-
Journal of Pain Research 2023To assess the inhibitory effect of acupuncture on pain symptoms in migraine models, and to further summarize the potential mechanisms of acupuncture in regulating... (Review)
Review
PURPOSE
To assess the inhibitory effect of acupuncture on pain symptoms in migraine models, and to further summarize the potential mechanisms of acupuncture in regulating hyperalgesia in the treatment of migraine.
MATERIALS AND METHODS
Literature search in databases such as China National Knowledge Infrastructure (CNKI), PubMed, and Web of Science (WOS) etc. The quality was evaluated by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) bias risk assessment tool and Collaborative Approach to Meta-analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist. Meta-analyses were performed using Stata 17.0 software.
RESULTS
Twenty-one studies involving 489 animals were identified. The qualitative score ranged from 3 to 9 points. Facial mechanical withdrawal threshold (FMWT) and paw mechanical withdrawal threshold (PMWT) measured by Von Frey filaments were selected as major outcomes, and serum calcitonin gene-related peptide (CGRP) levels measured by ELISA were selected as secondary outcome. Meta-analysis results revealed that true acupuncture (TA) group significantly increased FMWT, PMWT and CGRP compared to model group. TA group showed superior effect in FMWT, PMWT relative to sham acupuncture (SA) group. Subgroup analysis results showed that high risk of bias scores may be responsible for the high heterogeneity of FMWT; additionally, CGRP analysis suggests that acupoint selection and blood collection sites may be sources of heterogeneity. In the treatment of migraine pain symptoms, the underlying mechanism of acupuncture treatment is either the regulation of hyperalgesia and neurotransmitters, or the reduction of inflammatory factors.
CONCLUSION
The results indicate that TA treatment effectively increased the pain threshold and reduced hyperalgesia in migraine rats. In summary, our study highlights the potential of TA as an effective treatment for migraine, but further investigation is required to fully comprehend its mechanism of action and optimize its clinical application.
PubMed: 37521010
DOI: 10.2147/JPR.S422050 -
Frontiers in Immunology 2023Pre-clinical evidence shows that neuropathy is associated with complex neuroimmune responses, which in turn are associated with increased intensity and persistence of... (Meta-Analysis)
Meta-Analysis Review
The potential protective effects of pre-injury exercise on neuroimmune responses following experimentally-induced traumatic neuropathy: a systematic review with meta-analysis.
Pre-clinical evidence shows that neuropathy is associated with complex neuroimmune responses, which in turn are associated with increased intensity and persistence of neuropathic pain. Routine exercise has the potential to mitigate complications of future nerve damage and persistence of pain through neuroimmune regulation. This systematic review aimed to explore the effect of pre-injury exercise on neuroimmune responses, and other physiological and behavioural reactions following peripheral neuropathy in animals. Three electronic databases were searched from inception to July 2022. All controlled animal studies assessing the influence of an active exercise program prior to experimentally-induced traumatic peripheral neuropathy compared to a non-exercise control group on neuroimmune, physiological and behavioural outcomes were selected. The search identified 17,431 records. After screening, 11 articles were included. Meta-analyses showed that pre-injury exercise significantly reduced levels of IL-1β (SMD: -1.06, 95% CI: -1.99 to -0.13, n=40), but not iNOS (SMD: -0.71 95% CI: -1.66 to 0.25, n=82). From 72 comparisons of different neuroimmune outcomes at different anatomical locations, vote counting revealed reductions in 23 pro-inflammatory and increases in 6 anti-inflammatory neuroimmune outcomes. For physiological outcomes, meta-analyses revealed that pre-injury exercise improved one out of six nerve morphometric related outcomes (G-ratio; SMD: 1.95, 95%CI: 0.77 to 3.12, n=20) and one out of two muscle morphometric outcomes (muscle fibre cross-sectional area; SMD: 0.91, 95%CI: 0.27 to 1.54, n=48). For behavioural outcomes, mechanical allodynia was significantly less in the pre-injury exercise group (SMD -1.24, 95%CI: -1.87 to -0.61) whereas no overall effect was seen for sciatic function index. subgroup analysis suggests that timing of outcome measurement may influence the effect of pre-injury exercise on mechanical allodynia. Risk of bias was unclear in most studies, as the design and conduct of the included experiments were poorly reported. Preventative exercise may have potential neuroprotective and immunoregulatory effects limiting the sequalae of nerve injury, but more research in this field is urgently needed.
