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Pain Medicine (Malden, Mass.) Jan 2014Most migraineurs develop cutaneous allodynia during migraines, and many have cutaneous sensitization between attacks. Atypical pain modulation via the descending pain... (Comparative Study)
Comparative Study
OBJECTIVE
Most migraineurs develop cutaneous allodynia during migraines, and many have cutaneous sensitization between attacks. Atypical pain modulation via the descending pain system may contribute to this sensitization and allodynia. The objective of this study was to test the hypothesis that compared with non-allodynic migraineurs, allodynic migraineurs have atypical periaqueductal gray (PAG) and nucleus cuneiformis (NCF) resting-state functional connectivity (rs-fc) with other pain processing regions.
DESIGN
Ten minutes resting-state blood-oxygen-level-dependent data were collected from 38 adult migraineurs and 20 controls. Seed-based analyses compared whole-brain rs-fc with PAG and with NCF in migraineurs with severe ictal allodynia (N = 8) to migraineurs with no ictal allodynia (N = 8). Correlations between the strength of functional connections that differed between severely allodynic and non-allodynic migraineurs with allodynia severity were determined for all migraineurs (N = 38). PAG and NCF rs-fc in all migraineurs was compared with rs-fc in controls.
RESULTS
Migraineurs with severe allodynia had stronger PAG and NCF rs-fc to other brainstem, thalamic, insula and cerebellar regions that participate in discriminative pain processing, as well as to frontal and temporal regions implicated in higher order pain modulation. Evidence that these rs-fc differences were specific for allodynia included: 1) strong correlations between some rs-fc strengths and allodynia severity among all migraineurs; and 2) absence of overlap when comparing rs-fc differences in severely allodynic vs non-allodynic migraineurs with those in all migraineurs vs controls.
CONCLUSION
Atypical rs-fc of brainstem descending modulatory pain regions with other brainstem and higher order pain-modulating regions is associated with migraine-related allodynia.
Topics: Adolescent; Adult; Brain Mapping; Efferent Pathways; Female; Humans; Hyperalgesia; Magnetic Resonance Imaging; Male; Middle Aged; Migraine Disorders; Pain; Pain Threshold; Periaqueductal Gray; Skin; Tegmentum Mesencephali; Young Adult
PubMed: 24165094
DOI: 10.1111/pme.12267 -
The Journal of Pain Nov 2019We report the development and characterization of a novel, injury-free rat model in which nociceptive sensitization after red light is observed in multiple body areas...
We report the development and characterization of a novel, injury-free rat model in which nociceptive sensitization after red light is observed in multiple body areas reminiscent of widespread pain in functional pain syndromes. Rats were exposed to red light-emitting diodes (RLED) (LEDs, 660 nm) at an intensity of 50 Lux for 8 hours daily for 5 days resulting in time- and dose-dependent thermal hyperalgesia and mechanical allodynia in both male and female rats. Females showed an earlier onset of mechanical allodynia than males. The pronociceptive effects of RLED were mediated through the visual system. RLED-induced thermal hyperalgesia and mechanical allodynia were reversed with medications commonly used for widespread pain, including gabapentin, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs. Acetaminophen failed to reverse the RLED induced hypersensitivity. The hyperalgesic effects of RLED were blocked when bicuculline, a gamma-aminobutyric acid-A receptor antagonist, was administered into the rostral ventromedial medulla, suggesting a role for increased descending facilitation in the pain pathway. Key experiments were subjected to a replication study with randomization, investigator blinding, inclusion of all data, and high levels of statistical rigor. RLED-induced thermal hyperalgesia and mechanical allodynia without injury offers a novel injury-free rodent model useful for the study of functional pain syndromes with widespread pain. RLED exposure also emphasizes the different biological effects of different colors of light exposure. PERSPECTIVE: This study demonstrates the effect of light exposure on nociceptive thresholds. These biological effects of red LED add evidence to the emerging understanding of the biological effects of light of different colors in animals and humans. Understanding the underlying biology of red light-induced widespread pain may offer insights into functional pain states.
Topics: Animals; Disease Models, Animal; Female; Hyperalgesia; Light; Male; Pain; Rats; Rats, Sprague-Dawley
PubMed: 31054915
DOI: 10.1016/j.jpain.2019.04.008 -
PloS One 2015Ropivacaine is a local anesthetic widely used for regional anesthesia and epidural analgesia, but its relatively short duration limits its clinical use. A novel...
