Secondary Mechanical Hyperalgesia Research Articles

The effect of top-down attention on secondary mechanical hyperalgesia: improvements and controversies?

The effect of top-down attention on secondary mechanical hyperalgesia: improvements and controversies?

Osteosarcoma-Induced Pain Is Mediated by Glial Cell Activation in the Spinal Dorsal Horn, but Not Capsaicin-Sensitive Nociceptive Neurons: A Complex Functional and Morphological Characterization in Mice.

Bone cancer and its related chronic pain are huge clinical problems since the available drugs are often ineffective or cannot be used long term due to a broad range of side effects. The mechanisms, mediators and targets need to be identified to determine potential novel therapies. Here, we characterize a mouse bone cancer model induced by intratibial injection of K7M2 osteosarcoma cells using an integrative approach and investigate the role of capsaicin-sensitive peptidergic sensory nerves. The mechanical pain threshold was assessed by dynamic plantar aesthesiometry, limb loading by dynamic weight bearing, spontaneous pain-related behaviors via observation, knee diameter with a digital caliper, and structural changes by micro-CT and glia cell activation by immunohistochemistry in BALB/c mice of both sexes. Capsaicin-sensitive peptidergic sensory neurons were defunctionalized by systemic pretreatment with a high dose of the transient receptor potential vanilloid 1 (TRPV1) agonist resiniferatoxin (RTX). During the 14- and 28-day experiments, weight bearing on the affected limb and the paw mechanonociceptive thresholds significantly decreased, demonstrating secondary mechanical hyperalgesia. Signs of spontaneous pain and osteoplastic bone remodeling were detected both in male and female mice without any sex differences. Microglia activation was shown by the increased ionized calcium-binding adapter molecule 1 (Iba1) immunopositivity on day 14 and astrocyte activation by the enhanced glial fibrillary acidic protein (GFAP)-positive cell density on day 28 in the ipsilateral spinal dorsal horn. Interestingly, defunctionalization of the capsaicin-sensitive afferents representing approximately 2/3 of the nociceptive fibers did not alter any functional parameters. Here, we provide the first complex functional and morphological characterization of the K7M2 mouse osteosarcoma model. Bone-cancer-related chronic pain and hyperalgesia are likely to be mediated by central sensitization involving neuroinflammation via glial cell activation in the spinal dorsal horn, but not the capsaicin-sensitive sensory neuronal system.

Healthy women show more experimentally induced central sensitization compared with men.

Women more often experience chronic pain conditions than men. Central sensitization (CS) is one key mechanism in chronic pain that can differ between the sexes. It is unknown whether CS processes are already more pronounced in healthy women than in men. In 66 subjects (33 women), a thermal CS induction protocol was applied to the dorsum of one foot and a sham protocol to the other. Spatial extent [cm 2 ] of secondary mechanical hyperalgesia (SMH) and dynamic mechanical allodynia were assessed as subjective CS proxy measures, relying on verbal feedback. Changes in nociceptive withdrawal reflex magnitude (NWR-M) and response rate (NWR-RR) recorded through surface electromyography at the biceps and rectus femoris muscles were used as objective CS proxies. The effect of the CS induction protocol on SMH was higher in women than in men (effect size 2.11 vs 1.68). Nociceptive withdrawal reflex magnitude results were statistically meaningful for women (effect size 0.31-0.36) but not for men (effect size 0.12-0.29). Differences between men and women were not meaningful. Nociceptive withdrawal reflex response rate at the rectus femoris increased in women after CS induction and was statistically different from NWR-RR in men (median differences of 13.7 and 8.4% for 120 and 140% reflex threshold current). The objective CS proxy differences indicate that dorsal horn CS processes are more pronounced in healthy women. The even larger sex differences in subjective CS proxies potentially reflect greater supraspinal influence in women. This study shows that sex differences are present in experimentally induced CS in healthy subjects, which might contribute to women's vulnerability for chronic pain.

Reliability of quantitative sensory testing in the assessment of somatosensory function after high-frequency stimulation-induced sensitisation of central nociceptive pathways.

