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The Journal of Physiological Sciences :... Sep 2016Peripheral tissue inflammation can alter the properties of somatic sensory pathways, causing behavioral hypersensitivity and resulting in increased responses to pain... (Review)
Review
Peripheral tissue inflammation can alter the properties of somatic sensory pathways, causing behavioral hypersensitivity and resulting in increased responses to pain caused by noxious stimulation (hyperalgesia) and normally innocuous stimulation (allodynia). These hypersensitivities for nociception are caused by changes in the excitability of trigeminal ganglion (TG) neurons. These changes alter sensory information processing in the neurons in the medullary trigeminal nucleus of caudalis. Increasing information is becoming available regarding trigeminal neuron-neuron/neuron-satellite glial cells (SGCs) communication. The activation of intraganglionic communication plays an important role in the creation and maintenance of trigeminal pathological pain. Therefore, in this review, we focus on the recent findings for sensory functions and pharmacological modulation of TG neurons and SGCs under normal and pathological conditions, and we discuss potential therapeutic targets in glia-neuronal interactions for the prevention of trigeminal neuropathic and inflammatory pain.
Topics: Animals; Hyperalgesia; Neurons; Nociception; Pain; Trigeminal Ganglion
PubMed: 27023716
DOI: 10.1007/s12576-016-0448-1 -
Neuropharmacology Nov 2022Chemotherapy-induced neuropathic pain (CINP) is a debilitating and difficult-to-treat side effect of chemotherapeutic drugs. CINP is marked with oxidative stress and...
Chemotherapy-induced neuropathic pain (CINP) is a debilitating and difficult-to-treat side effect of chemotherapeutic drugs. CINP is marked with oxidative stress and neuronal hypersensitivities. The peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates genes involved in oxidative stress and inflammation. We hypothesize that PPARγ agonists are protective against CIPN by reducing oxidative stress and inhibiting neuronal hypersensitivities. To test our hypothesis, acute or chronic CIPN was introduced by short or long-term treatment of oxaliplatin in BALB/c mice. CIPN mice were treated with either a novel blood-brain barrier (BBB) penetrable PPARγ agonist ELB00824, or a BBB non-penetrable PPARγ agonist pioglitazone, or vehicle. Cold allodynia, mechanical allodynia, motor coordination, sedation and addiction were measured with dry ice, von Frey filaments, beam-walking tests, and conditioned place preference, respectively. Oxidative stress was accessed by measuring byproducts of protein oxidation (carbonyl and 3-Nitrotyrosine) and lipid peroxidation [Thiobarbituric acid reactive substances (TBARS)], as wells as gene expression of Cat, Sod2, Ppargc1a. The effects of ELB00824 on nociceptor excitability were measured using whole-cell electrophysiology of isolated dorsal root ganglion neurons. Preemptive ELB00824, but not pioglitazone, reduced oxaliplatin-induced cold and mechanical allodynia and oxidative stress. ELB0824 suppressed oxaliplatin-induced firing in IB4 neurons. ELB00824 did not cause motor discoordination or sedation/addiction or reduce the antineoplastic activity of oxaliplatin (measured with an MTS-based cell proliferation assay) in a human colon cancer cell line (HCT116) and a human oral cancer cell line (HSC-3). Our results demonstrated that ELB00824 prevents oxaliplatin-induced pain, likely via inhibiting neuronal hypersensitivities and oxidative stress.
Topics: Animals; Antineoplastic Agents; Humans; Hyperalgesia; Hypersensitivity; Mice; Neuralgia; Neurons; Oxaliplatin; Oxidative Stress; PPAR gamma
PubMed: 36007855
DOI: 10.1016/j.neuropharm.2022.109233 -
Cell Death & Disease May 2022Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent and impairing side effects of the antineoplastic...
Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent and impairing side effects of the antineoplastic agent paclitaxel. Here, we demonstrated that paclitaxel can bind and activate complement component 5a receptor 1 (C5aR1) and that this binding is crucial in the etiology of paclitaxel-induced CIPN and anaphylaxis. Starting from our previous data demonstrating the role of interleukin (IL)-8 in paclitaxel-induced neuronal toxicity, we searched for proteins that activate IL-8 expression and, by using the Exscalate platform for molecular docking simulations, we predicted the high affinity of C5aR1 with paclitaxel. By in vitro studies, we confirmed the specific and competitive nature of the C5aR1-paclitaxel binding and found that it triggers intracellularly the NFkB/P38 pathway and c-Fos. In F11 neuronal cells and rat dorsal root ganglia, C5aR1 inhibition protected from paclitaxel-induced neuropathological effects, while in paclitaxel-treated mice, the absence (knock-out mice) or the inhibition of C5aR1 significantly ameliorated CIPN symptoms-in terms of cold and mechanical allodynia-and reduced the chronic pathological state in the paw. Finally, we found that C5aR1 inhibition can counteract paclitaxel-induced anaphylactic cytokine release in macrophages in vitro, as well as the onset of HSRs in mice. Altogether these data identified C5aR1 as a key mediator and a new potential pharmacological target for the prevention and treatment of CIPN and HSRs induced by paclitaxel.
Topics: Animals; Antineoplastic Agents; Hyperalgesia; Mice; Molecular Docking Simulation; Paclitaxel; Peripheral Nervous System Diseases; Rats; Receptor, Anaphylatoxin C5a
PubMed: 35614037
DOI: 10.1038/s41419-022-04964-w -
Neuromodulation : Journal of the... Jan 2023Complex regional pain syndrome (CRPS) is a chronic debilitating disease characterized by sensory abnormalities. Spinal cord stimulation (SCS) is an effective therapy for... (Randomized Controlled Trial)
Randomized Controlled Trial
Allodynia, Hyperalgesia, (Quantitative) Sensory Testing and Conditioned Pain Modulation in Patients With Complex Regional Pain Syndrome Before and After Spinal Cord Stimulation Therapy.
OBJECTIVES
Complex regional pain syndrome (CRPS) is a chronic debilitating disease characterized by sensory abnormalities. Spinal cord stimulation (SCS) is an effective therapy for CRPS, but few studies have investigated the effects of SCS therapy on sensory characteristics. Therefore, this study investigated the effect of SCS on allodynia, hyperalgesia, electrical quantitative sensory testing (QST) parameters, and conditioned pain modulation (CPM) effect.
MATERIALS AND METHODS
This study is part of a multicenter randomized controlled trial (ISRCTN 36655259). Patients with CRPS in one extremity and eligible for SCS were included. The outcome parameters allodynia (symptom and sign), hyperalgesia (symptom), sensory thresholds with QST, CPM effect, and pain scores were tested before and after three months of SCS (40-Hz tonic SCS). Both the CRPS-affected extremity and the contralateral, clinically unaffected extremity were used to test three sensory thresholds with electrical QST: current perception threshold (CPT), pain perception threshold (PPT), and pain tolerance threshold (PTT). The PTT also was used as a test stimulus for the CPM paradigm both before and after the conditioning ice-water test. Nonparametric testing was used for all statistical analyses.
RESULTS
In total, 31 patients were included for analysis. Pain, allodynia (sign and symptom), and hyperalgesia (symptom) were all significantly reduced after SCS therapy. On the unaffected side, none of the QST thresholds (CPT, PPT, and PTT) was significantly altered after SCS therapy. However, the CPT on the CRPS-affected side was significantly increased after SCS therapy. A CPM effect was present both before and after SCS.
CONCLUSIONS
Standard 40-Hz tonic SCS significantly reduces pain, hyperalgesia, and allodynia in patients with CRPS. These findings suggest that SCS therapy should not be withheld from patients who suffer from allodynia and hyperalgesia, which contradicts previous findings derived from retrospective analysis and animal research. ISRCTN Registry: The ISRCTN registration number for the study is ISRCTN 36655259.
