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Psychopharmacology Oct 2023Asteoarthritis (OA) is a leading cause of chronic pain in the elderly population and is often associated with emotional comorbidities such as anxiety and depression....
RATIONALE
Asteoarthritis (OA) is a leading cause of chronic pain in the elderly population and is often associated with emotional comorbidities such as anxiety and depression. Despite age is a risk factor for both OA and mood disorders, preclinical studies are mainly conducted in young adult animals.
OBJECTIVES
Here, using young adult (11-week-old) and older adult (20-month-old) mice, we evaluate in a monosodium-iodoacetate-(MIA)-induced OA model the development of anxio-depressive-like behaviors and whether brain neuroinflammation may underlie the observed changes. We also test whether an effective pain treatment may prevent behavioral and biochemical alterations.
METHODS
Mechanical allodynia was monitored throughout the experimental protocol, while at the end of protocol (14 days), anxio-depressive-like behaviors and cognitive dysfunction were assessed. Neuroinflammatory condition was evaluated in prefrontal cortex, hippocampus and hypothalamus. Serum IFNγ levels were also measured. Moreover, we test the efficacy of a 1-week treatment with morphine (2.5 mg/kg) on pain, mood alterations and neuroinflammation.
RESULTS
We observed that young adult and older adult controls (CTRs) mice had comparable allodynic thresholds and developed similar allodynia after MIA injection. Older adult CTRs were characterized by altered behavior in the tests used to assess the presence of depression and cognitive impairment and by elevated neuroinflammatory markers in brain areas compared to younger ones. The presence of pain induced depressive-like behavior and neuroinflammation in adult young mice, anxiety-like behavior in both age groups and worsened neuroinflammation in older adult mice. Morphine treatment counteracted pain, anxio-depressive behaviors and neuroinflammatory activation in both young adult and older adult mice.
CONCLUSIONS
Here, we demonstrated that the presence of chronic pain in young adult mice induces mood alterations and supraspinal biochemical changes and aggravates the alterations already evident in older adult animals. A treatment with morphine, counteracting the pain, prevents the development of anxio-depressive disorders and reduces neuroinflammation.
Topics: Aged; Mice; Humans; Animals; Morphine; Chronic Pain; Neuroinflammatory Diseases; Disease Models, Animal; Osteoarthritis; Hyperalgesia; Depression
PubMed: 37530884
DOI: 10.1007/s00213-023-06436-1 -
NeuroImage Dec 2023Literature suggests that attention is a critical cognitive process for pain perception and modulation and may play an important role in placebo and nocebo effects. Here,... (Randomized Controlled Trial)
Randomized Controlled Trial
Modulation effects of repeated transcranial direct current stimulation on the dorsal attention and frontal parietal networks and its association with placebo and nocebo effects.
Literature suggests that attention is a critical cognitive process for pain perception and modulation and may play an important role in placebo and nocebo effects. Here, we investigated how repeated transcranial direct current stimulation (tDCS) applied at the dorsolateral prefrontal cortex (DLPFC) for three consecutive days can modulate the brain functional connectivity (FC) of two networks involved in cognitive control: the frontoparietal network (FPN) and dorsal attention network (DAN), and its association with placebo and nocebo effects. 81 healthy subjects were randomized to three groups: anodal, cathodal, and sham tDCS. Resting state fMRI scans were acquired pre- and post- tDCS on the first and third day of tDCS. An Independent Component Analysis (ICA) was performed to identify the FPN and DAN. ANCOVA was applied for group analysis. Compared to sham tDCS, 1) both cathodal and anodal tDCS increased the FC between the DAN and right parietal operculum; cathodal tDCS also increased the FC between the DAN and right postcentral gyrus; 2) anodal tDCS led to an increased FC between the FPN and right parietal operculum, while cathodal tDCS was associated with increased FC between the FPN and left superior parietal lobule/precuneus; 3) the FC increase between the DAN and right parietal operculum was significantly correlated to the placebo analgesia effect in the cathodal group. Our findings suggest that both repeated cathodal and anodal tDCS could modulate the FC of two important cognitive brain networks (DAN and FPN), which may modulate placebo / nocebo effects.
Topics: Humans; Transcranial Direct Current Stimulation; Nocebo Effect; Prefrontal Cortex; Brain; Pain
PubMed: 37939891
DOI: 10.1016/j.neuroimage.2023.120433 -
Molecular Neurobiology Sep 2023Mechanical sensing Piezo2 channel in primary sensory neurons has been shown contribute to mechanical allodynia in somatic chronic pain conditions. Interstitial cystitis...