Ropivacaine is a local anesthetic widely used for regional anesthesia and epidural analgesia, but its relatively short duration limits its clinical use. A novel sustained release lipid formulation of ropivacaine has been recently developed to prolong its duration. We examined the epidural anti-hypersensitivity and preemptive effects of ropivacaine in mesylate injection and sustained release suspension forms in a rat model of neuropathy produced by peripheral nerve injury. Epidural administration of ropivacaine mesylate injection specifically blocked mechanical allodynia and thermal hyperalgesia by approximately 50% with a biological half-effective duration of approximately 3 hrs. The equivalent dose of ropivacaine free-base in sustained release suspension significantly prolonged the duration of anti-allodynia and anti-hyperalgesia by approximately 2 times. Multiple daily epidural injections of ropivacaine in both the mesylate injection and sustained-release suspension forms did not induce tolerance or potentiation to anti-allodynia or anti-hyperalgesia. Moreover, the single or multiple daily administration of ropivacaine mesylate injection before surgery in particular, markedly blocked the initiation and development of neuropathic pain, increasing the biological half-effective duration from less than 4 hrs up to 1 or 2 days. The single and multiple daily epidural injection of ropivacaine sustained release suspension further delayed the biological half-lives to 2 and 3 days, respectively. Our results indicate that the epidural administration of ropivacaine effectively blocks neuropathic pain without the induction of analgesic tolerance, and significantly delays the development of neuropathy produced by peripheral nerve injury. Epidural ropivacaine sustained release suspension produces much longer blockade effects of mechanical allodynia and heat hyperalgesia, and more significantly delays the development of neuropathic pain.
Topics: Amides; Analgesia, Epidural; Anesthetics, Local; Animals; Delayed-Action Preparations; Hyperalgesia; Injections; Male; Mesylates; Motor Activity; Neuralgia; Peripheral Nerve Injuries; Rats; Rats, Wistar; Ropivacaine
PubMed: 25617901
DOI: 10.1371/journal.pone.0117321 -
Neuropharmacology Sep 2020Substance use disorders (SUDs) are frequently accompanied by affective symptoms that promote negative reinforcement mechanisms contributing to SUD maintenance or... (Review)
Review
Substance use disorders (SUDs) are frequently accompanied by affective symptoms that promote negative reinforcement mechanisms contributing to SUD maintenance or progression. Despite their widespread use as analgesics, chronic or excessive exposure to alcohol, opioids, and nicotine produces heightened nociceptive sensitivity, termed hyperalgesia. This review focuses on the contributions of neuropeptide (CRF, melanocortin, opioid peptide) and cytokine (IL-1β, TNF-α, chemokine) systems in the development and maintenance of substance-induced hyperalgesia. Few effective therapies exist for either chronic pain or SUD, and the common interaction of these disease states likely complicates their effective treatment. Here we highlight promising new discoveries as well as identify gaps in research that could lead to more effective and even simultaneous treatment of SUDs and co-morbid hyperalgesia symptoms.
Topics: Animals; Cytokines; Humans; Hyperalgesia; Motivation; Neuropeptides; Substance-Related Disorders
PubMed: 32470337
DOI: 10.1016/j.neuropharm.2020.108153 -
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 -
Journal of Pharmacological Sciences Sep 2021Oxaliplatin is a key drug used in the management of solid tumors, such as colorectal cancer; however, it causes peripheral neuropathy. In this study, we investigated the...
Oxaliplatin is a key drug used in the management of solid tumors, such as colorectal cancer; however, it causes peripheral neuropathy. In this study, we investigated the effect of ibudilast, a phosphodiesterase inhibitor, on oxaliplatin-induced mechanical allodynia and histological changes in rats. Ibudilast (7.5 mg/kg, i.p., 5 times per week) reduced mechanical allodynia and histological changes induced by oxaliplatin (4 mg/kg, i.p., twice a week). In contrast, ibudilast (0.01-10 μM) had no effect on oxaliplatin-induced tumor cytotoxicity in murine colon adenocarcinoma 26 cells. These findings suggest that ibudilast could be useful for preventing oxaliplatin-induced peripheral neuropathy in clinical settings.
Topics: Adenocarcinoma; Animals; Colonic Neoplasms; Hyperalgesia; Male; Mice; Oxaliplatin; Peripheral Nervous System Diseases; Phosphodiesterase Inhibitors; Pyridines; Rats, Sprague-Dawley; Tumor Cells, Cultured; Rats
PubMed: 34294361
DOI: 10.1016/j.jphs.2021.06.004 -
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 -
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 -
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