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The Journal of Headache and Pain Jan 2019OnabotulinumtoxinA is effective in treating chronic migraine (CM), but there are limited data assessing how allodynia affects preventive treatment responses. This...
BACKGROUND
OnabotulinumtoxinA is effective in treating chronic migraine (CM), but there are limited data assessing how allodynia affects preventive treatment responses. This subanalysis of the 108-week, multicenter, open-label COMPEL Study assessed the efficacy and safety of onabotulinumtoxinA in people with CM with and without allodynia.
METHODS
Patients (n = 715) were treated with onabotulinumtoxinA 155 U every 12 weeks for 9 treatment cycles. The Allodynia Symptom Checklist was used to identify patients with allodynia (scores ≥3). The primary outcome for this subanalysis was reduction in monthly headache days from baseline for weeks 105 to 108 in groups with and without allodynia. Other outcomes included assessments of moderate to severe headache days, disability (using the Migraine Disability Assessment [MIDAS] questionnaire), and health-related quality of life (Migraine-Specific Quality-of-Life Questionnaire [MSQ] v2). Adverse events and their relation to treatment were recorded.
RESULTS
OnabotulinumtoxinA was associated with a significant mean (SD) reduction in headache day frequency at week 108 relative to baseline in patients with (n = 289) and without (n = 426) allodynia (- 10.8 [7.1] and - 12.5 [7.4], respectively; both P < 0.001) that was significantly greater in patients without allodynia (P = 0.044 between-subgroup comparison). Moderate to severe headache days were significantly reduced at week 108 in patients with and without allodynia (- 9.6 [6.9] and - 10.5 [7.2]; both P < 0.001); reduction was similar between groups. MIDAS scores improved significantly at week 108 (- 53.0 [50.3] and - 37.7 [53.0]; both P < 0.001), with a significant between-group difference in favor of those with allodynia (P = 0.005). Similarly, MSQ subscale scores (Role Function Preventive, Role Function Restrictive, Emotional Function) significantly improved at week 108 for patients with and without allodynia: 20.6 (21.9) and 16.9 (20.7), 28.0 (23.3) and 24.7 (22.7), and 27.6 (26.5) and 24.9 (26.1), respectively (all P < 0.001). OnabotulinumtoxinA was well tolerated in patients with and without allodynia.
CONCLUSION
Results indicate that onabotulinumtoxinA is associated with reductions from baseline in multiple efficacy outcomes for up to 108 weeks whether or not allodynia is present. The allodynia group showed a smaller treatment response for reduction in headache days, but a similar or greater treatment response for improvement in other measures. No new safety concerns were identified.
Topics: Adolescent; Adult; Aged; Botulinum Toxins, Type A; Chronic Disease; Female; Humans; Hyperalgesia; Male; Middle Aged; Migraine Disorders; Quality of Life; Surveys and Questionnaires; Treatment Outcome; Young Adult
PubMed: 30669961
DOI: 10.1186/s10194-018-0952-1 -
Brain Research Jul 2024Bestrophin-1 and anoctamin-1 are members of the calcium-activated chloride channels (CaCCs) family and are involved in inflammatory and neuropathic pain. However, their...
Bestrophin-1 and anoctamin-1 are members of the calcium-activated chloride channels (CaCCs) family and are involved in inflammatory and neuropathic pain. However, their role in pain hypersensitivity induced by REM sleep deprivation (REMSD) has not been studied. This study aimed to determine if anoctamin-1 and bestrophin-1 are involved in the pain hypersensitivity induced by REMSD. We used the multiple-platform method to induce REMSD. REM sleep deprivation for 48 h induced tactile allodynia and a transient increase in corticosterone concentration at the beginning of the protocol (12 h) in female and male rats. REMSD enhanced c-Fos and α2δ-1 protein expression but did not change activating transcription factor 3 (ATF3) and KCC2 expression in dorsal root ganglia and dorsal spinal cord. Intrathecal injection of CaCC, a non-selective bestrophin-1 blocker, and T16A, a specific anoctamin-1 blocker, reverted REMSD-induced tactile allodynia. However, T16A had a higher antiallodynic effect in male than female rats. In addition, REMSD increased bestrophin-1 protein expression in DRG but not in DSC in male and female rats. In marked contrast, REMSD decreased anoctamin-1 protein expression in DSC but not in DRG, only in female rats. Bestrophin-1 and anoctamin-1 promote pain and maintain tactile allodynia induced by REM sleep deprivation in both male and female rats, but their expression patterns differ between the sexes.