Mechanical sensing Piezo2 channel in primary sensory neurons has been shown contribute to mechanical allodynia in somatic chronic pain conditions. Interstitial cystitis (IC)-associated pain is often triggered by bladder filling, a presentation that mimics the mechanical allodynia. In the present study, we aimed to examine the involvement of sensory Piezo2 channel in IC-associated mechanical allodynia using a commonly employed cyclophosphamide (CYP)-induced IC model rat. Piezo2 channels in dorsal root ganglia (DRGs) was knocked down by intrathecal injections of Piezo2 anti-sense oligodeoxynucleotides (ODNs) in CYP-induced cystitis rats, and mechanical stimulation-evoked referred bladder pain was measured in the lower abdomen overlying the bladder using von Frey filaments. Piezo2 expression at the mRNA, protein, and functional levels in DRG neurons innervating the bladder was detected by RNA-fluorescence in situ hybridization, western blotting, immunofluorescence, and Ca imaging, respectively. We found that Piezo2 channels were expressed on most (> 90%) of the bladder primary afferents, including afferents that express CGRP, TRPV1 and stained with isolectin B4. CYP-induced cystitis was associated with Piezo2 upregulation in bladder afferent neurons at the mRNA, protein, and functional levels. Knockdown of Piezo2 expression in DRG neurons significantly suppressed mechanical stimulation-evoked referred bladder pain as well as bladder hyperactivity in CYP rats compared to CYP rats treated with mismatched ODNs. Our results suggest upregulation of Piezo2 channels is involved in the development of bladder mechanical allodynia and bladder hyperactivity in CYP-induced cystitis. Targeting Piezo2 might be an attractive therapeutic approach for IC-related bladder pain.
Topics: Rats; Animals; Hyperalgesia; Up-Regulation; In Situ Hybridization, Fluorescence; Cystitis; Cyclophosphamide; Pain; RNA, Messenger
PubMed: 37227654
DOI: 10.1007/s12035-023-03386-9 -
The Journal of Headache and Pain Oct 2023BMP7 has been shown to have neuroprotective effects and to alleviate demyelination. However, its role in trigeminal neuralgia (TN) has not been well investigated. The...
BACKGROUND
BMP7 has been shown to have neuroprotective effects and to alleviate demyelination. However, its role in trigeminal neuralgia (TN) has not been well investigated. The current study aims to determine whether BMP7 plays a role in demyelination, its effects on pain behaviors and mechanism of action in rats with TN.
METHODS
We used an infraorbital-nerve chronic-constriction injury (ION-CCI) to establish a rat model of TN. Adeno-associated viruses (AAVs) were injected into the rats to upregulate or downregulate BMP7. The mechanical withdrawal thresholds (MWT) of the injured rats were detected using Von Frey filaments. The changes in expression levels of BMP7 and oligodendrocyte (OL) markers were examined by western blotting, quantitative real-time PCR, immunofluorescence, and transmission electron microscopy.
RESULTS
The ION-CCI induced mechanical allodynia, demyelination, and loss of OLs with a reduction of BMP7. Short-hairpin RNA (shRNA)-BMP7 that inhibited BMP7 expression also caused mechanical allodynia, demyelination, and loss of OLs, and its mechanism may be OL apoptosis. Overexpressing BMP7 in the trigeminal spinal subnucleus caudalis(VC) with AAV-BMP7 relieved all three phenotypes induced by the CCI, and its mechanism may be alleviating OLs apoptosis. Two signal pathways associated with apoptosis, STAT3 and p65, were significantly downregulated in the VC after CCI and rescued by BMP7 overexpression.
CONCLUSION
BMP7 can alleviate TN by reducing OLs apoptosis and subsequent demyelination. The mechanism behind this protection could be BMP7-mediated activation of the STAT3 and NF-κB/p65 signaling pathway and subsequent decrease in OL apoptosis. Importantly, our study presents clear evidence in support of BMP7 as a possible therapeutic target for the treatment of TN.
Topics: Rats; Animals; Trigeminal Neuralgia; Hyperalgesia; Rats, Sprague-Dawley; Apoptosis; Oligodendroglia; Demyelinating Diseases
PubMed: 37875834
DOI: 10.1186/s10194-023-01681-3 -
Cephalalgia : An International Journal... Jan 2024The trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) is identified as an essential element in migraine pathogenesis.
BACKGROUND
The trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) is identified as an essential element in migraine pathogenesis.
METHODS
and studies evaluated pharmacologic properties of the CGRP receptor antagonist atogepant. Radioligand binding using I-CGRP and cyclic adenosine monophosphate (cAMP) accumulation assays were conducted in human embryonic kidney 293 cells to assess affinity, functional potency and selectivity. Atogepant potency was assessed in the rat nitroglycerine model of facial allodynia and primate capsaicin-induced dermal vasodilation (CIDV) pharmacodynamic model. Cerebrospinal fluid/brain penetration and behavioral effects of chronic dosing and upon withdrawal were evaluated in rats.
