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Headache Sep 2023To examine whether sensory hypersensitivity contributes to headache-related disability in a secondary analysis of patients with post-traumatic headache.
OBJECTIVE
To examine whether sensory hypersensitivity contributes to headache-related disability in a secondary analysis of patients with post-traumatic headache.
BACKGROUND
Up to one-third of individuals with traumatic brain injuries report persistent headache 3 months post-injury. High rates of allodynia and photophobia have been observed in clinical studies and animal models of post-traumatic headache, but we do not fully understand how sensory amplifications impact post-traumatic headache-related disability.
METHODS
We identified a cross-sectional sample of patients from the American Registry for Migraine Research database with new or worsening headaches post-head injury from 2016 to 2020 and performed a secondary analysis of those data. We modeled the relationship between sensory sensitivity and Migraine Disability Assessment scores using questionnaires. Candidate variables included data collection features (study site and year), headache-related and general clinical features (headache frequency, migraine diagnosis, abuse history, sex, age, cognitive and affective symptom scores), and sensory symptoms (related to light, sound, and touch sensitivity).
RESULTS
The final sample included 193 patients (median age 46, IQR 22; 161/193, 83.4% female). Migraine Disability Assessment scores ranged from 0 to 260 (median 47, IQR 87). The final model included allodynia, hyperacusis, photosensitivity, headache days per month, abuse history, anxiety and depression, cognitive dysfunction, and age (R = 0.43). An increase of one point in allodynia score corresponded to a 3% increase in headache disability (95% CI: 0%-7%; p = 0.027), an increase of one-tenth of a point in the photosensitivity score corresponded to a 12% increase (95% CI: 3%-25%; p = 0.002), and an increase of one point in the hyperacusis score corresponded to a 2% increase (95% CI: 0%-4%; p = 0.016).
CONCLUSIONS
Increased photosensitivity, allodynia, and hyperacusis were associated with increased headache-related disability in this sample of patients with post-traumatic headache. Symptoms of sensory amplification likely contribute to post-traumatic headache-related disability and merit an ongoing investigation into their potential as disease markers and treatment targets.
Topics: Female; Animals; Male; Post-Traumatic Headache; Cross-Sectional Studies; Hyperacusis; Hyperalgesia; Headache; Migraine Disorders; Hypersensitivity
PubMed: 37638410
DOI: 10.1111/head.14604 -
Frontiers in Pain Research (Lausanne,... 2023An estimated 10%-50% of patients undergoing a surgical intervention will develop persistent postsurgical pain (PPP) lasting more than 3 months despite adequate acute... (Review)
Review
An estimated 10%-50% of patients undergoing a surgical intervention will develop persistent postsurgical pain (PPP) lasting more than 3 months despite adequate acute pain management and the availability of minimally invasive procedures. The link between early and late pain outcomes for surgical procedures remains unclear-some patients improve while others develop persistent pain. The elective nature of a surgical procedure offers a unique opportunity for prophylactic or early intervention to prevent the development of PPP and improve our understanding of its associated risk factors, such as pre-operative anxiety and the duration of severe acute postoperative pain. Current perioperative pain management strategies often include opioids, but long-term consumption can lead to tolerance, addiction, opioid-induced hyperalgesia, and death. Pre-clinical models provide the opportunity to dissect mechanisms underpinning the transition from acute to chronic, or persistent, postsurgical pain. This review highlights putative mechanisms of PPP, including sensitisation of peripheral sensory neurons, neuroplasticity in the central nervous system and nociceptive signalling along the neuro-immune axis.
PubMed: 37484030
DOI: 10.3389/fpain.2023.1154597 -
CNS Neuroscience & Therapeutics Dec 2023Epidemiological studies in patients with neuropathic pain have demonstrated a strong association between neuropathic pain and psychiatric conditions such as anxiety....
Electroacupuncture alleviates mechanical allodynia and anxiety-like behaviors induced by chronic neuropathic pain via regulating rostral anterior cingulate cortex-dorsal raphe nucleus neural circuit.