Topics: Animals; Female; Male; Rats; Anoctamin-1; Bestrophins; Calcium Channels, L-Type; Chloride Channels; Ganglia, Spinal; Hyperalgesia; Rats, Wistar; Sleep Deprivation; Sleep, REM; Spinal Cord
PubMed: 38582414
DOI: 10.1016/j.brainres.2024.148915 -
The Journal of Neuroscience : the... Oct 2019Regulator of G-protein signaling 4 (RGS4) is a potent modulator of G-protein-coupled receptor signal transduction that is expressed throughout the pain matrix. Here, we...
Regulator of G-protein signaling 4 (RGS4) is a potent modulator of G-protein-coupled receptor signal transduction that is expressed throughout the pain matrix. Here, we use genetic mouse models to demonstrate a role of RGS4 in the maintenance of chronic pain states in male and female mice. Using paradigms of peripheral inflammation and nerve injury, we show that the prevention of RGS4 action leads to recovery from mechanical and cold allodynia and increases the motivation for wheel running. Similarly, RGS4KO eliminates the duration of nocifensive behavior in the second phase of the formalin assay. Using the Complete Freud's Adjuvant (CFA) model of hindpaw inflammation we also demonstrate that downregulation of RGS4 in the adult ventral posterolateral thalamic nuclei promotes recovery from mechanical and cold allodynia. RNA sequencing analysis of thalamus (THL) from RGS4WT and RGS4KO mice points to many signal transduction modulators and transcription factors that are uniquely regulated in CFA-treated RGS4WT cohorts. Ingenuity pathway analysis suggests that several components of glutamatergic signaling are differentially affected by CFA treatment between RGS4WT and RGS4KO groups. Notably, Western blot analysis shows increased expression of metabotropic glutamate receptor 2 in THL synaptosomes of RGS4KO mice at time points at which they recover from mechanical allodynia. Overall, our study provides information on a novel intracellular pathway that contributes to the maintenance of chronic pain states and points to RGS4 as a potential therapeutic target. There is an imminent need for safe and efficient chronic pain medications. Regulator of G-protein signaling 4 (RGS4) is a multifunctional signal transduction protein, widely expressed in the pain matrix. Here, we demonstrate that RGS4 plays a prominent role in the maintenance of chronic pain symptoms in male and female mice. Using genetically modified mice, we show a dynamic role of RGS4 in recovery from symptoms of sensory hypersensitivity deriving from hindpaw inflammation or hindlimb nerve injury. We also demonstrate an important role of RGS4 actions in gene expression patterns induced by chronic pain states in the mouse thalamus. Our findings provide novel insight into mechanisms associated with the maintenance of chronic pain states and demonstrate that interventions in RGS4 activity promote recovery from sensory hypersensitivity symptoms.
Topics: Animals; Chronic Pain; Down-Regulation; Female; Hyperalgesia; Male; Mice; Mice, Knockout; Pain Measurement; RGS Proteins; Sex Factors; Signal Transduction; Thalamic Nuclei
PubMed: 31308097
DOI: 10.1523/JNEUROSCI.3154-18.2019 -
British Journal of Pharmacology Jul 2012Hydrogen sulfide, a gasotransmitter, facilitates somatic pain signals via activation of Ca(v)3.2 T-type calcium channels in rats. Given evidence for the activation of...
BACKGROUND AND PURPOSE
Hydrogen sulfide, a gasotransmitter, facilitates somatic pain signals via activation of Ca(v)3.2 T-type calcium channels in rats. Given evidence for the activation of transient receptor potential ankyrin-1 (TRPA1) channels by H(2)S, we asked whether TRPA1 channels, in addition to Ca(v)3.2 channels, contribute to the H(2)S-induced mechanical hyperalgesia and allodynia in mice.
EXPERIMENTAL APPROACH
Mechanical hyperalgesia and allodynia were evaluated by the von Frey test in mice. Ca(v)3.2 or TRPA1 channels in the sensory neurons were silenced by repeated intrathecal administration of antisense oligodeoxynucleotides in mice.
KEY RESULTS
Intraplantar administration of NaHS evoked hyperalgesia and allodynia in mice, an effect attenuated or abolished by NNC 55-0396 or mibefradil, T-type calcium channel blockers, and by ascorbic acid or zinc chloride, known to selectively inhibit Ca(v)3.2 channels, out of the three isoforms of T-type calcium channels. Silencing of Ca(v)3.2 channels in the sensory neurons also prevented the NaHS-induced hyperalgesia and allodynia in mice. The NaHS-induced hyperalgesia and allodynia in mice were significantly suppressed by AP18, a TRPA1 channel blocker, and by silencing of TRPA1 channels in the sensory neurons.
