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Cephalalgia : An International Journal... Sep 2021To assess photophobia and allodynia in subjects with post-traumatic headache and examine how these sensory hypersensitivities associate with clinical measures of disease...
OBJECTIVE
To assess photophobia and allodynia in subjects with post-traumatic headache and examine how these sensory hypersensitivities associate with clinical measures of disease burden.
BACKGROUND
Post-traumatic headache is the most frequent and disabling long-term consequence of mild traumatic brain injury. There is evidence of sensory dysfunction in acute post-traumatic headache, and it is known from other headache conditions that sensory amplifications correlate with more severe disease. However, systematic studies in post-traumatic headache are surprisingly scarce.
METHODS
We tested light and tactile sensitivity, along with measures of disease burden, in 30 persistent post-traumatic headache subjects and 35 controls.
RESULTS
In all, 79% of post-traumatic headache subjects exhibited sensory hypersensitivity based on psychophysical assessment. Of those exhibiting hypersensitivity, 54% exhibited both light and tactile sensitivity. Finally, sensory thresholds were correlated across modalities, as well as with headache attack frequency.
CONCLUSIONS
In this study, post-traumatic headache subjects with both light and tactile sensitivity had significantly higher headache frequencies and lower sensitivity thresholds to both modalities, compared to those with single or no sensory hypersensitivity. This pattern suggests that hypersensitivity across multiple modalities may be functionally synergistic, reflect a higher disease burden, and may serve as candidate markers of disease.
Topics: Adult; Brain Injuries, Traumatic; Central Nervous System Sensitization; Cost of Illness; Female; Headache; Humans; Hyperalgesia; Male; Photophobia; Post-Traumatic Headache; Severity of Illness Index; Tension-Type Headache
PubMed: 33910382
DOI: 10.1177/03331024211010304 -
Journal of Orthopaedic Surgery and... Jan 2023Complex regional pain syndrome (CRPS) is a chronic condition following inciting events such as fractures or surgeries with sensorimotor and autonomic manifestations and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Complex regional pain syndrome (CRPS) is a chronic condition following inciting events such as fractures or surgeries with sensorimotor and autonomic manifestations and poor prognosis. This review aimed to provide conclusive evidence about the sensory phenotype of CRPS based on quantitative sensory testing (QST) to understand the underlying pain mechanisms and guide treatment strategies.
DATABASES
Eight databases were searched based on a previously published protocol. Forty studies comparing QST outcomes (thermal, mechanical, vibration, and electric detection thresholds, thermal, mechanical, pressure, and electric pain thresholds, wind-up ratio, mechanical pain sensitivity, allodynia, flare area, area after pinprick hyperalgesia, pleasantness after C-tactile stimulation, and pain ratings) in chronic CRPS (adults and children) versus healthy controls were included.
RESULTS
From 37 studies (14 of low quality, 22 of fair quality, and 1 of good quality), adults with CRPS showed: (i) significant loss of thermal, mechanical, and vibration sensations, significant gain of thermal and mechanical pain thresholds, significant elevation of pain ratings, and no difference in wind-up ratio; (ii) significant reduction of pleasantness levels and increased area of pinprick hyperalgesia, in the affected limb. From three fair-quality studies, adolescents and children with CRPS showed loss of cold detection with cold hyperalgesia in the affected limb. There was moderate to substantial overall heterogeneity.
CONCLUSION
Diffuse thermal and mechanical hypoesthesia with primary and secondary hyperalgesia, enhanced pain facilitation evidenced by increased area of pinprick hyperalgesia, and elevated pain ratings are dominant in adults with CRPS. Adolescents and children with CRPS showed less severe sensory abnormalities.
Topics: Humans; Hyperalgesia; Pain Measurement; Pain; Complex Regional Pain Syndromes; Pain Threshold
PubMed: 36593515
DOI: 10.1186/s13018-022-03461-2 -
Molecular Brain Feb 2018Neuropathic pain is a complex, chronic pain state characterized by hyperalgesia, allodynia, and spontaneous pain. Accumulating evidence has indicated that the microglial...