AIMS
Epidemiological studies in patients with neuropathic pain have demonstrated a strong association between neuropathic pain and psychiatric conditions such as anxiety. Preclinical and clinical work has demonstrated that electroacupuncture (EA) effectively alleviates anxiety-like behaviors induced by chronic neuropathic pain. In this study, a potential neural circuitry underlying the therapeutic action of EA was investigated.
METHODS
The effects of EA stimulation on mechanical allodynia and anxiety-like behaviors in animal models of spared nerve injury (SNI) were examined. EA plus chemogenetic manipulation of glutamatergic (Glu) neurons projecting from the rostral anterior cingulate cortex (rACC ) to the dorsal raphe nucleus (DRN) was used to explore the changes of mechanical allodynia and anxiety-like behaviors in SNI mice.
RESULTS
Electroacupuncture significantly alleviated both mechanical allodynia and anxiety-like behaviors with increased activities of glutamatergic neurons in the rACC and serotoninergic neurons in the DRN. Chemogenetic activation of the rACC -DRN projections attenuated both mechanical allodynia and anxiety-like behaviors in mice at day 14 after SNI. Chemogenetic inhibition of the rACC -DRN pathway did not induce mechanical allodynia and anxiety-like behaviors under physiological conditions, but inhibiting this pathway produced anxiety-like behaviors in mice at day 7 after SNI; this effect was reversed by EA. EA plus activation of the rACC -DRN circuit did not produce a synergistic effect on mechanical allodynia and anxiety-like behaviors. The analgesic and anxiolytic effects of EA could be blocked by inhibiting the rACC -DRN pathway.
CONCLUSIONS
The role of rACC -DRN circuit may be different during the progression of chronic neuropathic pain and these changes may be related to the serotoninergic neurons in the DRN. These findings describe a novel rACC -DRN pathway through which EA exerts analgesic and anxiolytic effects in SNI mice exhibiting anxiety-like behaviors.
Topics: Rats; Humans; Mice; Animals; Hyperalgesia; Electroacupuncture; Gyrus Cinguli; Dorsal Raphe Nucleus; Anti-Anxiety Agents; Rats, Sprague-Dawley; Neuralgia; Analgesics; Anxiety; Disease Models, Animal
PubMed: 37401033
DOI: 10.1111/cns.14328 -
Journal of Neuroimmunology Aug 2023Migraines are a considerable social problem and economic burden worldwide. Current acute treatments are based on inhibiting meningeal neurogenic inflammation which has...
Migraines are a considerable social problem and economic burden worldwide. Current acute treatments are based on inhibiting meningeal neurogenic inflammation which has poor results in some patients, whereas the site of action of prophylactic medicines are unknown; therefore, exploring new treatment mechanisms and methods is increasingly needed. Recent evidence suggests that microglia and microglia-mediated neuroinflammation are important in migraine pathogenesis. In the cortical spreading depression (CSD) migraine model, microglia were activated after multiple CSD stimulations, suggesting that microglial activation may be associated with recurrent attacks of migraine with aura. In the nitroglycerin-induced chronic migraine model, the microglial response to extracellular stimuli leads to the activation of surface purine receptors P2X4、P2X7、P2Y12, which mediate signal transduction through intracellular signalling cascades, such as the BDNF/TrkB, NLRP3/IL-1β and RhoA/ROCK signalling pathways, and release inflammatory mediators and cytokines that enhance pain by increasing the excitability of nearby neurons. Inhibition of the expression or function of these microglial receptors and pathways inhibits the abnormal excitability of TNC (trigeminal nucleus caudalis) neurons and intracranial as well as extracranial hyperalgesia in migraine animal models. These findings suggest that microglia may be central in migraine recurrent attacks and a potential target for the treatment of chronic headaches.
Topics: Animals; Microglia; Migraine Disorders; Nitroglycerin; Hyperalgesia; Signal Transduction
PubMed: 37295033
DOI: 10.1016/j.jneuroim.2023.578118 -
The Journal of Headache and Pain Aug 2023Central sensitisation is an important mechanism in migraine chronification. It is presumed to occur in second and third order neurons sequentially, resulting in an... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Central sensitisation is an important mechanism in migraine chronification. It is presumed to occur in second and third order neurons sequentially, resulting in an analogous spatial distribution of cutaneous allodynia with cephalic and extracephalic symptoms. We investigated whether allodynia, and its subtypes based on spatial distribution and type of stimulus, predict response to treatment in chronic migraine patients.
