Peripheral Pain Sensitization Research Articles

Spinal PTP1B Regulated NMDA Receptor-mediated Nociceptive Transmission and Peripheral Inflammation-induced Pain Sensitization.

Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of several pain-related substrates in spinal cord dorsal horn and are critically involved in the modification of pain transmission. The current study demonstrated that protein tyrosine phosphatase 1B (PTP1B), a unique endoplasmic reticulum-resident member of PTP family, displayed an activity-dependent increase in its protein expression and synaptic localization in spinal dorsal horn of adult male rats. PTP1B interacted with the Src Homology 3 (SH3) domain of Synapse-Associated Protein 102 (SAP102), one of the postsynaptic scaffolding proteins that anchored PTP1B at postsynaptic sites. The SAP102-tethered PTP1B augmented the synaptic transmission mediated specifically by GluN2B subunit-containing N-methyl-D-aspartate subtype glutamate receptors. Interference with PTP1B activity or disruption of its interaction with SAP102 attenuated GluN2B-mediated nociceptive transmission and ameliorated pain sensitization induced by intraplantar injection of Complete Freund's Adjuvant. These data suggested that the activity-dependent synaptic redistribution of PTP1B served as an important mechanism regulating GluN2B receptor activity and that manipulation of PTP1B synaptic targeting might represent an effective approach for the treatment of chronic inflammatory pain.

Central Sensitization: The Missing Link Between Psychological Distress and Poor Outcome Following Primary Total Knee Arthroplasty

BackgroundWhile preoperative psychological distress is known to predict risk for worse total knee arthroplasty (TKA) outcomes, distress may be too broad and nonspecific a predictor in isolation. We tested whether there are distinct preoperative TKA patient types based jointly on psychological status and measures of altered pain processing that predict adverse clinical outcomes. MethodsIn 112 TKA patients, we preoperatively assessed psychological status (depression, anxiety, and catastrophizing) and altered pain processing via a simple quantitative sensory testing protocol capturing peripheral and central pain sensitization. Outcomes (pain, function, opioid use) were prospectively evaluated at 6 weeks and 6 months after TKA. Cluster analyses were used to empirically identify TKA patient subgroups. ResultsThere were 3 distinct preoperative TKA patient subgroups identified from the cluster analysis. A low-risk (LR) group was characterized by low psychological distress and low peripheral and central sensitization. In addition, 2 subgroups with similarly elevated preoperative psychological distress were identified, differing by pain processing alterations observed: high-risk centralized pain and high-risk peripheral pain. Relative to LR patients, high-risk centralized pain patients displayed significantly worse function and greater opioid use at 6 months after TKA (P values <.05). The LR and high-risk peripheral pain patient subgroups had similar 6-month outcomes (P values >.05). ConclusionsAmong patients who have psychological comorbidity, only patients who have central sensitization were at elevated risk for poor functional outcomes and increased opioid use. Central sensitization may be the missing link between psychological comorbidity and poor TKA clinical outcomes. Preoperative testing for central sensitization may have clinical utility for improving risk stratification in TKA patients who have psychosocial risk factors.

Associations between pain sensitization and measures of physical function in people with hand osteoarthritis: Results from the Nor-Hand study

To examine whether pain sensitization is associated with hand and lower extremity function in people with hand osteoarthritis (OA) in the Nor-Hand study. Pain sensitization was assessed by pressure pain thresholds (PPTs) and temporal summation (TS). Hand function was assessed by Australian/Canadian Osteoarthritis Hand Index (AUSCAN) (range: 0-36), grip strength and Moberg pick-up test, and lower extremity function was assessed by Western Ontario and McMaster Universities Osteoarthritis Index (range: 0-68), 30-s chair stand test, and 40-m walk test. We examined whether sex-standardized PPT and TS values were cross-sectionally associated with measures of physical function using linear regression analyses. Beta coefficients were presented per sex-specific standard deviation of PPT and TS. The mediating effect of pain was examined by causal-inference based mediation analysis. In 206 participants, higher PPTs at/near the hand, indicative of less peripheral and/or central pain sensitization, were associated with greater grip strength and better self-reported hand function (beta for PPT at finger joint on AUSCAN function: -1.41, 95% CI -2.40, -0.42). Higher PPTs at/near the hand, near the knee and at trapezius were associated with lower extremity function, although not statistically significant for all outcomes. Self-reported pain severity mediated the effect of PPT on self-reported function. TS was not associated with hand or lower extremity function. Peripheral sensitization, and possibly central sensitization, was associated with impaired function. Effects of PPTs on self-reported function were mediated by self-reported pain, whereas there might be a direct effect of sensitization or effects through other mediators on performance-based function.