Neuropathic pain is a complex, chronic pain state characterized by hyperalgesia, allodynia, and spontaneous pain. Accumulating evidence has indicated that the microglial Toll-like receptor 4 (TLR4) and autophagy are implicated in neurodegenerative diseases, but their relationship and role in neuropathic pain remain unclear. In this study, we examined TLR4 and its association with autophagic activity using a chronic constriction injury (CCI)-induced neuropathic pain model in wild-type (WT) and TLR4-knockout (KO) mice. The mice were assigned into four groups: WT-Contralateral (Contra), WT-Ipsilateral (Ipsi), TLR4 KO-Contra, and TLR4 KO-Ipsi. Behavioral and mechanical allodynia tests and biochemical analysis of spinal cord tissue were conducted following CCI to the sciatic nerve. Compared with the Contra group, mechanical allodynia in both the WT- and TLR4 KO-Ipsi groups was significantly increased, and a marked decrease of allodynia was observed in the TLR4 KO-Ipsi group. Although glial cells were upregulated in the WT-Ipsi group, no significant change was observed in the TLR4 KO groups. Moreover, protein expression and immunoreactive cell regulation of autophagy (Beclin 1, p62) were significantly increased in the neurons, but not microglia, of WT-Ipsi group compared with the WT-Contra group. The level of PINK1, a marker for mitophagy was increased in the neurons of WT, but not in TLR4 KO mice. Together, these results show that TLR4-mediated p62 autophagic impairment plays an important role in the occurrence and development of neuropathic pain. And what is more, microglial TLR4-mediated microglial activation might be indirectly coupled to neuronal autophage.
Topics: Animals; Astrocytes; Autophagy; Beclin-1; Chronic Disease; Constriction; Hyperalgesia; Male; Mice, Inbred C57BL; Mice, Knockout; Microglia; Microtubule-Associated Proteins; Mitophagy; Models, Neurological; Neuralgia; Nociception; Protein Kinases; Sequestosome-1 Protein; Spinal Cord Dorsal Horn; Spinal Nerves; Toll-Like Receptor 4; Walking
PubMed: 29486776
DOI: 10.1186/s13041-018-0354-y -
Journal of Neurochemistry Dec 2020Morphine is a key drug for the treatment of pain but its side effects limit its clinical application. MEL-0614, an endomorphin-1 analog, has fewer side effects than...
Morphine is a key drug for the treatment of pain but its side effects limit its clinical application. MEL-0614, an endomorphin-1 analog, has fewer side effects than morphine in addition to its powerful analgesic effect. In this study, we measured the effect of morphine and MEL-0614 on hyperalgesia (7 days) and neuropathic allodynia (14 days) after thermal, mechanical, and cold stimulation. We found that after four and eight consecutive days of intrathecal administration (1, 3, and 10 nmol), morphine induced severe hyperalgesia and neuropathic allodynia, respectively. MEL-0614 did not induce hyperalgesia at low doses (1 and 3 nmol) and had a mitigating effect on morphine-induced neuropathic exacerbations in spared nerve injury mice. Hyperalgesia was blocked by Dynorphin A (1-17) antibody but not by an opioid receptor antagonist. To explore the reasons for the different results of morphine and MEL-0614, we used quantitative PCR and immunofluorescence to explore the effects of both on N-methyl-D-aspartate (NMDA) receptor subtype 2B (NR2B), microglia marker iba-1, and inflammatory mediators. After 8 days of consecutive administration, morphine (10 nmol) promoted an increase in the number of NR2B, iba-1, and inflammatory mediators in the spinal cord of mice. MEL-0614 (10 nmol) had no significant effect on these factors, and after co-administration with morphine, the expression of NR2B, iba-1, and inflammatory mediators was lower than that with morphine injection alone. Our research showed the advantage of MEL-0614 in terms of hyperalgesia and neuropathic allodynia, which may provide clinical relief of hyperalgesia and neuropathic allodynia caused by morphine.
Topics: Analgesics, Opioid; Animals; Hyperalgesia; Injections, Spinal; Mice; Morphine; Neuralgia; Oligopeptides; Pain Measurement; Receptors, N-Methyl-D-Aspartate
PubMed: 32666510
DOI: 10.1111/jnc.15127 -
CNS Neuroscience & Therapeutics Jul 2023Beyond digestion, bile acids have been recognized as signaling molecules with broad paracrine and endocrine functions by activating plasma membrane receptor (Takeda G...
AIMS
Beyond digestion, bile acids have been recognized as signaling molecules with broad paracrine and endocrine functions by activating plasma membrane receptor (Takeda G protein-coupled receptor 5, TGR5) and the nuclear farnesoid X receptor (FXR). The present study investigated the role of bile acids in alleviating neuropathic pain by activating TGR5 and FXR.
METHOD
Neuropathic pain was induced by spared nerve injury (SNI) of the sciatic nerve. TGR5 or FXR agonist was injected intrathecally. Pain hypersensitivity was measured with Von Frey test. The amount of bile acids was detected using a bile acid assay kit. Western blotting and immunohistochemistry were used to assess molecular changes.
RESULTS
We found that bile acids were downregulated, whereas the expression of cytochrome P450 cholesterol 7ahydroxylase (CYP7A1), a rate-limiting enzyme for bile acid synthesis, was upregulated exclusively in microglia in the spinal dorsal horn after SNI. Furthermore, the expression of the bile acid receptors TGR5 and FXR was increased in glial cells and GABAergic neurons in the spinal dorsal horn on day 7 after SNI. Intrathecal injection of either TGR5 or FXR agonist on day 7 after SNI alleviated the established mechanical allodynia in mice, and the effects were blocked by TGR5 or FXR antagonist. Bile acid receptor agonists inhibited the activation of glial cells and ERK pathway in the spinal dorsal horn. All of the above effects of TGR5 or FXR agonists on mechanical allodynia, on the activation of glial cells, and on ERK pathway were abolished by intrathecal injection of the GABA receptor antagonist bicuculline.