METHODS
This study was conducted as part of the CHARM study (NTR3440), a randomized, double-blind, placebo-controlled trial in chronic migraine patients with medication overuse. We included 173 patients. The presence of cutaneous allodynia at baseline was established with the Allodynia Symptom Checklist. Primary endpoint was reversion from chronic to episodic migraine.
RESULTS
Of all patients, 74.6% reported cutaneous allodynia. Absence of allodynia compared to presence of allodynia was predictive for reversion from chronic to episodic migraine, odds ratio (OR): 2.45 (95% CI: 1.03-5.84), p = 0.042. The predictive value was more pronounced when subdivided for spatial distribution, for participants without allodynia versus cephalic (OR: 4.16 (95% CI: 1.21-14.30), p = 0.024) and extracephalic (OR: 7.32 (95% CI: 1.98- 27.11), p = 0.003) allodynia. Mechanical, but not thermal, allodynia, was associated with outcome.
CONCLUSIONS
Cutaneous allodynia, an important marker for central sensitization, likely has predictive value for treatment response in chronic migraine.
Topics: Humans; Cohort Studies; Hyperalgesia; Central Nervous System Sensitization; Migraine Disorders; Neurons
PubMed: 37644420
DOI: 10.1186/s10194-023-01651-9 -
The Korean Journal of Pain Apr 2024Nociplastic pain by the "International Association for the Study of Pain" is defined as pain that arises from altered nociception despite no clear evidence of...
Nociplastic pain by the "International Association for the Study of Pain" is defined as pain that arises from altered nociception despite no clear evidence of nociceptive or neuropathic pain. Augmented central nervous system pain and sensory processing with altered pain modulation are suggested to be the mechanism of nociplastic pain. Clinical criteria for possible nociplastic pain affecting somatic structures include chronic regional pain and evoked pain hypersensitivity including allodynia with after-sensation. In addition to possible nociplastic pain, clinical criteria for probable nociplastic pain are pain hypersensitivity in the region of pain to non-noxious stimuli and presence of comorbidity such as generalized symptoms with sleep disturbance, fatigue, or cognitive problems with hypersensitivity of special senses. Criteria for definitive nociplastic pain is not determined yet. Eight specific disorders related to central sensitization are suggested to be restless leg syndrome, chronic fatigue syndrome, fibromyalgia, temporomandibular disorder, migraine or tension headache, irritable bowel syndrome, multiple chemical sensitivities, and whiplash injury; non-specific emotional disorders related to central sensitization include anxiety or panic attack and depression. These central sensitization pain syndromes are overlapped to previous functional pain syndromes which are unlike organic pain syndromes and have emotional components. Therefore, nociplastic pain can be understood as chronic altered nociception related to central sensitization including both sensory components with nociceptive and/or neuropathic pain and emotional components. Nociplastic pain may be developed to explain unexplained chronic pain beyond tissue damage or pathology regardless of its origin from nociceptive, neuropathic, emotional, or mixed pain components.
PubMed: 38504389
DOI: 10.3344/kjp.23326 -
Military Medical Research Mar 2024Tactile and mechanical pain are crucial to our interaction with the environment, yet the underpinning molecular mechanism is still elusive. Endophilin A2 (EndoA2) is an...
BACKGROUND
Tactile and mechanical pain are crucial to our interaction with the environment, yet the underpinning molecular mechanism is still elusive. Endophilin A2 (EndoA2) is an evolutionarily conserved protein that is documented in the endocytosis pathway. However, the role of EndoA2 in the regulation of mechanical sensitivity and its underlying mechanisms are currently unclear.
METHODS
Male and female C57BL/6 mice (8-12 weeks) and male cynomolgus monkeys (7-10 years old) were used in our experiments. Nerve injury-, inflammatory-, and chemotherapy-induced pathological pain models were established for this study. Behavioral tests of touch, mechanical pain, heat pain, and cold pain were performed in mice and nonhuman primates. Western blotting, immunostaining, co-immunoprecipitation, proximity ligation and patch-clamp recordings were performed to gain insight into the mechanisms.
