controls (4.8±0.5 versus 9.1±0.9; p=0.04) and had an increased size of the referred pain areas to the mechanical stimulations (32.9±6.2 versus 64.9±18.3?cm²; p=0.01). After sensitization with acid, the patients developed hyperalgesia (p<0.001), whereas no significant changes were seen in controls. Conclusions. NCCP patients showed facilitated central pain mechanisms (temporal summation and visceral hyperalgesia after sensitization). This could be used in the diagnosis and understanding of the symptoms in these patients.     

Peripheral and central sensitization in musculoskeletal pain disorders: an experimental approach

This report provides a brief introduction to the manifestations of peripheral and central sensitization involved in musculoskeletal pain disorders. It has become increasingly evident that muscle hyperalgesia, referred pain, referred hyperalgesia, and widespread hyperalgesia play an important role in chronic musculoskeletal pain. A better understanding of the involved basic mechanisms and better methods to assess muscle pain in the clinic may provide new possibilities for designing rational therapies and for targeting the pharmacologic intervention optimally. Peripheral sensitization plays an important role for increased sensitivity of deep tissue. However, central sensitization may be equally important but less addressed. Quantitative sensory testing provides the possibility to evaluate these manifestations in a standardized way in patients with musculoskeletal pain or in healthy volunteers (eg, experimentally induced referred pain can be used to assess the potential involvement of central sensitization in musculoskeletal pain conditions). Central sensitization may play a role in the persistence, amplification, and spread of pain. Interventions should take this aspect into consideration.