Topics: Animals; Hyperalgesia; Exercise; Neuralgia
PubMed: 37767095
DOI: 10.3389/fimmu.2023.1215566 -
Cephalalgia : An International Journal... Oct 2023To investigate whether clinical and sociodemographic factors are associated with calcitonin gene-related peptide (CGRP) induced migraine attacks.
OBJECTIVE
To investigate whether clinical and sociodemographic factors are associated with calcitonin gene-related peptide (CGRP) induced migraine attacks.
METHODS
A total of 139 participants with migraine received a 20-minute intravenous infusion of CGRP (1.5 µg/min) on a single experiment day. The incidence of CGRP-induced migraine attacks was recorded using a headache diary during the 12-hour observational period post-infusion. Univariable and multivariable regression analyses were conducted to examine potential predictors' relationship with CGRP-induced migraine attacks.
RESULTS
CGRP-induced migraine attacks were reported in 110 (79%) of 139 participants. Univariable analysis revealed that participants with cutaneous allodynia had higher odds of developing CGRP-induced migraine attacks, compared with those without allodynia (OR, 2.97, 95% CI, 1.28 to 7.43). The subsequent multivariable analysis confirmed this association (OR, 3.26, 95% CI, 1.32 to 8.69) and also found that participants with migraine with aura had lower odds of developing CGRP-induced migraine attacks (OR, 0.32, 95% CI, 0.12 to 0.84).
CONCLUSION
Our results suggest that cutaneous allodynia and aura play a role in CGRP-induced migraine attacks, while other clinical and sociodemographic factors do not seem to have any noticeable impact. This indicates that the CGRP provocation model is robust, as the CGRP hypersensitivity remained unaffected despite differences among a heterogeneous migraine population.Trial Registration: ClinicalTrials.gov Identifier: NCT04592952.
Topics: Humans; Calcitonin Gene-Related Peptide; Headache; Hyperalgesia; Migraine Disorders; Sociodemographic Factors
PubMed: 37815254
DOI: 10.1177/03331024231206375 -
Brain Research Jul 2023Bone cancer pain (BCP) remains a clinical challenge due to the limited and side effects of therapeutic methods. Folic acid has been known as an FDA approved dietary...
BACKGROUND
Bone cancer pain (BCP) remains a clinical challenge due to the limited and side effects of therapeutic methods. Folic acid has been known as an FDA approved dietary supplement and proved to have an analgesic effect in neuropathic pain. Here we investigate the role and mechanism of folic acid in bone cancer pain of a rat model.
METHODS
Walker 256 tumor cells were inoculated into the left tibia of rats to induce bone cancer pain model. Pain reflex were assessed by paw withdrawal threshold (PWT) response to Von Frey filaments and paw withdrawal latency (PWL) response to thermal stimulation. Folic acid was injected intraperitoneally to evaluate its analgesic effect in rats with bone cancer pain. Western blotting and qPCR were used to determine P2X2/3 receptor protein and mRNA levels in ipsilateral L4-6 dorsal root ganglion (DRG) and spinal dorsal horn (SDH).
RESULTS
The PWT and PWL of rats with bone cancer pain were obviously decreased compared to the naïve and sham rats. Interestingly, continuous folic acid treatment significantly increased the PWT and PWL of rats with bone cancer pain. P2X2 and P2X3 receptors were clearly upregulated at both mRNA and protein expression in L4-6 DRG and SDH of rats with bone cancer pain. P2X2 and P2X3 receptors were mainly localized with CGRP (calcitonin gene-related peptide) or IB4 (isolectin B4) positive neurons in L4-6 DRG of rats with bone cancer pain. Notably, continuous folic acid treatment significantly reduced the expression of P2X2 and P2X3 receptors in L4-6 DRG and SDH of rats with bone cancer pain. Finally, intrathecal injection of A317491 (a selective antagonist of P2X2/3 receptors) markedly elevated the PWT and PWL of rats with bone cancer pain.