Investigation of pain sensitivity following 3 nights of disrupted sleep in healthy individuals.

Poor quality sleep is a common complaint among people with chronic pain. The co-occurrence of poor sleep quality and chronic pain often comes with increased pain intensity, more disability and a higher cost of healthcare. Poor sleep has been suggested to affect measures of peripheral and central pain mechanisms. To date, sleep provocations are the only models proven to affect measures of central pain mechanisms in healthy subjects. However, there are limited studies investigating the effect of several nights of sleep disruption on measures of central pain mechanisms. The current study implemented three nights of sleep disruption with three planned awakenings per night in 30 healthy subjects sleeping at home. Pain testing was conducted at the same time of day at baseline and follow-up for each subject. Pressure pain thresholds were assessed bilaterally on the infraspinatus and gastrocnemius muscles. Using handheld pressure algometry, suprathreshold pressure pain sensitivity and area were also investigated on the dominant infraspinatus muscle. Cuff-pressure pain detection and tolerance thresholds, temporal summation of pain and conditioned pain modulation were investigated using cuff-pressure algometry. Temporal summation of pain was significantly facilitated (p= 0.022), suprathreshold pain areas (p= 0.005) and intensities (p< 0.05) were significantly increased, and all pressure pain thresholds were decreased (p< 0.005) after sleep disruption compared to baseline. The current study found that three consecutive nights of sleep disruption at home induced pressure hyperalgesia and increased measures of pain facilitation in healthy subjects, which is consistent with previous findings. Poor quality of sleep is often experienced by patients with chronic pain, with the most common complaint being nightly awakenings. This exploratory study is the first to investigate changes in measures of central and peripheral pain sensitivity in healthy subjects after sleep disruptions for three consecutive nights without any restrictions on total sleep time. The findings suggest that disruptions to sleep continuity in healthy individuals can induce increased sensitivity to measures of central and peripheral pain sensitization.

Concepts of Entheseal Pain.

Pain is the main symptom in entheseal diseases (enthesopathies) despite a paucity of nerve endings in the enthesis itself. Eicosanoids, cytokines, and neuropeptides released during inflammation and repeated nonphysiologic mechanical challenge not only stimulate or sensitize primary afferent neurons present in structures adjacent to the enthesis, but also trigger a "neurovascular invasion" that allows the spreading of nerves and blood vessels into the enthesis. Nociceptive pseudounipolar neurons support this process by releasing neurotransmitters from peripheral endings that induce neovascularization and peripheral pain sensitization. This process may explain the frequently observed dissociation between subjective symptoms such as pain and the structural findings on imaging in entheseal disease.

VALUE OF USING GABAPENTIN FOR KNEE OA PATIENTS: A COST-EFFECTIVENESS ANALYSIS.

Purpose: Pain in individuals with knee OA is understood to be multifactorial. In addition to nociceptive pain arising from tissue pathology, roughly one in three persons with knee OA report nociplastic pain symptoms reflecting peripheral and/or central pain sensitization. This highlights the importance of additional mechanisms that produce pain in persons with OA. Patients with nociplastic mechanisms contributing to their pain may receive less relief from NSAIDs, corticosteroid injections and TKR.