CONCLUSIONS AND IMPLICATIONS
Mechanical hyperalgesia and allodynia induced by NaHS/H(2)S required activation of both Ca(v)3.2 and TRPA1 channels in mice.
Topics: Animals; Calcium Channel Blockers; Calcium Channels, T-Type; Gene Silencing; Hydrogen Sulfide; Hyperalgesia; Isothiocyanates; Male; Mice; Oligodeoxyribonucleotides; Sensory Receptor Cells; TRPA1 Cation Channel; Transient Receptor Potential Channels
PubMed: 22300342
DOI: 10.1111/j.1476-5381.2012.01886.x -
Journal of Integrative Neuroscience May 2023Apigenin has been reported to exhibit anti-inflammatory and anti-oxidative activities. This study aimed to investigate the protective role of Apigenin on...
BACKGROUND
Apigenin has been reported to exhibit anti-inflammatory and anti-oxidative activities. This study aimed to investigate the protective role of Apigenin on chemotherapy-induced peripheral neuropathy (CIPN).
METHODS
CIPN mouse model was established using Paclitaxel treatment. Hot plate and tail prick latency tests were performed to examine the allodynia and hyperalgesia behaviors. Anti-inflammatory and anti-oxidative effects of Apigenin on CIPN were determined by enzyme-linked immunosorbent (ELISA) assay, Western blot, and qRT-PCR. Nuclear recruitment of nuclear factor erythroid 2-related factor 2 (NRF2) was analyzed to evaluate the underlying mechanisms of the protective effects of Apigenin.
RESULTS
Apigenin significantly alleviated CIPN-induced nociceptive behaviors of CIPN mice. It also decreased the TNF-α and IL-1β levels, suppressed oxidative stress and inflammation in the surgical spinal cord tissues. Mechanistically, Apigenin altered the pro-inflammatory and anti-inflammatory phenotypes ratio of microglia through promoting the nuclear recruitment of NRF2 and activating the NRF2/Antioxidant Response Element (ARE) signaling pathway.
CONCLUSIONS
In summary, Apigenin relieves CIPN by regulating microglia activation and polarization, which provides a potential therapeutic strategy for CIPN treatment.
Topics: Mice; Animals; Hyperalgesia; Apigenin; Microglia; NF-E2-Related Factor 2; Peripheral Nervous System Diseases; Anti-Inflammatory Agents; Antineoplastic Agents
PubMed: 37258427
DOI: 10.31083/j.jin2203064 -
International Journal of Molecular... Oct 2018Primary damage or dysfunction of the nervous system may cause or initiate neuropathic pain. However, it has been difficult to establish an effective treatment for...
Primary damage or dysfunction of the nervous system may cause or initiate neuropathic pain. However, it has been difficult to establish an effective treatment for neuropathic pain, as the mechanisms responsible for its pathology remain largely unknown. Autophagy is closely associated with the pathological process of neurodegenerative diseases, neuropathic injury and cancer, among others. The aim of the present study was to examine the changes in the autophagy‑lysosomal pathway and discuss the effects of autophagy on allodynia, hyperalgesia and astrocyte activation in neuropathic pain. A neuropathic pain model was induced by chronic constriction injury (CCI) in rats. Inducers and inhibitors of autophagy and lysosomes were used to assess autophagy, allodynia, hyperalgesia and astrocyte activity. Neuropathic pain was found to induce an increase in the levels of the autophagy‑related proteins, LC3II and Beclin 1 and, and in those of the lysosomal proteins, lysosomal‑associated membrane protein type 2 (LAMP2) and Ras‑related protein Rab‑7a (RAB7), whereas p62 levels were found to decrease from day 1 to 14 following CCI. The autophagy inducer, rapamycin, further increased the LC3II, Beclin 1, lysosomal‑associated membrane protein 2 (LAMP2) and Ras‑related protein Rab‑7a (RAB7) expression levels, and decreased the p62 expression levels, which were accompanied by alleviation of allodynia, hyperalgesia and astrocyte activation in the rats subjected to CCI; the autophagy inhibitor, 3‑methyladenine, reversed these effects. The use of the lysosomal inhibitors, bafilomycin and chloroquine, resulted in the accumulation of LC3II and Beclin 1, a decrease in the levels of LAMP2 and RAB7, and the exacerbation of allodynia, hyperalgesia and astrocyte activation in rats with neuropathic pain. On the whole, the findings of this study indicate that neuropathic pain activates autophagy, which alleviates mechanical and thermal hyperalgesia and suppresses astrocyte activity. Therefore, neuropathic pain induced by CCI in rats appears to be mediated via the autophagy‑lysosomal pathway.