CONCLUSION
These results suggest that activation of TGR5 or FXR counteracts mechanical allodynia. The effect was mediated by potentiating function of GABA receptors, which then inhibited the activation of glial cells and neuronal sensitization in the spinal dorsal horn.
Topics: Mice; Animals; Hyperalgesia; Signal Transduction; Spinal Cord Dorsal Horn; Bile Acids and Salts; Neuralgia
PubMed: 36880297
DOI: 10.1111/cns.14154 -
The Journal of Headache and Pain Feb 2019Administration of endogenous mediators or exogenous chemicals in migraine patients provoke early headaches and delayed migraine-like attacks. Although migraine provoking...
BACKGROUND
Administration of endogenous mediators or exogenous chemicals in migraine patients provoke early headaches and delayed migraine-like attacks. Although migraine provoking substances are normally vasodilators, dilation of arterial vessels does not seem to be the sole contributing factor, and the underlying mechanisms of the delayed migraine pain are mostly unknown. Sustained mechanical allodynia is a common response associated with the local administration of various proalgesic substances in experimental animals and humans. Here, we investigated the ability of a series of endogenous mediators which provoke or do not provoke migraine in patients, to cause or not cause mechanical allodynia upon their injection in the mouse periorbital area.
METHODS
Mechanical allodynia was assessed with the von Frey filament assay. Stimuli were given by subcutaneous injection in the periorbital area of C57BL/6J mice; antagonists were administered by local and systemic injections.
RESULTS
Calcitonin gene related peptide (CGRP), but not adrenomedullin and amylin, pituitary adenylyl cyclase activating peptide (PACAP), but not vasoactive intestinal polypeptide (VIP), histamine, prostaglandin E (PGE) and prostacyclin (PGI), but not PGF evoked a dose-dependent periorbital mechanical allodynia. The painful responses were attenuated by systemic or local (periorbital) administration of antagonists for CGRP (CLR/RAMP1), PACAP (PAC-1), histamine H, PGE (EP), and PGI (IP) receptors, respectively.
CONCLUSIONS
The correspondence between substances that provoke (CGRP; PACAP, histamine, PGE, PGI), or do not provoke (VIP and PGF), migraine-like attacks in patients and periorbital allodynia in mice suggests that the study of allodynia in mice may provide information on the proalgesic mechanisms of migraine-provoking agents in humans. Results underline the ability of migraine-provoking substances to initiate mechanical allodynia by acting on peripheral terminals of trigeminal afferents.
Topics: Animals; Calcitonin Gene-Related Peptide; Disease Models, Animal; Hyperalgesia; Mice; Mice, Inbred C57BL; Migraine Disorders; Nociception; Receptor Activity-Modifying Protein 1; Vasodilator Agents
PubMed: 30764776
DOI: 10.1186/s10194-019-0968-1 -
Molecular Pain 2018Background Surgeries causing nerve injury can result in chronic neuropathic pain, which is clinically managed by using antidepressant or anticonvulsant drugs. Currently,... (Comparative Study)
Comparative Study
Background Surgeries causing nerve injury can result in chronic neuropathic pain, which is clinically managed by using antidepressant or anticonvulsant drugs. Currently, there is a growing interest for investigating preemptive treatments that would prevent this long-term development of neuropathic pain. Our aim was to compare analgesic drugs using two distinct treatment modalities: either treatment onset at surgery time or following a couple of weeks of neuropathic pain. Methods In male C57BL/6J mice, neuropathic pain was induced by cuffing the sciatic nerve, and allodynia was assessed using von Frey filaments. We tested the effect of anticonvulsants (gabapentin 10 mg/kg and carbamazepine 40 mg/kg), antidepressants (desipramine 5 mg/kg, duloxetine 10 mg/kg, and fluoxetine 10 mg/kg), dexamethasone (2 mg/kg), and ketamine (15 mg/kg). Drugs were injected daily or twice a day, starting either at surgery time or on day 25 postsurgery (15 days of treatment for antidepressants and 10 days for other drugs). Results Ketamine was the only effective treatment during the early postsurgical period. Although early anticonvulsant treatment was not immediately effective, it prevented chronification of allodynia. When treatments started at day 25 postsurgery, desipramine, duloxetine, and anticonvulsants suppressed the mechanical allodynia. Conclusions Our data show that allodynia measured in experimental neuropathic pain model likely results from a combination of different processes (early vs. late allodynia) that display different sensitivity to treatments. We also propose that early anticonvulsant treatment with gabapentin or carbamazepine may have a prophylactic effect on the chronification of allodynia following nerve injury.