Post-traumatic headache: Pathophysiology and management - A review

Background Post-traumatic headache (PTH) is a common secondary headache due to traumatic brain injury. In the past, significant research has been conducted to understand the pathophysiology and treatment options for PTH. However, PTH still lacks evidence-based treatment, and most of the management depends on the primary phenotype observed in the patient. Objective The main objective of this review is to provide a single reference that covers the current understanding of the pathophysiology and the treatment options available for PTH. Methods A detailed literature search on PubMed was performed, and a narrative review was prepared. Results The pathophysiology of PTH is multifactorial. Acute PTH may be attributed to increased peripheral pain sensitization with impaired pain inhibiting pathways. Chronic or persistent PTH may be due to a chronic inflammatory response and peripheral as well as central sensitization. The mechanism responsible for the transition of acute to persistent PTH is unknown. The migraine-like phenotype is reported to be the most prevalent headache type seen in PTH. New targets for preventive treatment have been identified in recent years, such as neuropeptides like calcitonin-gene-related peptide (CGRP), nitric oxide, and glutamate. The preventive pharmacological and non-pharmacological strategies employed for migraine (e.g. anti-CGRP monoclonal antibodies, onabotulinumtoxinA, physical therapy, cognitive and behavioral treatment, and neurostimulation techniques) have shown in preliminary studies that they are potentially efficacious, but large, randomized, double blind, placebo controlled trials are needed to further establish these as treatment options for PTH. Conclusions The lack of evidence-based treatment for PTH has created a need for future large trials to confirm the safety and efficacy of the currently employed treatments.

Mechanisms of Peripheral and Central Pain Sensitization: Focus on Ocular Pain.

Persistent ocular pain caused by corneal inflammation and/or nerve injury is accompanied by significant alterations along the pain axis. Both primary sensory neurons in the trigeminal nerves and secondary neurons in the spinal trigeminal nucleus are subjected to profound morphological and functional changes, leading to peripheral and central pain sensitization. Several studies using animal models of inflammatory and neuropathic ocular pain have provided insight about the mechanisms involved in these maladaptive changes. Recently, the advent of new techniques such as optogenetics or genetic neuronal labelling has allowed the investigation of identified circuits involved in nociception, both at the spinal and trigeminal level. In this review, we will describe some of the mechanisms that contribute to the perception of ocular pain at the periphery and at the spinal trigeminal nucleus. Recent advances in the discovery of molecular and cellular mechanisms contributing to peripheral and central pain sensitization of the trigeminal pathways will be also presented.

Sympathetic and sensory nerve fiber function in multiple system atrophy and idiopathic Parkinson\u2019s disease

ObjectiveTo explore small fiber somatosensory and sympathetic function in PD and MSA.MethodsWe recruited 20 PD patients (7 women, median age 65.5 years; IQR 54.75–70.0), 10 MSA patients (4 women; median age 68 years; IQR 66.25–74.0), and 10 healthy subjects (HC; 4 women, median age 68; IQR 59.0–71.0 years). Autonomic testing included forehead cooling, intradermal microdialysis of norepinephrine (NE; 10–5; 10–6; 10–7; and 10–8), and orthostatic hypotension (OH); somatosensory testing included quantitative sensory testing (QST) according to the protocol of the German Research Network on Neuropathic Pain (DFNS).ResultsOH occurred more frequently in PD (p = 0.018) and MSA (p = 0.002) compared to HC. Vasoconstriction responses were stronger in PD compared to MSA during forehead cooling (p = 0.044) and microdialysis of physiologically concentrated NE solutions (10–7; 10–8; p = 0.017). PD and MSA had impaired cold (PD: p < 0.01; MSA: p < 0.05) and warm detection thresholds (PD and MSA, both p < 0.05). The mechanical detection threshold was higher in PD (p < 0.01). Conversely, mechanical pain thresholds were decreased in PD and MSA (both p < 0.001), indicating mechanical hyperalgesia.ConclusionIn contrast to MSA, we found evidence of peripheral adrenoreceptor hypersensitivity in PD, probably caused by peripheral sympathetic denervation. Sensory testing revealed peripheral neuropathy and central pain sensitization in PD and MSA. Jointly, our data demonstrate autonomic and somatosensory dysfunction in PD and MSA.