Topics: Humans; Hyperalgesia; Spinal Cord Stimulation; Retrospective Studies; Pain Threshold; Complex Regional Pain Syndromes; Chronic Disease; Spinal Cord
PubMed: 36050204
DOI: 10.1016/j.neurom.2022.06.009 -
Pain Medicine (Malden, Mass.) Apr 2016Dry eye is a multi-factorial disorder that manifests with painful ocular symptoms and visual disturbances, which can only be partly attributed to tear dysfunction. This... (Review)
Review
OBJECTIVE
Dry eye is a multi-factorial disorder that manifests with painful ocular symptoms and visual disturbances, which can only be partly attributed to tear dysfunction. This disorder may also involve neuroplasticity in response to neuronal injury. This review will emphasize the key characteristics of dry eye pain and its pathologic mechanisms, making the argument that a subset of dry eye represents a neuropathic pain disorder of the eye, more appropriately called "burning eye syndrome."
METHODS
A literature review was conducted using a PubMed search focusing on dry eye, corneal nociception, and neuropathic pain. Articles were reviewed and those discussing clinical course, pathophysiology, and neuronal regulation of chronic ocular pain as related to dry eye were summarized.
RESULTS
We found that there is a discordance between ocular pain and dryness on the ocular surface. Although tear dysfunction may be one of the initial insults, its persistence may be associated with repeated ocular sensory nerve injury leading to an acute-to-chronic pain transition associated with neuropathologic changes (peripheral and central sensitization), neuronal dysfunction, and spontaneous ocular pain.
CONCLUSION
Dry eye is becoming a major health concern due to its increasing incidence, significant morbidity, and economic burden. Recent evidence suggests that a subset of dry eye may be better represented as a chronic neuropathic pain disorder due to its features of dysesthesia, spontaneous pain, allodynia, and hyperalgesia. Future therapies targeted at the underlying neuroplasticity may yield improved efficacy for patients with this subset of dry eye, which we term "burning eye syndrome."
Topics: Dry Eye Syndromes; Humans; Hyperalgesia; Neuralgia
PubMed: 26814296
DOI: 10.1093/pm/pnv070 -
Alcohol Research : Current Reviews 2021People living with pain report drinking alcohol to relieve pain. Acute alcohol use reduces pain, and chronic alcohol use facilitates the emergence or exaggeration of... (Review)
Review
People living with pain report drinking alcohol to relieve pain. Acute alcohol use reduces pain, and chronic alcohol use facilitates the emergence or exaggeration of pain. Recently, funding agencies and neuroscientists involved in basic research have turned their attention to understanding the neurobiological mechanisms that underlie pain-alcohol interactions, with a focus on circuit and molecular mediators of alcohol-induced changes in pain-related behavior. This review briefly discusses some examples of work being done in this area, with a focus on reciprocal projections between the midbrain and extended amygdala, as well as some neurochemical mediators of pain-related phenotypes after alcohol exposure. Finally, as more work accumulates on this topic, the authors highlight the need for the neuroscience field to carefully consider sex and age in the design and analysis of pain-alcohol interaction experiments.
Topics: Alcoholism; Amygdala; Humans; Hyperalgesia; Mesencephalon; Peptides
PubMed: 34729286
DOI: 10.35946/arcr.v41.1.13 -
Drug Design, Development and Therapy 2021Peripheral inflammation leads to the development of persistent thermal hyperalgesia and mechanical allodynia associated with increased expression of interleukin-1β...
BACKGROUND
Peripheral inflammation leads to the development of persistent thermal hyperalgesia and mechanical allodynia associated with increased expression of interleukin-1β (IL-1β) in the spinal cord. The aim of the present study was to investigate the effects of thiazolidine derivatives, 1b ([2-(2-hydroxyphenyl)-1,3-thiazolidin-4-yl](morpholin-4-yl)methanone) and 1d (2-hydroxy-4-{[2-(2-hydroxyphenyl)-1,3-thiazolidine-4-carbonyl]amino}benzoic acid), on thermal hyperalgesia, mechanical allodynia and on IL-1β expression during carrageenan-induced inflammation in the spinal cord in mice. Inflammatory pain was induced by injecting 1% carrageenan into the right hind paw of the mice.