RESULTS
Atogepant exhibited high human CGRP receptor-binding affinity and potently inhibited human α-CGRP-stimulated cAMP responses. Atogepant exhibited significant affinity for the amylin1 receptor but lacked appreciable affinities for adrenomedullin, calcitonin and other known neurotransmitter receptor targets. Atogepant dose-dependently inhibited facial allodynia in the rat nitroglycerine model and produced significant CIDV inhibition in primates. Brain penetration and behavioral/physical signs during chronic dosing and abrupt withdrawal were minimal in rats.
CONCLUSIONS
Atogepant is a competitive antagonist with high affinity, potency and selectivity for the human CGRP receptor. Atogepant demonstrated a potent, concentration-dependent exposure/efficacy relationship between atogepant plasma concentrations and inhibition of CGRP-dependent effects.
Topics: Humans; Rats; Animals; Calcitonin Gene-Related Peptide; Receptors, Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Hyperalgesia; Piperidines; Pyridines; Pyrroles; Spiro Compounds
PubMed: 38215228
DOI: 10.1177/03331024231226186 -
Science Signaling Sep 2023Oral cancer causes pain associated with cancer progression. We report here that the function of the Ca channel ORAI1 is an important regulator of oral cancer pain. was...
Oral cancer causes pain associated with cancer progression. We report here that the function of the Ca channel ORAI1 is an important regulator of oral cancer pain. was highly expressed in tumor samples from patients with oral cancer, and ORAI1 activation caused sustained Ca influx in human oral cancer cells. RNA-seq analysis showed that ORAI1 regulated many genes encoding oral cancer markers such as metalloproteases (MMPs) and pain modulators. Compared with control cells, oral cancer cells lacking formed smaller tumors that elicited decreased allodynia when inoculated into mouse paws. Exposure of trigeminal ganglia neurons to MMP1 evoked an increase in action potentials. These data demonstrate an important role of ORAI1 in oral cancer progression and pain, potentially by controlling MMP1 abundance.
Topics: Animals; Humans; Mice; Action Potentials; Hyperalgesia; Matrix Metalloproteinase 1; Mouth Neoplasms; Nociceptive Pain; ORAI1 Protein
PubMed: 37669398
DOI: 10.1126/scisignal.adf9535 -
Frontiers in Pharmacology 2023Current evidence suggests that activation of glial and immune cells leads to increased production of proinflammatory mediators, creating a neuroinflammatory state.... (Review)
Review
Current evidence suggests that activation of glial and immune cells leads to increased production of proinflammatory mediators, creating a neuroinflammatory state. Neuroinflammation has been proven to be a fundamental mechanism in the genesis of acute pain and its transition to neuropathic and chronic pain. A noxious event that stimulates peripheral afferent nerve fibers may also activate pronociceptive receptors situated at the dorsal root ganglion and dorsal horn of the spinal cord, as well as peripheral glial cells, setting off the so-called peripheral sensitization and spreading neuroinflammation to the brain. Once activated, microglia produce cytokines, chemokines, and neuropeptides that can increase the sensitivity and firing properties of second-order neurons, upregulating the signaling of nociceptive information to the cerebral cortex. This process, known as central sensitization, is crucial for chronification of acute pain. Immune-neuronal interactions are also implicated in the lesser-known complex regulatory relationship between pain and opioids. Current evidence suggests that activated immune and glial cells can alter neuronal function, induce, and maintain pathological pain, and disrupt the analgesic effects of opioid drugs by contributing to the development of tolerance and dependence, even causing paradoxical hyperalgesia. Such alterations may occur when the neuronal environment is impacted by trauma, inflammation, and immune-derived molecules, or when opioids induce proinflammatory glial activation. Hence, understanding these intricate interactions may help in managing pain signaling and opioid efficacy beyond the classical pharmacological approach.
PubMed: 38161698
DOI: 10.3389/fphar.2023.1297931 -
The Journal of Physiological Sciences :... Jan 2024We reviewed fundamental studies on muscular pain, encompassing the characteristics of primary afferent fibers and neurons, spinal and thalamic projections, several... (Review)
Review
We reviewed fundamental studies on muscular pain, encompassing the characteristics of primary afferent fibers and neurons, spinal and thalamic projections, several muscular pain models, and possible neurochemical mechanisms of muscle pain. Most parts of this review were based on data obtained from animal experiments, and some researches on humans were also introduced. We focused on delayed-onset muscle soreness (DOMS) induced by lengthening contractions (LC), suitable for studying myofascial pain syndromes. The muscular mechanical withdrawal threshold (MMWT) decreased 1-3 days after LC in rats. Changing the speed and range of stretching showed that muscle injury seldom occurred, except in extreme conditions, and that DOMS occurred in parameters without muscle damage. The B2 bradykinin receptor-nerve growth factor (NGF) route and COX-2-glial cell line-derived neurotrophic factor (GDNF) route were involved in the development of DOMS. The interactions between these routes occurred at two levels. A repeated-bout effect was observed in MMWT and NGF upregulation, and this study showed that adaptation possibly occurred before B2 bradykinin receptor activation. We have also briefly discussed the prevention and treatment of DOMS.