Effects of Interleukin-1β in Glycinergic Transmission at the Central Amygdala

Interleukin-1β (IL-1β) is an important cytokine that modulates peripheral and central pain sensitization at the spinal level. Among its effects, it increases spinal cord excitability by reducing inhibitory Glycinergic and GABAergic neurotransmission. In the brain, IL-1β is released by glial cells in regions associated with pain processing during neuropathic pain. It also has important roles in neuroinflammation and in regulating NMDA receptor activity required for learning and memory. The modulation of glycine-mediated inhibitory activity via IL-1β may play a critical role in the perception of different levels of pain. The central nucleus of the amygdala (CeA) participates in receiving and processing pain information. Interestingly, this nucleus is enriched in the regulatory auxiliary glycine receptor (GlyR) β subunit (βGlyR); however, no studies have evaluated the effect of IL-1β on glycinergic neurotransmission in the brain. Hence, we hypothesized that IL-1β may modulate GlyR-mediated inhibitory activity via interactions with the βGlyR subunit. Our results show that the application of IL-1β (10 ng/ml) to CeA brain slices has a biphasic effect; transiently increases and then reduces sIPSC amplitude of CeA glycinergic currents. Additionally, we performed molecular docking, site-directed mutagenesis, and whole-cell voltage-clamp electrophysiological experiments in HEK cells transfected with GlyRs containing different GlyR subunits. These data indicate that IL-1β modulates GlyR activity by establishing hydrogen bonds with at least one key amino acid residue located in the back of the loop C at the ECD domain of the βGlyR subunit. The present results suggest that IL-1β in the CeA controls glycinergic neurotransmission, possibly via interactions with the βGlyR subunit. This effect could be relevant for understanding how IL-1β released by glia modulates central processing of pain, learning and memory, and is involved in neuroinflammation.

Nociceptive mechanisms driving pain in a post-traumatic osteoarthritis mouse model

In osteoarthritis (OA), pain is the dominant clinical symptom, yet the therapeutic approaches remain inadequate. The knowledge of the nociceptive mechanisms in OA, which will allow to develop effective therapies for OA pain, is of utmost need. In this study, we investigated the nociceptive mechanisms involved in post-traumatic OA pain, using the destabilization of the medial meniscus (DMM) mouse model. Our results revealed the development of peripheral pain sensitization, reflected by augmented mechanical allodynia. Along with the development of pain behaviour, we observed an increase in the expression of calcitonin gene-related peptide (CGRP) in both the sensory nerve fibers of the periosteum and the dorsal root ganglia. Interestingly, we also observed that other nociceptive mechanisms commonly described in non-traumatic OA phenotypes, such as infiltration of the synovium by immune cells, neuropathic mechanisms and also central sensitization were not present. Overall, our results suggest that CGRP in the sensory nervous system is underlying the peripheral sensitization observed after traumatic knee injury in the DMM model, highlighting the CGRP as a putative therapeutic target to treat pain in post-traumatic OA. Moreover, our findings suggest that the nociceptive mechanisms involved in driving pain in post-traumatic OA are considerably different from those in non-traumatic OA.

Clinical Relevance of Skin Pain in Atopic Dermatitis

Skin pain is increasingly recognized as an impactful symptom in atopic dermatitis (AD) because of its association with patient discomfort, disease burden, and reduced quality of life. Although the nature of skin pain in AD has not been systematically studied and is therefore not well understood, patients report soreness, discomfort, and tenderness that may reflect peripheral and central pain sensitization. The high prevalence of skin pain suggests that it is not adequately addressed by current therapies for AD and may be undertreated compared with other symptoms. This review discusses the clinical relevance of skin pain with respect to its experience, pathophysiology, relationship with itch, and treatment implications. Recent studies suggest that skin pain presents as a neuropathic symptom independent from itch and the &ldquo;itch-scratch cycle&rdquo;, and poses a unique burden to patients. Recognition of the significant consequences of skin pain and discomfort should reinforce the need to assess and treat this symptom in patients with moderate-to-severe AD. J Drugs Dermatol. 2020;19(10)921-926. doi:10.36849/JDD.2020.5498.