METHODS
The animals were administered thiazolidine derivatives, 1b and 1d (1 mg/kg, 3 mg/kg, or 10 mg/kg), intraperitoneally 30 minutes before carrageenan administration. The animals' behavior was evaluated by measuring thermal hyperalgesia, mechanical allodynia, and motor coordination. The IL-1β expression was measured by enzyme-linked immunosorbent assay. Acute and sub-acute toxicity studies were conducted to evaluate the toxicity profile of compounds.
RESULTS
Treatment with the thiazolidine derivative, 1b and 1d, attenuated carrageenan-induced thermal hyperalgesia and mechanical allodynia at doses of 1 mg/kg, 3 mg/kg, and 10 mg/kg. No motor coordination deficits were observed in animals. The compounds also reduced IL-1β expression in the spinal cord of mice. Acute and sub-acute toxicity studies revealed that both compounds were safe.
CONCLUSION
The compounds exhibit promising activity against inflammatory pain due to their ability to produce anti-hyperalgesic and anti-allodynic effects and to inhibit IL-1β expression in the spinal cord.
Topics: Animals; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hyperalgesia; Inflammation; Male; Mice; Mice, Inbred BALB C; Molecular Structure; Pain; Structure-Activity Relationship; Thiazolidines
PubMed: 33574656
DOI: 10.2147/DDDT.S281559 -
Journal of Biomedical Science Apr 2023Ingestion of alcoholic beverages is a known trigger of migraine attacks. However, whether and how ethanol exerts its pro-migraine action remains poorly known. Ethanol...
BACKGROUND
Ingestion of alcoholic beverages is a known trigger of migraine attacks. However, whether and how ethanol exerts its pro-migraine action remains poorly known. Ethanol stimulates the transient receptor potential vanilloid 1 (TRPV1) channel, and its dehydrogenized metabolite, acetaldehyde, is a known TRP ankyrin 1 (TRPA1) agonist.
METHODS
Periorbital mechanical allodynia following systemic ethanol and acetaldehyde was investigated in mice after TRPA1 and TRPV1 pharmacological antagonism and global genetic deletion. Mice with selective silencing of the receptor activated modifying protein 1 (RAMP1), a component of the calcitonin gene-related peptide (CGRP) receptor, in Schwann cells or TRPA1 in dorsal root ganglion (DRG) neurons or Schwann cells, were used after systemic ethanol and acetaldehyde.
RESULTS
We show in mice that intragastric ethanol administration evokes a sustained periorbital mechanical allodynia that is attenuated by systemic or local alcohol dehydrogenase inhibition, and TRPA1, but not TRPV1, global deletion, thus indicating the implication of acetaldehyde. Systemic (intraperitoneal) acetaldehyde administration also evokes periorbital mechanical allodynia. Importantly, periorbital mechanical allodynia by both ethanol and acetaldehyde is abrogated by pretreatment with the CGRP receptor antagonist, olcegepant, and a selective silencing of RAMP1 in Schwann cells. Periorbital mechanical allodynia by ethanol and acetaldehyde is also attenuated by cyclic AMP, protein kinase A, and nitric oxide inhibition and pretreatment with an antioxidant. Moreover, selective genetic silencing of TRPA1 in Schwann cells or DRG neurons attenuated periorbital mechanical allodynia by ethanol or acetaldehyde.