Topics: Humans; Animals; Rats; Myalgia; Nerve Growth Factor; Neurons; Up-Regulation; Receptors, Bradykinin
PubMed: 38267849
DOI: 10.1186/s12576-023-00896-y -
BMC Neurology Oct 2023Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and ultimately fatal neurodegenerative condition caused by prions. The clinical symptoms of CJD vary with its...
BACKGROUND
Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and ultimately fatal neurodegenerative condition caused by prions. The clinical symptoms of CJD vary with its subtype, and may include dementia, visual hallucinations, myoclonus, ataxia, (extra)pyramidal signs and akinetic mutism. In the early course of disease however, several clinical symptoms of CJD may mimic those of co-existing morbidities.
CASE PRESENTATION
We report a male in his 60s with a history of situs inversus totalis and Churg Strauss syndrome, who presented with speech fluency disturbances, neuropsychiatric symptoms and allodynia, a few months after becoming a widower. Initially presumed a bereavement disorder along with a flare-up of Churg Strauss, his symptoms gradually worsened with apraxia, myoclonic jerks and eventually, akinetic mutism. MRI revealed hyperintensities at the caudate nucleus and thalami, while the cerebrospinal fluid was positive for the 14-3-3 protein and the real-time quick test, making the diagnosis of CJD highly probable. This case illustrates the complexities that may arise in diagnosing CJD when pre-existing multimorbidity may cloud the clinical presentation. We also discuss the potential mechanisms underlying the co-occurrence of three rare conditions (situs inversus totalis, Churg Strauss syndrome, CJD) in one patient, taking into consideration the possibility of coincidence as well as common underlying factors.
CONCLUSIONS
The diagnosis of CJD may be easily missed when its clinical symptoms are obscured by those of pre-existing (rare) multimorbidity. This case highlights that when the multimorbidity has neurological manifestations, an extensive evaluation remains crucial to establish the diagnosis, minimize the risk of prion-transmission and provide appropriate guidance to patients and their caregivers.
Topics: Humans; Male; Creutzfeldt-Jakob Syndrome; Akinetic Mutism; Churg-Strauss Syndrome; Multimorbidity; Myoclonus; Situs Inversus
PubMed: 37784069
DOI: 10.1186/s12883-023-03401-5 -
Scientific Reports Oct 2023Deficiency of an extracellular matrix glycoprotein tenascin-X (TNX) leads to a human heritable disorder Ehlers-Danlos syndrome, and TNX-deficient patients complain of...
Deficiency of an extracellular matrix glycoprotein tenascin-X (TNX) leads to a human heritable disorder Ehlers-Danlos syndrome, and TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. We previously reported that TNX-deficient (Tnxb) mice exhibit mechanical allodynia and hypersensitivity to myelinated A-fibers. Here, we investigated the pain response of Tnxb mice using pharmacological silencing of A-fibers with co-injection of N-(2,6-Dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314), a membrane-impermeable lidocaine analog, plus flagellin, a toll-like receptor 5 (TLR5) ligand. Intraplantar co-injection of QX-314 and flagellin significantly increased the paw withdrawal threshold to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aβ fiber responses), but not 5 Hz (C fiber responses) in wild-type mice. The QX-314 plus flagellin-induced silencing of Aδ- and Aβ-fibers was also observed in Tnxb mice. Co-injection of QX-314 and flagellin significantly inhibited the mechanical allodynia and neuronal activation of the spinal dorsal horn in Tnxb mice. Interestingly, QX-314 alone inhibited the mechanical allodynia in Tnxb mice, and it increased the paw withdrawal threshold to stimuli at frequencies of 250 Hz and 2000 Hz in Tnxb mice, but not in wild-type mice. The inhibition of mechanical allodynia induced by QX-314 alone was blocked by intraplantar injection of a TLR5 antagonist TH1020 in Tnxb mice. These results suggest that mechanical allodynia due to TNX deficiency is caused by the hypersensitivity of Aδ- and Aβ-fibers, and it is induced by constitutive activation of TLR5.
Topics: Animals; Humans; Mice; Ehlers-Danlos Syndrome; Extracellular Matrix; Flagellin; Hyperalgesia; Nerve Fibers, Unmyelinated; Tenascin; Toll-Like Receptor 5
PubMed: 37898719
DOI: 10.1038/s41598-023-45638-7