The high frequency stimulation (HFS) model can be used alongside quantitative sensory testing (QST) to assess the sensitisation of central nociceptive pathways. However, the validity and between-session reliability of using QST z -score profiles to measure changes in mechanical and thermal afferent pathways in the HFS model are poorly understood. In this study, 32 healthy participants underwent QST before and after HFS (5× 100 Hz trains; 10× electrical detection threshold) in the same heterotopic skin area across 2 repeated sessions. The only mechanical QST z -score profiles that demonstrated a consistent gain of function across repeated test sessions were mechanical pain threshold (MPT) and mechanical pain sensitivity (MPS), which were associated with moderate and good reliability, respectively. There was no relationship between HFS intensity and MPT and MPS z -score profiles. There was no change in low intensity, but a consistent facilitation of high-intensity pin prick stimuli in the mechanical stimulus response function across repeated test sessions. There was no change in cold pain threshold (CPT) and heat pain threshold (HPT) z -score profiles across session 1 and 2, which were associated with moderate and good reliability, respectively. There were inconsistent changes in the sensitivity to innocuous thermal QST parameters, with cool detection threshold (CDT), warm detection threshold (WDT), and thermal sensory limen (TSL) all producing poor reliability. These data suggest that HFS-induced changes in MPS z -score profiles is a reliable way to assess experimentally induced central sensitisation and associated secondary mechanical hyperalgesia in healthy participants.

Pramipexole inhibits formalin-induce acute and long-lasting mechanical hypersensitivity via NF-kB pathway in rats.

Pain is one of the most frequent causes for patients to seek medical care. It interferes with daily functioning and affects the quality of life of the patient. There is a clear need to investigate nonopioid or non-nonsteroidal anti-inflammatory drug alternatives for the treatment of pain. In this study, we determined the effect of acute pre- and posttreatment with pramipexole (PPX), a dopamine D2/D3 selective agonist, on formalin 1%-induced acute and long-lasting nociceptive behavior sensitivity in rats. Moreover, we sought to investigate whether the antiallodynic and antihyperalgesic effect induced by PPX was mediated through the nuclear factor-κB(NF-kB) signaling pathway. Moreover, acute systemic pretreatment with PPX (1 and 3 mg/kg, ip) suppressed the formalin-induced nociceptive behavior during both phases of the formalin test and the development of formalin-induced secondary mechanical allodynia and hyperalgesia in both paws. Acute systemic posttreatment with PPX (3 mg/kg, ip) reverted the formalin-induced long-lasting secondary mechanical allodynia and hyperalgesia. Furthermore, PPX inhibits the protein expression of NF-κB-p65 and the levels of tumor necrosis factor-α and interleukin-1β in the spinal cord of animals with secondary mechanical allodynia and hyperalgesia induced by formalin. These data suggest that PPX has a potential role in producing anti-inflammatory activity. Moreover, the antiallodynic and antihyperalgesic effects induced by PPX can be mediated through the NF-kB signaling pathway.

Chronic temporomandibular disorders are associated with higher propensity to develop central sensitization: a case-control study.

Temporomandibular disorders (TMD) include a group of musculoskeletal disorders that may involve increased responsiveness of nociceptive neurons in the central nervous system (ie, central sensitization). To test this hypothesis further, this study examined whether, as compared with healthy subjects, patients with chronic TMD have a greater propensity to develop secondary mechanical hyperalgesia-a phenomenon that can be confidently attributed to central sensitization. In this case-control study, we assessed the area of secondary mechanical hyperalgesia induced experimentally by delivering high-frequency electrical stimulation (HFS) to the volar forearm skin in 20 participants with chronic TMD and 20 matched healthy controls. High-frequency electrical stimulation consisted in 12 trains of constant-current electrical pulses (5 mA) delivered at 42 Hz. The area of secondary mechanical hyperalgesia was evaluated 30 minutes after applying HFS. The area of secondary mechanical hyperalgesia induced by HFS was on average 76% larger in the chronic TMD group (M = 67.7 cm 2 , SD = 28.2) than in the healthy control group (M = 38.4 cm 2 , SD = 14.9; P = 0.0003). Regarding secondary outcomes, there was no group difference in the intensity of secondary mechanical hyperalgesia, but allodynia to cotton after HFS was more frequent in the chronic TMD group. To the best of our knowledge, this is the first study to show that individuals with chronic TMD have an increased propensity to develop secondary hyperalgesia in a site innervated extratrigeminally. Our results contribute to a better understanding of the pathophysiology of chronic TMD.