Long-term small-fiber neuropathy and pain sensitization in survivors of pediatric acute lymphoblastic leukemia after stem cell transplantation

PurposeWe aimed at describing for the first time peripheral small-fiber neurotoxicity and pain sensitization in survivors of pediatric acute lymphoblastic leukemia after stem cell transplantation (SCT).MethodsIn a cross-sectional, retrospective, single-center study, we assessed 25 relapse-free long-term survivors (median age at SCT: 11 ± 4.9 years; median time between SCT and testing: 8.25 years, 19 males) using a reduced version of the pediatric-modified total neuropathy score for clinical assessment and Quantitative Sensory Testing (QST). Inclusion criteria: ge 6 years old at testing, le 18 years old at time of SCT, ge 1 year between SCT and testing.ResultsNine patients (36%) had peripheral neuropathy as defined by the clinical red-pmTNS (≥ 4). The QST parameters mechanical pain sensitivity, mechanical detection threshold, thermal sensory limen, vibration detection threshold and pressure pain threshold were significantly abnormal in the survivor cohort (p < 0.0038). Except for one, all survivors showed at least one abnormal QST parameter. When using QST, signs of small and large fiber dysfunction were present in 22 (88%) and 17 (68%) survivors, respectively. More than half of all survivors were found to experience pathologic sensitization to pain.Conclusions and implications for cancer survivorsSurvivors of pediatric acute lymphoblastic leukemia after SCT are at high risk for long-term peripheral neuropathy with a dominating small-fiber and pain sensitization pattern.

Relation of pain mechanisms to development of knee pain in osteoarthritis in the multicenter osteoarthritis study

Purpose: The mechanism by which intermittent, activity-related or weight-bearing pain in knee osteoarthritis (OA) progresses to more persistent pain is not clear. Peripheral and central pain sensitization have been associated with pain severity, and abnormal descending pain modulation has been postulated to also be important in the pain experience, but as yet little is known about its role in those with knee OA. Whether any of these mechanisms impact the risk of developing knee pain, more pain severity, and/or change in pain patterns from intermittent to more persistent pain is not clear.

Pre-operative pressure pain thresholds do not meaningfully explain satisfaction or improvement in pain after knee replacement: a cohort study

Pain sensitization could be a risk factor for poor outcomes after knee replacement surgery (KR) for knee osteoarthritis (KOA). We aimed to evaluate the association between pre-operative central and peripheral pain sensitization measured using a digital pressure algometer and KR outcomes. Consecutive patients with severe KOA listed for KR were recruited. Sociodemographic and symptoms data were collected prior to surgery. Pre-operative pressure pain thresholds (PPTs) were measured using a digital pressure algometer at the index knee and forearm. Patient satisfaction at 6 and 12 months after KR was assessed using a 4-point Likert scale, and dichotomized to satisfied and dissatisfied to KR. Western Ontario and McMaster Universities Index (WOMAC) Pain and function was assessed. The associations between pre-operative PPTs with KR outcomes at 6 and 12 months were evaluated. Of the 243 patients recruited, response rate at 6 and 12 months were 95.5% and 96.7%. The dissatisfaction rates were 8.2% and 5.1% at 6 and 12 months. There was no statistically significant association between pre-operative index knee or forearm PPTs and patient satisfaction. PPTs measured at the knee, but not the forearm, were weakly associated with change in the WOMAC pain score at 12 months, after adjustment for confounding factors. Pre-operative central sensitization, measured by handheld digital algometry, was not statistically significantly associated with satisfaction or change in pain after KR. Pre-operative peripheral sensitization was associated with change in pain symptoms after KR; however, this association was weak and unlikely to be a meaningful predictor of KR outcome in clinical practice.