Topics: Animals; Astrocytes; Autophagy; Beclin-1; Disease Models, Animal; Hyperalgesia; Lysosomal-Associated Membrane Protein 2; Male; Microtubule-Associated Proteins; Neuralgia; Rats; Rats, Sprague-Dawley; rab GTP-Binding Proteins; rab7 GTP-Binding Proteins
PubMed: 30015858
DOI: 10.3892/ijmm.2018.3763 -
Pain Nov 2018Enhanced sensitivity to light (photophobia) and patterns is common in migraine and can be regarded as visual allodynia. We aimed to develop and validate a questionnaire...
Enhanced sensitivity to light (photophobia) and patterns is common in migraine and can be regarded as visual allodynia. We aimed to develop and validate a questionnaire to easily quantify sensitivity to light and patterns in large populations, and to assess and compare visual allodynia across different migraine subtypes and states. We developed the Leiden Visual Sensitivity Scale (L-VISS), a 9-item scale (score range 0-36 points), based on literature and patient interviews, and examined its construct validity. Furthermore, we assessed ictal and interictal visual sensitivity in episodic migraine with (n = 67) and without (n = 66) aura and chronic migraine with (n = 20) and without (n = 19) aura, and in healthy controls (n = 86). Differences between migraine subtypes and states were tested using a linear mixed model with 3 fixed factors (episodic/chronic, with/without aura, and ictal/interictal). Test-retest reliability and construct validity of L-VISS were good. Leiden Visual Sensitivity Scale scores correlated in the expected direction with light discomfort (Kendall's τ = -0.25) and pattern glare tests (τ = 0.35). Known-group comparisons confirmed its construct validity. Within migraine subtypes, L-VISS scores were higher in migraine with aura versus without aura and in chronic versus episodic migraine. The linear mixed model showed all factors affected the outcome (P < 0.001). The L-VISS is an easy-to-use scale to quantify and monitor the burden of bothersome visual sensitivity to light and patterns in large populations. There are remarkable ictal and interictal differences in visual allodynia across migraine subtypes, possibly reflecting dynamic differences in cortical excitability.
Topics: Adult; Female; Humans; Hyperalgesia; Linear Models; Male; Middle Aged; Migraine Disorders; Photic Stimulation; Reproducibility of Results; Surveys and Questionnaires; Visual Perception
PubMed: 30015708
DOI: 10.1097/j.pain.0000000000001343 -
European Journal of Pain (London,... Nov 2022Quantitative sensory testing (QST) assesses the functional integrity of small and large nerve fibre afferents and central somatosensory pathways; QST was assumed to...
BACKGROUND
Quantitative sensory testing (QST) assesses the functional integrity of small and large nerve fibre afferents and central somatosensory pathways; QST was assumed to provide insight into the mechanisms of neuropathy. We analysed QST profiles and phenotypes in patients with diabetes mellitus to study whether these could differentiate patients with and without pain and neuropathy.
METHODS
A standardized QST protocol was performed and 'loss and gain of function' abnormalities were analysed in four groups of subjects: diabetic patients with painful (pDSPN; n = 220) and non-painful distal symmetric polyneuropathy (nDSPN; n = 219), diabetic patients without neuropathy (DM; n = 23) and healthy non-diabetic subjects (n = 37). Based on the QST findings, diabetic subjects were further stratified into four predefined prototypic phenotypes: sensory loss (SL), thermal hyperalgesia (TH), mechanical hyperalgesia (MH) and healthy individuals.
RESULTS
Patients in the pDSPN group showed the greatest hyposensitivity ('loss of function'), and DM patients showed the lowest, with statistically significant increases in thermal, thermal pain, mechanical and mechanical pain sensory thresholds. Accordingly, the frequency of the SL phenotype was significantly higher in the pDSPN subgroup (41.8%), than expected (p < 0.0042). The proportion of 'gain of function' abnormalities was low in both pDSPN and nDSPN patients without significant differences.
CONCLUSIONS
There is a continuum in the sensory profiles of diabetic patients, with a more pronounced sensory loss in pDSPN group probably reflecting somatosensory nerve fibre degeneration. An analysis of 'gain of function' abnormalities (allodynia, hyperalgesia) did not offer a key to understanding the pathophysiology of spontaneous diabetic peripheral neuropathic pain.