CONCLUSION
These results suggest that folic acid has an effective antinociceptive effect on bone cancer pain, which is mediated by downregulating P2X2/3 receptors in L4-6 DRG and SDH of rats with bone cancer pain. Folic acid may be a novel therapeutic strategy in cancer patients for pain relief.
Topics: Rats; Animals; Cancer Pain; Rats, Sprague-Dawley; Folic Acid; Neuralgia; Bone Neoplasms; Analgesics; RNA, Messenger; Ganglia, Spinal; Hyperalgesia
PubMed: 37164174
DOI: 10.1016/j.brainres.2023.148405 -
Pain Jan 2024The persistence of inflammatory and neuropathic pain is poorly understood. We investigated a novel therapeutic paradigm by targeting gene networks that sustain or...
The persistence of inflammatory and neuropathic pain is poorly understood. We investigated a novel therapeutic paradigm by targeting gene networks that sustain or reverse persistent pain states. Our prior observations found that Sp1-like transcription factors drive the expression of TRPV1, a pain receptor, that is blocked in vitro by mithramycin A (MTM), an inhibitor of Sp1-like factors. Here, we investigate the ability of MTM to reverse in vivo models of inflammatory and chemotherapy-induced peripheral neuropathy (CIPN) pain and explore MTM's underlying mechanisms. Mithramycin reversed inflammatory heat hyperalgesia induced by complete Freund adjuvant and cisplatin-induced heat and mechanical hypersensitivity. In addition, MTM reversed both short-term and long-term (1 month) oxaliplatin-induced mechanical and cold hypersensitivity, without the rescue of intraepidermal nerve fiber loss. Mithramycin reversed oxaliplatin-induced cold hypersensitivity and oxaliplatin-induced TRPM8 overexpression in dorsal root ganglion (DRG). Evidence across multiple transcriptomic profiling approaches suggest that MTM reverses inflammatory and neuropathic pain through broad transcriptional and alternative splicing regulatory actions. Mithramycin-dependent changes in gene expression following oxaliplatin treatment were largely opposite to and rarely overlapped with changes in gene expression induced by oxaliplatin alone. Notably, RNAseq analysis revealed MTM rescue of oxaliplatin-induced dysregulation of mitochondrial electron transport chain genes that correlated with in vivo reversal of excess reactive oxygen species in DRG neurons. This finding suggests that the mechanism(s) driving persistent pain states such as CIPN are not fixed but are sustained by ongoing modifiable transcription-dependent processes.
Topics: Humans; Plicamycin; Oxaliplatin; Antineoplastic Agents; Neuralgia; Hyperalgesia; Ganglia, Spinal
PubMed: 37366593
DOI: 10.1097/j.pain.0000000000002972 -
Biomedicines Jun 2024A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in...
A complication of diabetes is neuropathic pain, which is difficult to control with medication. We have confirmed that neuropathic pain due to mechanical allodynia in diabetic mice is mediated by a characteristic neuropeptide in the spinal cord. We evaluated the strength of mechanical allodynia in mice using von Frey filaments. When mice were intravenously injected with streptozotocin, mechanical allodynia appeared 3 days later. Antibodies of representative neuropeptides were intrathecally (i.t.) administered to allodynia-induced mice 7 days after the intravenous administration of streptozotocin, and allodynia was reduced by anti-cholecystokinin octapeptide antibodies, anti-nociceptin/orphanin FQ antibodies, and anti-hemokinin-1 antibodies. In contrast, i.t.-administered anti-substance P antibodies, anti-somatostatin antibodies, and anti-angiotensin II antibodies did not affect streptozotocin-induced diabetic allodynia mice. Mechanical allodynia was attenuated by the i.t. administration of CCK-B receptor antagonists and ORL-1 receptor antagonists. The mRNA level of CCK-B receptors in streptozotocin-induced diabetic allodynia mice increased in the spinal cord, but not in the dorsal root ganglion. These results indicate that diabetic allodynia is caused by cholecystokinin octapeptide, nociceptin/orphanin FQ, and hemokinin-1 released from primary afferent neurons in the spinal cord that transmit pain to the brain via the spinal dorsal horn.
PubMed: 38927539
DOI: 10.3390/biomedicines12061332 -
Advanced Science (Weinheim,... Jun 2024Neuropathic pain can occur during the prediabetic stage, even in the absence of hyperglycemia. The presence of prediabetic neuropathic pain (PDNP) poses challenges to...