Central and peripheral pain sensitization during an ultra-marathon competition.

Background and aims The participation in ultra-marathons and other ultra-endurance events has increased exponentially over the past decade. There is insufficient data on variation in pain mechanisms in exercise overall but especially in the ultra-endurance athlete population. To further understand peripheral and central pain sensitization we have investigated pressure pain threshold and conditioned pain modulation during three separate ultra-marathon competitions. Methods Each ultra-marathon investigated was held in the state of Florida, USA, over flat, sandy and paved surfaces under generally warm to hot, humid conditions. Pressure pain threshold was measured utilizing a Baseline © Dolorimeter. The blunt end of the dolorimeter stylus was placed onto the distal dominant arm, equidistant between the distal radius and ulna, three times in a blinded manner to insure that the testing technician did not influence the subject's responses. Conditioned pain modulation was measured immediately after the PPT measures by placing the non-dominant hand in a cool water bath maintained at 15°C. The same dolorimeter measurement was repeated two more times on the dominant arm while the non-dominant hand remained in the water. Data was analyzed with a paired t-test. Results Pressure pain threshold was significantly decreased (p<0.05) at 25, 50 and 100 miles. Conditioned pain modulation was also significantly decreased (p<0.05) at 25, 50 and 100 miles of an ultra-marathon competition. Conclusions Together these data suggest an increased peripheral and/or central pain sensitization starting at 25 miles and continuing throughout an ultra-marathon competition run in these conditions. This is the first study that provides evidence of a decreased peripheral pain threshold and decreased central pain inhibition from ultra-marathon running. Decreases in both the peripheral pain threshold and central inhibition may result from nociceptor plasticity, central sensitization or a combination of both. Implications Based on previous research that has indicated a central sensitization resulting from inflammation and the well-documented inflammatory response to the rigors of ultra-marathon competition, we suggest the decreased peripheral pain threshold and decreased descending pain inhibition results from this inflammatory response of running an ultra-marathon.

Progress in gap junction protein 43 in chronic pain

Gap junction (GJ) plays an important role in cell communication. It is widely distributed in mammalian organs and tissues (except red blood cells and skeletal muscle). The overexpression of GJ and the enhancement of function are closely related to the mechanism of peripheral and central pain sensitization. Astrocytes are the most abundant type of glial cell in the central nervous system, and the major structural components of gap junctions are the connexin 43 (Cx43) subunit. Cx43 may play key role in chronic pain process, including the regulation of the coupling and function of GJ.

CGRP Monoclonal Antibodies for Migraine: Rationale and Progress.

Calcitonin gene-related peptide (CGRP), a neuropeptide abundant in the trigeminal system and widely expressed in both the peripheral and central nervous systems, has recently emerged as a promising target for migraine management. While known as a potent arterial vasodilator, the role of CGRP in migraine is likely mediated by modulating nociception and sustaining neurogenic inflammation that leads to further peripheral and central pain sensitization. Functional blockade of CGRP, which involves either CGRP receptor antagonists or monoclonal antibodies (mAbs) to CGRP or its receptor, has recently shown clinical efficacy in migraine management. The site of action, although still being studied, is likely in nervous system structures outside the blood-brain barrier. To date, four CGRP function-blocking mAbs (three target CGRP and one targets the CGRP receptor) are under clinical investigation for migraine prophylaxis. Phase II and III studies were promising with favorable safety profiles. CGRP function-blocking mAbs may potentially revolutionize the management of migraine. This review discusses in depth the fundamental role of CGRP in migraine pathogenesis as well as the clinical efficacy of CGRP function-blocking mAbs.

The scaffold protein calcium/calmodulin-dependent serine protein kinase controls ATP release in sensory ganglia upon P2X3 receptor activation and is part of an ATP keeper complex.