Topics: Animals; Anticonvulsants; Antidepressive Agents; Dexamethasone; Hyperalgesia; Ketamine; Mice, Inbred C57BL; Neuralgia
PubMed: 29212409
DOI: 10.1177/1744806917749683 -
Headache Apr 2015Despite being the mainstay of pain management, opioids are limited in their clinical utility by adverse effects, such as tolerance and paradoxical hyperalgesia. Research... (Review)
Review
Despite being the mainstay of pain management, opioids are limited in their clinical utility by adverse effects, such as tolerance and paradoxical hyperalgesia. Research of the past 15 years has extended beyond neurons, to implicate central nervous system immune signaling in these adverse effects. This article will provide an overview of these central immune mechanisms in opioid tolerance and paradoxical hyperalgesia, including those mediated by Toll-like receptor 4, purinergic, ceramide, and chemokine signaling. Challenges for the future, as well as new lines of investigation will be highlighted.
Topics: Analgesia; Analgesics, Opioid; Animals; Central Nervous System; Drug Tolerance; Humans; Hyperalgesia; Signal Transduction; Toll-Like Receptor 4
PubMed: 25833219
DOI: 10.1111/head.12552 -
Brain, Behavior, and Immunity Feb 2019In rheumatoid arthritis, joint pain can persist despite resolution of swelling. Similarly, in the murine K/BxN serum transfer model, a persistent tactile allodynia is...
In rheumatoid arthritis, joint pain can persist despite resolution of swelling. Similarly, in the murine K/BxN serum transfer model, a persistent tactile allodynia is observed after the resolution of joint inflammation (post-inflammatory pain) in male mice. Here, we found female wild type (WT) mice show inflammatory, but reduced post-inflammatory tactile allodynia. The transition to the post-inflammatory phenotype is dependent on TLR4 signaling. At the spinal level, we found differences in TNF and IFNβ mRNA expression in WT and TLR4 deficient males. In wild type male and female mice, there is differential temporal spinal expression of TNF and IFNβ. In WT males, blockade of TNF or administration of IFNβ was insufficient to affect the persistent allodynia. However, co-administration of intrathecal (IT) IFNβ and anti-TNF antibodies in male WT mice permanently reversed tactile allodynia. IT IFNβ treatment induces expression of anti-inflammatory proteins, contributing to the beneficial effect. Together, these experiments illustrated differences in the transition to chronic tactile allodynia in male and female animals and the complexities of effective pharmacologic interventions.
Topics: Animals; Arthritis; Arthritis, Rheumatoid; Central Nervous System; Disease Models, Animal; Female; Hyperalgesia; Interferon-beta; Male; Mice; Mice, Inbred C57BL; Pain; Sex Factors; Signal Transduction; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 30465880
DOI: 10.1016/j.bbi.2018.11.014 -
Cellular and Molecular Life Sciences :... Aug 2022Intractable neuropathic pain following spinal cord injury (NP-SCI) reduces a patient's quality of life. Excessive release of ATP into the extracellular space evokes...
Intractable neuropathic pain following spinal cord injury (NP-SCI) reduces a patient's quality of life. Excessive release of ATP into the extracellular space evokes neuroinflammation via purinergic receptor. Neuroinflammation plays an important role in the initiation and maintenance of NP. However, little is known about whether or not extracellular ATP cause NP-SCI. We found in the present study that excess of intracellular ATP at the lesion site evokes at-level NP-SCI. No significant differences in the body weight, locomotor function, or motor behaviors were found in groups that were negative and positive for at-level allodynia. The intracellular ATP level at the lesion site was significantly higher in the allodynia-positive mice than in the allodynia-negative mice. A metabolome analysis revealed that there were no significant differences in the ATP production or degradation between allodynia-negative and allodynia-positive mice. Dorsal horn neurons in allodynia mice were found to be inactivated in the resting state, suggesting that decreased ATP consumption due to neural inactivity leads to a build-up of intracellular ATP. In contrast to the findings in the resting state, mechanical stimulation increased the neural activity of dorsal horn and extracellular ATP release at lesion site. The forced production of intracellular ATP at the lesion site in non-allodynia mice induced allodynia. The inhibition of P2X4 receptors in allodynia mice reduced allodynia. These results suggest that an excess buildup of intracellular ATP in the resting state causes at-level NP-SCI as a result of the extracellular release of ATP with mechanical stimulation.
Topics: Adenosine Triphosphate; Animals; Hyperalgesia; Mice; Neuralgia; Quality of Life; Spinal Cord; Spinal Cord Dorsal Horn; Spinal Cord Injuries
PubMed: 35972649
DOI: 10.1007/s00018-022-04510-z