CONCLUSIONS
Results suggest that, in mice, periorbital mechanical allodynia, a response that mimics cutaneous allodynia reported during migraine attacks, is elicited by ethanol via the systemic production of acetaldehyde that, by releasing CGRP, engages the CGRP receptor in Schwann cells. The ensuing cascade of intracellular events results in a Schwann cell TRPA1-dependent oxidative stress generation that eventually targets neuronal TRPA1 to signal allodynia from the periorbital area.
Topics: Mice; Animals; Hyperalgesia; Receptors, Calcitonin Gene-Related Peptide; Ethanol; Calcitonin Gene-Related Peptide; Ankyrins; Acetaldehyde; TRPA1 Cation Channel; Migraine Disorders; Schwann Cells; Mice, Inbred C57BL
PubMed: 37101198
DOI: 10.1186/s12929-023-00922-6 -
The Journal of International Medical... May 2020Pain induced by inflammation and nerve injury arises from abnormal neural activity of primary afferent nociceptors in response to tissue damage, which causes long-term... (Review)
Review
Pain induced by inflammation and nerve injury arises from abnormal neural activity of primary afferent nociceptors in response to tissue damage, which causes long-term elevation of the sensitivity and responsiveness of spinal cord neurons. Inflammatory pain typically resolves following resolution of inflammation; however, nerve injury-either peripheral or central-may cause persistent neuropathic pain, which frequently manifests as hyperalgesia or allodynia. Neuralgias, malignant metastatic bone disease, and diabetic neuropathy are some of the conditions associated with severe, often unremitting chronic pain that is both physically and psychologically debilitating or disabling. Therefore, optimal pain management for patients with chronic neuropathic pain requires a multimodal approach that comprises pharmacological and psychological interventions. Non-opioid analgesics (e.g., paracetamol, aspirin, or other non-steroidal anti-inflammatory drugs) are first-line agents used in the treatment of mild-to-moderate acute pain, while opioids of increasing potency are indicated for the treatment of persistent, moderate-to-severe inflammatory pain. N-methyl D-aspartate receptor antagonists, antidepressants, anticonvulsants, or a combination of these should be considered for the treatment of chronic neuropathic pain. This review discusses the various neural signals that mediate acute and chronic pain, as well as the general principles of pain management.
Topics: Analgesics; Anticonvulsants; Antidepressive Agents; Cancer Pain; Chronic Pain; Diabetic Neuropathies; Drug Therapy, Combination; Humans; Hyperalgesia; Neoplasms; Neuralgia; Pain Management; Pain Measurement; Trauma, Nervous System; Treatment Outcome
PubMed: 32408839
DOI: 10.1177/0300060520903653 -
Arquivos de Neuro-psiquiatria Mar 2017To evaluate cutaneous allodynia among patients with chronic and episodic migraine in a tertiary headache clinic. (Comparative Study)
Comparative Study
OBJECTIVE
To evaluate cutaneous allodynia among patients with chronic and episodic migraine in a tertiary headache clinic.
METHODS
80 subjects with episodic migraine and 80 with chronic migraine were assessed in a tertiary hospital. The 12-item Allodynia Symptom Checklist/Brazil questionnaire was applied to classify subjects according to the presence and severity of cutaneous allodynia.
RESULTS
Cutaneous allodynia was identified in 81.3% of the episodic migraine group and 92.5% of the chronic migraine group (p = 0.03). No increased association could be attributed to chronic migraine when adjusted by years with disease (PR = 1.12; 95%CI = 0.99 to 1.27; p = 0.06). The groups also did not differ in the severity of allodynia, and severe presentation was the most frequent.
DISCUSSION
Both groups seemed to be similarly affected in the cephalic and extracephalic regions, with the same severity.
CONCLUSION
Cutaneous allodynia is more frequent in chronic migraine, and its presence and severity seems to be more associated with the duration of the disease.
Topics: Adult; Chronic Disease; Female; Humans; Hyperalgesia; Male; Migraine Disorders; Severity of Illness Index; Skin Diseases; Socioeconomic Factors; Time Factors
PubMed: 28355322
DOI: 10.1590/0004-282X20170015