Neuropathic pain can occur during the prediabetic stage, even in the absence of hyperglycemia. The presence of prediabetic neuropathic pain (PDNP) poses challenges to the management of individuals with prediabetes. However, the mechanisms underlying this pain remain unclear. This study aims to investigate the underlying mechanism and identify potential therapeutic targets of PDNP. A prediabetic animal model induced by a high-energy diet exhibits both mechanical allodynia and thermal hyperalgesia. Furthermore, hyperexcitability and decreased potassium currents are observed in the dorsal root ganglion (DRG) neurons of these rats. TREK1 and TREK2 channels, which belong to the two-pore-domain K channel (K) family and play an important role in controlling cellular excitability, are downregulated in DRG neurons. Moreover, this alteration is modulated by Sortilin, a molecular partner that modulates the expression of TREK1. The overexpression of Sortilin negatively affects the expression of TREK1 and TREK2, leading to increased neuronal excitability in the DRG and enhanced peripheral pain sensitivity in rats. Moreover, the downregulation of Sortilin or activation of TREK1 and TREK2 channels by genetic or pharmacological approaches can alleviate PDNP. Therefore, targeting the Sortilin-mediated TREK1/2 pathway may provide a therapeutic approach for ameliorating PDNP.
Topics: Animals; Potassium Channels, Tandem Pore Domain; Rats; Neuralgia; Adaptor Proteins, Vesicular Transport; Male; Disease Models, Animal; Rats, Sprague-Dawley; Sensory Receptor Cells; Prediabetic State; Ganglia, Spinal
PubMed: 38626370
DOI: 10.1002/advs.202310295 -
Pain Oct 2023Exposure to severely stressful events during childhood is associated with poor health outcomes in later life, including chronic pain and substance use disorder. However,...
Exposure to severely stressful events during childhood is associated with poor health outcomes in later life, including chronic pain and substance use disorder. However, the mediators and mechanisms are unclear. We investigated the impact of a well-characterized mouse model of early-life adversity, fragmented maternal care (FC) between postnatal day 2 and 9, on nociception, inflammatory hypersensitivity, and responses to morphine. Male and female mice exposed to FC exhibited prolonged basal thermal withdrawal latencies and decreased mechanical sensitivity. In addition, morphine had reduced potency in mice exposed to FC and their development of tolerance to morphine was accelerated. Quantitative PCR analysis in several brain regions and the spinal cords of juvenile and adult mice revealed an impact of FC on the expression of genes encoding opioid peptide precursors and their receptors. These changes included enhanced abundance of δ opioid receptor transcript in the spinal cord. Acute inflammatory hypersensitivity (induced by hind paw administration of complete Freund's adjuvant) was unaffected by exposure to FC. However, after an initial recovery of mechanical hypersensitivity, there was a reappearance in mice exposed to FC by day 15, which was not seen in control mice. Changes in nociception, morphine responses, and hypersensitivity associated with FC were apparent in males and females but were absent from mice lacking δ receptors or β-arrestin2. These findings suggest that exposure to early-life adversity in mice enhances δ receptor expression leading to decreased basal sensitivity to noxious stimuli coupled with accelerated morphine tolerance and enhanced vulnerability to persistent inflammatory hypersensitivity.
Topics: Animals; Female; Male; Mice; Analgesics, Opioid; Hyperalgesia; Morphine; Pain; Receptors, Opioid, delta; Stress, Psychological; Up-Regulation
PubMed: 37171192
DOI: 10.1097/j.pain.0000000000002925 -
Neural Regeneration Research Aug 2023Experimental studies have shown that exercise and human adipose-derived stem cells (ADSCs) play positive roles in spinal cord injury (SCI). However, whether ADSCs and/or...