P2X3 receptors, gated by extracellular ATP, are expressed by sensory neurons and are involved in peripheral nociception and pain sensitization. The ability of P2X3 receptors to transduce extracellular stimuli into neuronal signals critically depends on the dynamic molecular partnership with the calcium/calmodulin-dependent serine protein kinase (CASK). The present work used trigeminal sensory neurons to study the impact that activation of P2X3 receptors (evoked by the agonist α,β-meATP) has on the release of endogenous ATP and how CASK modulates this phenomenon. P2X3 receptor function was followed by ATP efflux via Pannexin1 (Panx1) hemichannels, a mechanism that was blocked by the P2X3 receptor antagonist A-317491, and by P2X3 silencing. ATP efflux was enhanced by nerve growth factor, a treatment known to potentiate P2X3 receptor function. Basal ATP efflux was not controlled by CASK, and carbenoxolone or Pannexin silencing reduced ATP release upon P2X3 receptor function. CASK-controlled ATP efflux followed P2X3 receptor activity, but not depolarization-evoked ATP release. Molecular biology experiments showed that CASK was essential for the transactivation of Panx1 upon P2X3 receptor activation. These data suggest that P2X3 receptor function controls a new type of feed-forward purinergic signaling on surrounding cells, with consequences at peripheral and spinal cord level. Thus, P2X3 receptor-mediated ATP efflux may be considered for the futuredevelopment of pharmacological strategies aimed at containing neuronal sensitization. P2X3 receptors are involved in sensory transduction and associate to CASK. We have studied in primary sensory neurons the molecular mechanisms downstream P2X3 receptor activation, namely ATP release and partnership with CASK or Panx1. Our data suggest that CASK and P2X3 receptors are part of an ATP keeper complex, with important feed-forward consequences at peripheral and central level.

Neural correlates of hyperalgesia in the monosodium iodoacetate model of osteoarthritis pain.

BackgroundThe mechanisms driving osteoarthritic pain remain poorly understood, but there is increasing evidence for a role of the central nervous system in the chronification of pain. We used functional magnetic resonance imaging to investigate the influence of a model of unilateral knee osteoarthritis on nociceptive processing.ResultsFour to five weeks post intra-articular injection of monosodium iodoacetate (MIA, 1 mg) into the left knee, Sprague Dawley rats were anesthetized for functional magnetic resonance imaging studies to characterize the neural response to a noxious stimulus (intra-articular capsaicin injection). In a two-arm cross-over design, 5 µM/50 µl capsaicin was injected into either the left knee (n = 8, CAPS-MIA) or right control knee (n = 8, CAPS-CON), preceded by contralateral vehicle (SAL) injection. To assess neural correlates of mechanical hyperalgesia, hindpaws were stimulated with von Frey hairs (8 g: MIA; 15 g: control knee, based on behavioral withdrawal responses). The CAPS-MIA group exhibited significant activation of the periaqueductal gray, unilateral thalamus and bilateral mensencephalon, superior-colliculus, and hippocampus, with no significant activation in the other groups/conditions. Capsaicin injection increased functional connectivity in the mid-brain network and mediodorsal thalamic nucleus, hippocampus, and globus pallidus, which was significantly stronger in CAPS-MIA compared to CAPS-CON groups. Mechanical stimulation of the hyperalgesic (ipsilateral to MIA knee) and normalgesic (contralateral) hindpaws evoked qualitatively different brain activation with more widespread brainstem and anterior cingulate (ACC) activation when stimulating the hyperalgesic paw, and clearer frontal sensory activation from the normalgesic paw.ConclusionsWe provide evidence for modulation of nociceptive processing in a chronic knee osteoarthritis pain model with stronger brain activation and alteration of brain networks induced by the pro-nociceptive stimulus. We also report a shift to a medial pain activation pattern following stimulation of the hyperalgesic hindpaw. Taken together, our data support altered neural pain processing as a result of peripheral and central pain sensitization in this model.