SIGNIFICANCE
This article, using quantitative sensory testing profiles in large cohorts of diabetic patients with and without polyneuropathy and pain, presents a continuum in the sensory profiles of diabetic patients, with more pronounced 'loss of function' abnormalities in painful polyneuropathy patients. Painful diabetic polyneuropathy probably represents a 'more progressed' type of neuropathy with more pronounced somatosensory nerve fibre degeneration. The proportion of 'gain of function' sensory abnormalities was low, and these offer limited understanding of pathophysiological mechanisms of spontaneous neuropathic pain.
Topics: Diabetes Mellitus; Diabetic Neuropathies; Humans; Hyperalgesia; Neuralgia; Pain Measurement; Pain Threshold; Polyneuropathies
PubMed: 36069121
DOI: 10.1002/ejp.2034 -
Scientific Reports Sep 2018Detection of cold allodynia is a very important aspect in the study of pain behavior. An effective and concise device for detecting cold pain has always been the hope of...
Detection of cold allodynia is a very important aspect in the study of pain behavior. An effective and concise device for detecting cold pain has always been the hope of many researchers. Here, an easily produced and operated cold plate device is presented for the assessment of cold allodynia in mice. The device used to detect cold allodynia has two components: a chamber consists of a cylinder for animal experiment and a cube box around the chamber for holding ice to keep temperature stable. In the testing chamber, a mouse was placed on the circular plexiglass plate steady at 4 °C above ice for five minutes. The tested mouse will lift its paw when exposed to the cold plate. The number of lifts will present animal's response to the degree of cold stimulation. To evaluate this approach, three commonly used pain models of mice were tested: formalin test, bone cancer pain (BCP), and chronic constriction injury (CCI). As is reported in other literatures, these three pain mice models showed increased sensitivity to cold stimulation. The new device is indeed suitable for detecting cold allodynia behavior in mice. Comparisons with existing devices of detecting cold allodynia, such as the cold plate in the market (UGO, Panlab, Columbus, etc.), the new device has the advantages of low cost, simple operation and easy popularization and can detect cold allodynia behavior of mice very well. This is a very practical and economical device to detect cold allodynia behavior.
Topics: Animals; Behavior, Animal; Cancer Pain; Carcinoma, Lewis Lung; Cold Temperature; Constriction, Pathologic; Disease Models, Animal; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Pain Measurement
PubMed: 30228362
DOI: 10.1038/s41598-018-31741-7 -
CNS Neuroscience & Therapeutics Nov 2023Neuropathic pain after spinal cord injury (SCI) remains a common and thorny problem, influencing the life quality severely. This study aimed to elucidate the...
Neuropathic pain following spinal cord hemisection induced by the reorganization in primary somatosensory cortex and regulated by neuronal activity of lateral parabrachial nucleus.
AIMS
Neuropathic pain after spinal cord injury (SCI) remains a common and thorny problem, influencing the life quality severely. This study aimed to elucidate the reorganization of the primary sensory cortex (S1) and the regulatory mechanism of the lateral parabrachial nucleus (lPBN) in the presence of allodynia or hyperalgesia after left spinal cord hemisection injury (LHS).
METHODS
Through behavioral tests, we first identified mechanical allodynia and thermal hyperalgesia following LHS. We then applied two-photon microscopy to observe calcium activity in S1 during mechanical or thermal stimulation and long-term spontaneous calcium activity after LHS. By slice patch clamp recording, the electrophysiological characteristics of neurons in lPBN were explored. Finally, exploiting chemogenetic activation or inhibition of the neurons in lPBN, allodynia or hyperalgesia was regulated.
RESULTS
The calcium activity in left S1 was increased during mechanical stimulation of right hind limb and thermal stimulation of tail, whereas in right S1 it was increased only with thermal stimulation of tail. The spontaneous calcium activity in right S1 changed more dramatically than that in left S1 after LHS. The lPBN was also activated after LHS, and exploiting chemogenetic activation or inhibition of the neurons in lPBN could induce or alleviate allodynia and hyperalgesia in central neuropathic pain.
CONCLUSION
The neuronal activity changes in S1 are closely related to limb pain, which has accurate anatomical correspondence. After LHS, the spontaneously increased functional connectivity of calcium transient in left S1 is likely causing the mechanical allodynia in right hind limb and increased neuronal activity in bilateral S1 may induce thermal hyperalgesia in tail. This state of allodynia and hyperalgesia can be regulated by lPBN.
Topics: Humans; Hyperalgesia; Parabrachial Nucleus; Calcium; Somatosensory Cortex; Spinal Cord; Neuralgia; Neurons; Spinal Cord Injuries
PubMed: 37170721
DOI: 10.1111/cns.14258