A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5–7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

Multichanneltranscranial direct current stimulation over the left dorsolateral prefrontalcortex may modulate the induction of secondary hyperalgesia, a double-blinded cross-over study in healthy volunteers.

Central sensitization is thought to play a critical role in the development of chronic pain, and secondary mechanical hyperalgesia is considered one of its hall-mark features. Consequently, interventions capable of modulating its development could have important therapeutic value. Non-invasive neuromodulation of the left dorsolateral prefrontal cortex (DLPFC) has shown potential to reduce pain, both in healthy volunteers and in patients. Whether it can modulate the induction of central sensitization, however, is less well known. To determine whether multifocal transcranial direct current stimulation (tDCS) targeting the left DLPFC affects the development of secondary mechanical hyperalgesia. In this within-subjects, cross-over, double-blinded study, eighteen healthy volunteers participated in three experimental sessions. After 20 minutes of either anodal, cathodal, or sham multichannel tDCS over the left DLPFC, secondary mechanical hyperalgesia was induced using high-frequency electrical stimulation (HFS) of the volar forearm. We assessed intensity of perception to 128 mN mechanical pinprick stimuli at baseline and up to 240 minutes after HFS. We also mapped the area of mechanical hyperalgesia. HFS resulted in a robust and unilateral increase in the intensity of perception to mechanical pinprick stimuli at the HFS arm, which was not different between tDCS stimulation conditions. However, the area of hyperalgesia was reduced after anodal tDCS compared to sham. Anodal tDCS over the left DLPFC modestly modulates the size of the HFS-induced area of secondary mechanical hyperalgesia, suggesting that non-invasive neuromodulation targeting the left DLPFC may be a potential intervention to limit the development of central sensitization.

Modulation of the N13 component of the somatosensory evoked potentials in an experimental model of central sensitization in humans

The N13 component of somatosensory evoked potential (N13 SEP) represents the segmental response of dorsal horn neurons. In this neurophysiological study, we aimed to verify whether N13 SEP might reflect excitability changes of dorsal horn neurons during central sensitization. In 22 healthy participants, we investigated how central sensitization induced by application of topical capsaicin to the ulnar nerve territory of the hand dorsum modulated N13 SEP elicited by ulnar nerve stimulation. Using a double-blind placebo-controlled crossover design, we also tested whether pregabalin, an analgesic drug with proven efficacy on the dorsal horn, influenced capsaicin-induced N13 SEP modulation. Topical application of capsaicin produced an area of secondary mechanical hyperalgesia, a sign of central sensitization, and increased the N13 SEP amplitude but not the peripheral N9 nor the cortical N20-P25 amplitude. This increase in N13 SEP amplitude paralleled the mechanical hyperalgesia and persisted for 120 min. Pregabalin prevented the N13 SEP modulation associated with capsaicin-induced central sensitization, whereas capsaicin application still increased N13 SEP amplitude in the placebo treatment session. Our neurophysiological study showed that capsaicin application specifically modulates N13 SEP and that this modulation is prevented by pregabalin, thus suggesting that N13 SEP may reflect changes in dorsal horn excitability and represent a useful biomarker of central sensitization in human studies.

TREK-1 potassium channels participate in acute and long-lasting nociceptive hypersensitivity induced by formalin in rats

TREK-1 potassium channels participate in acute and long-lasting nociceptive hypersensitivity induced by formalin in rats

Functional brain response to painful mechanical stimulation and painful stimulation in areas of secondary mechanical hyperalgesia: A meta-analysis

Functional brain response to painful mechanical stimulation and painful stimulation in areas of secondary mechanical hyperalgesia: A meta-analysis

Evidence of Widespread Mechanical Hyperalgesia but Not Exercise-Induced Analgesia in Athletes With Mild Patellar Tendinopathy Compared With Pain-Free Matched Controls: A Blinded Exploratory Study.