RESULTS
The results showed that EndoA2 was primarily distributed in neurofilament-200-positive (NF200) medium-to-large diameter dorsal root ganglion (DRG) neurons of mice and humans. Loss of EndoA2 in mouse NF200 DRG neurons selectively impaired the tactile and mechanical allodynia. Furthermore, EndoA2 interacted with the mechanically sensitive ion channel Piezo2 and promoted the membrane trafficking of Piezo2 in DRG neurons. Moreover, as an adaptor protein, EndoA2 also bound to kinesin family member 5B (KIF5B), which was involved in the EndoA2-mediated membrane trafficking process of Piezo2. Loss of EndoA2 in mouse DRG neurons damaged Piezo2-mediated rapidly adapting mechanically activated currents, and re-expression of EndoA2 rescued the MA currents. In addition, interference with EndoA2 also suppressed touch sensitivity and mechanical hypersensitivity in nonhuman primates.
CONCLUSIONS
Our data reveal that the KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and for sustaining transmission of touch and mechanical hypersensitivity signals. EndoA2 regulates touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking in sensory neurons. Our findings identify a potential new target for the treatment of mechanical pain.
Topics: Animals; Female; Male; Mice; Hyperalgesia; Ion Channels; Kinesins; Mechanotransduction, Cellular; Mice, Inbred C57BL; Pain; Primates; Touch; Acyltransferases
PubMed: 38475827
DOI: 10.1186/s40779-024-00520-z -
Frontiers in Pharmacology 2023Chemotherapy-induced neuropathic pain (CINP) is a debilitating side effect in individuals undergoing cancer treatment. Treatment of CINP with the current available...
Chemotherapy-induced neuropathic pain (CINP) is a debilitating side effect in individuals undergoing cancer treatment. Treatment of CINP with the current available classes of drugs is limited and often yields unsatisfactory results. Finding therapeutic alternatives of plant origin could provide a new way for the management of CINP. (CM) resin extract has been reported to have anti-inflammatory and analgesic activities, but the effect of CM on neuropathic pain is yet to be investigated in CINP. The aim of this study was to investigate the antinociceptive effect of CM extract in a mouse model of paclitaxel-induced neuropathic pain (PINP). The effects of CM on thermal hyperalgesia and mechanical allodynia were assessed in female BALB/c mice with PINP using a hot plate and a plantar aesthesiometer, respectively. Motor coordination was evaluated using a rotarod apparatus. The involvement of transient receptor potential vanilloid channel 1 (TRPV1) in CM actions was investigated using a capsaicin (a TRPV1 agonist)-induced nociception test. The genetic expression of , , , and was assessed using real-time PCR, while protein expression of TRPV1, Iba-1, and CD11b was assessed using Wes™. Administration of CM to mice with established PINP produced a dose-dependent reduction in thermal hyperalgesia. Prophylactic treatment of mice with CM prevented the development of paclitaxel-induced thermal hyperalgesia and mechanical allodynia. CM did not change the motor coordination of mice, as the reaction latency and the rotational velocity of animals pretreated with CM extract were similar to those of animals pretreated with vehicle. CM significantly decreased the number and duration of the flick responses following capsaicin injection into the dorsal surface of the hind paw of mice. The protein expression of TRPV1 was upregulated in the spinal cord of paclitaxel-treated animals compared to vehicle-only-treated control animals, while CM-treated animals had values similar to vehicle-only-treated control animals. The mRNA expression of , a major antioxidant transcription factor, was upregulated in the paw skin of mice treated with CM compared to those treated with paclitaxel alone. These results indicate that CM may both treat established and prevent the development of paclitaxel-induced thermal hyperalgesia and mechanical allodynia without any impairment in the motor activity of mice. CM may mediate its action through the peripheral inhibition of TRPV1 channel activity, restoration of normal TRPV1 protein expression in the spinal cord, and elevation of cellular antioxidant defenses. CM has the potential to be used as a therapeutic alternative to treat CINP.
PubMed: 38186647
DOI: 10.3389/fphar.2023.1295096