554 research outputs found
Impaired chronic pain-like behaviour and disruption of the opioidergic system in the TASTPM mouse model of Alzheimerās disease
CD206+/MHCIIā macrophage accumulation at nerve injury site correlates with attenuation of allodynia in TASTPM mouse model of Alzheimer's disease
Chronic pain is undertreated in people with Alzheimer's disease (AD) and better understanding of the underlying mechanisms of chronic pain in this neurodegenerative disease is essential. Neuropathic pain and AD share a significant involvement of the peripheral immune system. Therefore, we examined the development of nerve injury-induced allodynia in TASTPM (APPsweXPS1.M146V) mice and assessed monocytes/macrophages at injury site. TASTPM developed partial allodynia compared to WT at days 7, 14 and 21 days after injury, and showed complete allodynia only after treatment with naloxone methiodide, a peripheralized opioid receptor antagonist. Since macrophages are one of the sources of endogenous opioids in the periphery, we examined macrophage infiltration at injury site and observed that CD206+/MHCIIā cells were more numerous in TASTPM than WT. Accordingly, circulating TASTPM Ly6Chigh (classical) monocytes, which are pro-inflammatory and infiltrate at the site of injury, were less abundant than in WT. In in vitro experiments, TASTPM bone marrow-derived macrophages showed efficient phagocytosis of myelin extracts containing amyloid precursor protein, acquired CD206+/MHCIIā phenotype, upregulated mRNA expression of proenkephalin (PENK) and accumulated enkephalins in culture media. These data suggest that in TASTPM nerve-injured mice, infiltrating macrophages which derive from circulating monocytes and may contain amyloid fragments, acquire M2-like phenotype after myelin engulfment, and release enkephalins which are likely to inhibit nociceptive neuron activity via activation of opioid receptors
Calcitonin gene-related peptide-expressing sensory neurons and spinal microglial reactivity contribute to pain states in collagen-induced arthritis
Objective
To evaluate the contribution of sensory neurons in ankle joints and adjacent tissue to the development of pain in collagenāinduced arthritis (CIA), and to determine the relationship between pain and the appearance of clinical signs.
Methods
Mechanical and heat hypersensitivity and hind paw swelling were assessed in Lewis rats before and until 18 days following collagen immunization. We examined the effect of intrathecal administration of a calcitonin geneārelated peptide (CGRP) antagonist (CGRP8ā37) from day 11 to day 18 postimmunization on CIAāinduced hypersensitivity. During CIA development, CGRP and pāERK immunoreactivity was quantified in lumbar dorsal root ganglia in which sensory neurons innervating the ankle joint were identified by retrograde labeling with FluoroāGold. Microgliosis in the lumbar dorsal horn was assessed by immunohistochemistry, and release of CGRP evoked by activity of primary afferent fibers was measured using a preparation of isolated dorsal horn with dorsal roots attached.
Results
CIA was associated with mechanical hypersensitivity that was evident before hind paw swelling and that was exacerbated with the development of swelling. Heat hyperalgesia developed along with swelling. Concomitant with the development of mechanical hypersensitivity, joint innervating neurons exhibited enhanced CGRP expression and an activated phenotype (increased pāERK expression), and significant microgliosis became evident in the dorsal horn; these peripheral and central changes were augmented further with disease progression. CGRP release evoked by dorsal root stimulation was higher in the dorsal horn on day 18 in rats with CIA compared to control rats. Prolonged intrathecal administration of CGRP8ā37 attenuated established mechanical hypersensitivity and reduced spinal microgliosis.
Conclusion
Sensory neuronāderived CGRP sustains mechanical hypersensitivity and spinal microglial reactivity in CIA, suggesting that central mechanisms play critical roles in chronic inflammatory pain. Blockade of these central events may provide pain relief in rheumatoid arthritis patients
Computational simulation of round thermal jets in an ambient cross flow using a large-scale hydrodynamic model
A refined rat primary neonatal microglial culture method that reduces time, cost and animal use
We thank the Development Trust of The University of Aberdeen and the Scottish Rugby Union for their financial support. We also thank Dr Elizabeth Old from Wolfson Centre for Age-related Diseases, Kingās College London for providing technical training with the previous protocol and helping in the editorial process of this manuscript.Peer reviewedPostprin
Neuron-immune mechanisms contribute to pain in early stages of arthritis
Background: Rheumatoid arthritis (RA) patients frequently show weak correlations between the magnitude of pain and inflammation suggesting that mechanisms other than overt peripheral inflammation contribute to pain in RA. We assessed changes in microglial reactivity and spinal excitability and their contribution to pain-like behaviour in the early stages of collagen-induced arthritis (CIA) model.
Methods: Mechanically evoked hypersensitivity, spinal nociceptive withdrawal reflexes (NWRs) and hind paw swelling were evaluated in female Lewis rats before and until 13 days following collagen immunization. In the spinal dorsal horn, microgliosis was assayed using immunohistochemistry (Iba-1/p-p38) and cyto(chemo)kine levels in the cerebrospinal fluid (CSF). Intrathecal administration of microglia-targeting drugs A-438079 (P2X7 antagonist) and LHVS (cathepsin S inhibitor) were examined upon hypersensitivity, NWRs, microgliosis andcyto(chemo)kine levels in the early phase of CIA.
Results: The early phase of CIA was associated with mechanical allodynia and exaggerated mechanically evoked spinal NWRs, evident before hind paw swelling, and exacerbated with the development of swelling. Concomitant with the development of hypersensitivity was the presence of reactive spinal microgliosis and an increase of IL-1Ī² levels in CSF (just detectable in plasma). Prolonged intrathecal administration of microglial inhibitors attenuated the development of mechanical allodynia, reduced microgliosis and attenuated IL-1Ī² increments. Acute spinal application of either microglial inhibitor significantly diminished the sensitization of the spinal NWRs.
Conclusions: Mechanical hypersensitivity in the early phase of CIA is associated with central sensitization that is dependent upon microglial-mediated release of IL-1Ī² in the spinal cord. Blockade of these spinal events may provide pain relief in RA patients
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