The aim of the study was to assess centrally induced pain processing with pressure pain thresholds bilaterally and remotely in active volleyball and basketball athletes with mild patellar tendinopathy compared with asymptomatic control athletes. Secondary objective was to explore the role of exercise-induced analgesia during a training session in athletes with patellar tendinopathy. In this exploratory study, pressure pain thresholds of 21 patellar tendinopathy athletes and 16 age- and sex-matched asymptomatic team members were measured by a blinded assessor bilaterally on the patellar tendon and unilaterally on the elbow extensor tendon with a pressure algometer before, during, and after a regular training session. Patellar tendinopathy athletes had a significantly higher average body mass index compared with asymptomatic athletes (mean difference 1.75 kg/m2; 95% confidence interval = 0.35-3.15, P = 0.02). At baseline, athletes with patellar tendinopathy showed lowered pressure pain thresholds in the affected knee (P = 0.001), unaffected knee (P < 0.001), and elbow (P = 0.01) compared with controls. No clear patterns were identified to explain between-group differences in pressure pain thresholds before, during, and after exercise. This exploratory study found primary and secondary mechanical hyperalgesia in athletes with patellar tendinopathy compared with asymptomatic athletes. Further research is required on the effects of an acute exercise bout on pain thresholds in this population.

Does central sensitization affect hyperalgesia after staged bilateral total knee arthroplasty? A randomized controlled trial.

ObjectiveOsteoarthritis (OA) patients who undergo staged bilateral total knee arthroplasty (TKA) feel postoperative hyperalgesia in the second operated knee compared with the first knee. Ketamine is an important drug for central temporal summation and inhibition of secondary mechanical hyperalgesia. This study investigated whether central sensitization has a significant effect on hyperalgesia after consecutive operations.MethodsSeventy-one of 80 OA patients were randomly allocated to the ketamine or saline group. A bolus of ketamine (group K) or saline (group C) (0.5 mg/kg) was injected before induction and at an infusion rate of 3 µg/kg/minute during surgery. A visual analog scale (VAS) was used to assess resting and moving pain and opioid consumption on postoperative days 1, 2, and 3.ResultsThe difference in the VAS score between stages 1 and 2 (DV2-V1) was higher in the ketamine compared with the saline group. DV2-V1 for movement between the two groups was not inferior for all periods. Ketamine did not show a large analgesic effect on second-operated knee hyperalgesia in staged bilateral TKAs.ConclusionsWe could not confirm that hyperalgesia was only related to central sensitization with low-dose ketamine. Other factors might be also associated with the hyperexcitability of nociceptive stimuli.Clinical Research Information Service (CRIS) trial registry no: KCT0001481

Capsaicin-Induced Changes in Electrical Pain Perception Threshold Can Be Used to Assess the Magnitude of Secondary Hyperalgesia in Humans.

Areas of secondary hyperalgesia can be assessed using quantitative sensory testing (QST). Delivering noxious electrocutaneous stimulation could provide added benefit by allowing multiple measurements of the magnitude of hyperalgesia. We aimed to characterize the use of electrical pain perception (EPP) thresholds alongside QST as a means by which to measure changes in pain thresholds within an area of secondary mechanical hyperalgesia. EPP and heat pain thresholds (HPTs) were measured at five distinct points at baseline and following 1% capsaicin cream application, one within a central zone and four within a secondary zone. Areas of secondary mechanical hyperalgesia were mapped using QST. In a further 14 participants, capsaicin-induced reduction in EPP thresholds was mapped using a radial lines approach across 24 points. There was a reduction in EPP threshold measured at the four points within the secondary zone, which was within the mapped area of mechanical secondary hyperalgesia. The magnitude of secondary hyperalgesia could be split into a mild (∼4% reduction) and severe (∼21% reduction) area within an individual subject. There was no reduction in HPT within the secondary zone, but there was a reduction in both HPT and EPP threshold within the primary zone. EPP mapping revealed differences in the magnitude and spread of hyperalgesia across all subjects. Measuring capsaicin-induced reduction in EPP thresholds can be used to map hyperalgesic areas in humans. This semi-automated approach allows rapid assessment of the magnitude of hyperalgesia, both within an individual subject and across a study population.

Anodal transcranial direct current stimulation over the primary motor cortex attenuates capsaicin-induced dynamic mechanical allodynia and mechanical pain sensitivity in humans.