Experimental studies have shown that exercise and human adipose-derived stem cells (ADSCs) play positive roles in spinal cord injury (SCI). However, whether ADSCs and/or exercise have a positive effect on SCI-induced neuropathic pain is still unclear. Thus, there is a need to explore the effects of exercise combined with administration of ADSCs on neuropathic pain after SCI. In this study, a thoracic 11 (T11) SCI contusion model was established in adult C57BL/6 mice. Exercise was initiated from 7 days post-injury and continued to 28 days post-injury, and approximately 1 × 10 ADSCs were transplanted into the T11 spinal cord lesion site immediately after SCI. Motor function and neuropathic pain-related behaviors were assessed weekly using the Basso Mouse Scale, von Frey filament test, Hargreaves method, and cold plate test. Histological studies (Eriochrome cyanine staining and immunohistochemistry) were performed at the end of the experiment (28 days post-injury). Exercise combined with administration of ADSCs partially improved early motor function (7, 14, and 21 days post-injury), mechanical allodynia, mechanical hypoalgesia, thermal hyperalgesia, and thermal hypoalgesia. Administration of ADSCs reduced white and gray matter loss at the lesion site. In addition, fewer microglia and astrocytes (as identified by expression of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, respectively) were present in the lumbar dorsal horn in the SCI + ADSCs and SCI + exercise + ADSCs groups compared with the sham group. Our findings suggest that exercise combined with administration of ADSCs is beneficial for the early recovery of motor function and could partially ameliorate SCI-induced neuropathic pain.
PubMed: 36751814
DOI: 10.4103/1673-5374.361533 -
Cephalalgia : An International Journal... Nov 2023Post-traumatic headache is very common after a mild traumatic brain injury. Post-traumatic headache may persist for months to years after an injury in a substantial...
BACKGROUND
Post-traumatic headache is very common after a mild traumatic brain injury. Post-traumatic headache may persist for months to years after an injury in a substantial proportion of people. The pathophysiology underlying post-traumatic headache remains unknown but is likely distinct from other headache disorders. Identification of brain areas activated in acute and persistent phases of post-traumatic headache can provide insights into the underlying circuits mediating headache pain. We used an animal model of mild traumatic brain injury-induced post-traumatic headache and c-fos immunohistochemistry to identify brain regions with peak activity levels across the acute and persistent phases of post-traumatic headache.
METHODS
Male and female C57BL/6 J mice were briefly anesthetized and subjected to a sham procedure or a weight drop closed-head mild traumatic brain injury . Cutaneous allodynia was assessed in the periorbital and hindpaw regions using von Frey filaments. Immunohistochemical c-fos based neural activity mapping was then performed on sections from whole brain across the development of post-traumatic headache (i.e. peak of the acute phase at 2 days post- mild traumatic brain injury), start of the persistent phase (i.e. >14 days post-mild traumatic brain injury) or after provocation with stress (bright light). Brain areas with consistent and peak levels of c-fos expression across mild traumatic brain injury induced post-traumatic headache were identified and included for further analysis.
RESULTS
Following mild traumatic brain injury, periorbital and hindpaw allodynia was observed in both male and female mice. This allodynia was transient and subsided within the first 14 days post-mild traumatic brain injury and is representative of acute post-traumatic headache. After this acute post-traumatic headache phase, exposure of mild traumatic brain injury mice to a bright light stress reinstated periorbital and hindpaw allodynia for several hours - indicative of the development of persistent post-traumatic headache. Acute post-traumatic headache was coincident with an increase in neuronal c-fos labeling in the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and the nucleus accumbens. Neuronal activation returned to baseline levels by the persistent post-traumatic headache phase in the spinal nucleus of the trigeminal caudalis and primary somatosensory cortex but remained elevated in the nucleus accumbens. In the persistent post-traumatic headache phase, coincident with allodynia observed following bright light stress, we observed bright light stress-induced c-fos neural activation in the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and nucleus accumbens.
CONCLUSION
Examination of mild traumatic brain injury-induced changes in peak c-fos expression revealed brain regions with significantly increased neural activity across the acute and persistent phases of post-traumatic headache. Our findings suggest mild traumatic brain injury-induced post-traumatic headache produces neural activation along pain relevant pathways at time-points matching post-traumatic headache-like pain behaviors. These observations suggest that the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and nucleus accumbens may contribute to both the induction and maintenance of post-traumatic headache.
Topics: Humans; Mice; Male; Female; Animals; Post-Traumatic Headache; Brain Concussion; Hyperalgesia; Mice, Inbred C57BL; Headache; Brain; Pain
PubMed: 38016977
DOI: 10.1177/03331024231217469