Anodal transcranial direct current stimulation over the primary cortex has been shown to activate regions of the brain involved in the descending modulation of pain sensitivity. However, more research is required to dissect the spinal cord analgesic mechanisms associated with the development of central sensitization. In this randomized, double blind, crossover study 12 healthy participants had baseline mechanical stimulus response (S/R) functions measured before and after the development of capsaicin-induced ongoing pain sensitivity. The effects of 20min of either real or sham transcranial direct current stimulation (tDCS, 2mA) over the primary motor cortex on dynamic mechanical allodynia (DMA) and mechanical pain sensitivity (MPS) were then investigated. Topical application of capsaicin resulted in an increase in area under the pain ratings curve for both DMA (p<.01) and MPS (p<.01). The effects of tDCS on the area under the curve ratio (i.e. post-/pre-treatment) revealed significant analgesic effects over DMA (p<.05) and MPS (p<.05) when compared with sham. This study demonstrates that anodal tDCS over the primary motor cortex can reduce both dynamic and static forms of mechanical pain sensitivity associated with the development of DMA and MPS, respectively. The use of tDCS may provide a novel mechanism-driven therapy in chronic pain patients with altered mechanical S/R functions. This research shows new evidence that anodal tDCS over the primary motor cortex can reduce dynamic and static forms of mechanical pain sensitivity in the capsaicin model of ongoing pain. By using this approach, it may be possible to provide mechanism-driven analgesia in chronic pain patients who have dynamic mechanical allodynia and/or secondary mechanical hyperalgesia.

Effects of Intramuscular Heating-needle Stimulation in Controlling Adjuvant-induced Muscle Nociception in Rats: Differential Roles of Thalamic Purinergic P2X3 Receptors

Effects of Intramuscular Heating-needle Stimulation in Controlling Adjuvant-induced Muscle Nociception in Rats: Differential Roles of Thalamic Purinergic P2X3 Receptors

Pain-related behaviors associated with persistence of mechanical hyperalgesia after antigen-induced arthritis in rats.

Upon transient musculoskeletal diseases, some patients develop persistent pain while others recover from pain. Here, we studied whether such heterogeneity also occurs in rats after recovery from unilateral antigen-induced arthritis (AIA) in the knee joint, and which pain phenotype may predict the course of pain. Typically, inflammatory swelling lasts about 3 weeks. Pain-related behaviors were monitored for 84 days after AIA induction. Unbiased cluster analysis of intragroup differences at day 84 of AIA revealed that about one-third of the rats (cluster 1) showed persistent mechanical hyperalgesia at the injected knee joint, whereas the other rats (cluster 2) had recovered from pain. Retrograde analysis of pain-related behaviors revealed that cluster 1 rats exhibited more severe mechanical hyperalgesia at the injected knee from day 3 of AIA and mechanical hyperalgesia at the contralateral knee. Cluster 1 and 2 rats did not show different inflammatory swelling, secondary mechanical and thermal hyperalgesia at the ipsilateral hindpaw, guarding score, and asymmetry of weight bearing during AIA. Thus, in particular, early severe mechanical hyperalgesia in the inflamed joint and segmental contralateral mechanical hyperalgesia seem to be a risk factor for the development of persistent mechanical hyperalgesia pointing to the importance of spinal mechanisms. However, none of the rats showed an expression of ATF3 in dorsal root ganglion neurons, nor morphological spinal microglia activation thus not suggesting development of neuropathic pain. Both clusters showed a persistent upregulation of pCREB in dorsal root ganglion neurons, inversely correlated with mechanical hyperalgesia at the knee. The role of pCREB needs to be further explored.

Effect of phenolic compounds from Oenothera rosea on the kaolin-carrageenan induced arthritis model in mice

Effect of phenolic compounds from Oenothera rosea on the kaolin-carrageenan induced arthritis model in mice

The focus of spatial attention during the induction of central sensitization can modulate the subsequent development of secondary hyperalgesia

The focus of spatial attention during the induction of central sensitization can modulate the subsequent development of secondary hyperalgesia

Calcium Channel α2δ1 Subunit Mediates Secondary Orofacial Hyperalgesia Through PKC-TRPA1/Gap Junction Signaling

Calcium Channel α2δ1 Subunit Mediates Secondary Orofacial Hyperalgesia Through PKC-TRPA1/Gap Junction Signaling