Browse by Audience
Vasculitic peripheral neuropathy (VPN) arises from an inflammatory obstruction in the blood vessels supplying peripheral nerves and subsequent ischemic insults, which exhibits the clinical features of neuropathic pain and impaired peripheral nerve function. VPN induced by ischemia-reperfusion (IR) has been reported to involve nuclear factor-κB (NF-κB)-mediated neuroinflammation. Recent studies have suggested that endoplasmic reticulum (ER) stress has been implicated in the development of peripheral neuropathies. Resveratrol possesses a potent anti-inflammatory capacity. We hypothesized that resveratrol may exert a protective effect against VPN through modulating the interrelated ER stress and NF-κB pathways. Male Sprague-Dawley rats were allocated into 5 groups: sham, sham + resveratrol 40 mg/kg (R40), IR, IR + R20 and IR + R40. VPN was induced by occluding the right femoral artery for 4 hours followed by reperfusion. Our data has shown that VPN induced by IR led to hind paw mechanical allodynia, heat hyperalgesia, and impaired motor nerve conduction velocity (MNCV). With resveratrol intervention, the behavioral parameters were improved in a dose-dependent manner and the MNCV levels were increased as well. The molecular data revealed that VPN induced by IR significantly increased the expression of NF-κB as well as the ER stress sensor proteins, protein kinase RNA-like endoplasmic reticulum kinase, inositol-requiring enzyme 1 and activating transcription factor 6 in the sciatic nerves. More importantly, resveratrol significantly attenuated the expression of NF-κB and the ER stress sensor proteins after IR. In conclusion, resveratrol alleviates VPN induced by IR. The mechanisms may involve modulating NF-κB-mediated neuroinflammation via suppressing ER stress. This article is protected by copyright. All rights reserved.
The neurosteroid dehydroepiandrosterone sulphate (DHEAS) activates the sigma-1 receptor, inhibits gamma-aminobutyric acid A (GABA) and glycine receptors, and induces hyperalgesic effects. Although its effects have been studied in various tissues of the nervous system, its synaptic mechanisms in nociceptive pathways remain to be elucidated.
The use of opioid analgesics is severely limited due to the development of intractable constipation, mediated through activation of mu opioid receptors (MOR) expressed by enteric neurons. The related delta opioid receptor (DOR) is an emerging therapeutic target for chronic pain, depression and anxiety. Whether DOR agonists also promote sustained inhibition of colonic transit is unknown. This study examined acute and chronic tolerance to SNC80 and ARM390, which were full and partial DOR agonists in neural pathways controlling colonic motility, respectively. Excitatory pathways developed acute and chronic tolerance to SNC80, whereas only chronic tolerance developed in inhibitory pathways. Both pathways remained functional after acute or chronic ARM390 exposure. Propagating colonic motor patterns were significantly reduced after acute or chronic SNC80 treatment, but not by ARM390 pre-treatment. These findings demonstrate that SNC80 has a prolonged inhibitory effect on propagating colonic motility. ARM390 had no effect on motor patterns and thus may have fewer gastrointestinal side-effects.
Vasculitic peripheral neuropathy (VPN) is characterized by acute-to-subacute onset of painful sensory and motor disturbances that result from inflammatory obliteration of nerve blood vessels and subsequent ischaemic injury. Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of various peripheral neuropathies, and 4-phenylbutyric acid (4-PBA) is a chemical chaperone that inhibits ER stress signaling. We investigated the effects of 4-PBA on neuropathic pain associated with VPN induced by ischaemia-reperfusion (IR) and its underlying mechanisms. Male Sprague-Dawley rats were allocated to one of the following groups: sham, sham + 4-PBA, IR, and IR + 4-PBA. IR was achieved by occluding the femoral artery for 4 h followed by reperfusion. The behavioral parameters were assessed, and the expression of ER stress markers and nuclear factor (NF)-κB in sciatic nerves was measured. The behavioral data confirmed that VPN induced by IR leads to hindpaw mechano-allodynia and heat hyperalgesia as well as impaired hindpaw grip strength, indicating the development of neuropathic pain and debilitating symptoms of VPN. The molecular data revealed that VPN induced by IR activated ER stress sensors and effector molecules as well as NF-κB in the sciatic nerves, indicating the involvement of ER stress and NF-κB-mediated neuroinflammation. Notably, 4-PBA significantly reduced the expression of all these markers and improved all behavioral changes induced by IR. This study demonstrated that ER stress and NF-κB-mediated neuroinflammation contribute to VPN induced by IR and that 4-PBA has protective potential against neuropathic pain associated with VPN.
The trigeminal root entry zone (TREZ) is the transitional zone of central and peripheral tissue compartments in the trigeminal root. Microvascular compression on the TREZ is the main etiology of most idiopathic trigeminal neuralgia (TN) patients. However, the pathogenesis of TN is still uncertain. To investigate the glial plasticity changes in oligodendrocytes, Schwann cells, astrocytes and microglia/macrophages in the TREZ in TN, immunohistochemical staining and Western blot methods were performed in rats with TN induced by compression injury. The results showed that mechanical compression injury in the trigeminal nerve of the TN rats induced glial plasticity in the TREZ, which dynamically changed the glial interface of the CNS-PNS transitional zone. Additionally, glial fibrillary acidic protein (GFAP)-immunoreactive astrocyte processes significantly proliferated and extended distally from the central region to the peripheral side of the TREZ after nerve compression injury in the TN group. Moreover, the expression of p75 in Schwann cells was upregulated on the peripheral side of the TREZ, and activated Iba-1-immunoreactive microglia/macrophages were observed on both sides of the TREZ. A significantly higher number of Schwann cells, astrocytes and microglia/macrophages were found in the TN group than in the sham operation group (p < 0.05). In conclusion, mechanical compression injury in the TN rats activated various glial cells, including oligodendrocytes, astrocytes, Schwann cells and microglia/macrophages, in the CNS-PNS transitional zone of TREZ. Changes in glial cell plasticity in the TREZ after compression injury might be involved in TN pathogenesis.
Deregulation of innate immune TLR4 signaling contributes to various diseases including neuropathic pain and drug addiction. Naltrexone is one of the rare TLR4 antagonists with good blood-brain barrier permeability and showing no stereoselectivity for TLR4. By linking 2 naltrexone units through a rigid pyrrole spacer, the bivalent ligand norbinaltorphimine was formed. Interestingly, (+)-norbinaltorphimine ((+)-1) showed ∼25 times better TLR4 antagonist activity than naltrexone in microglia BV-2 cell line, whereas (-)-norbinaltorphimine ((-)-1) lost TLR4 activity. The enantioselectivity of norbinaltorphimine was further confirmed in primary microglia, astrocytes, and macrophages. The activities of meso isomer of norbinaltorphimine and the molecular dynamic simulation results demonstrate that the stereochemistry of (+)-1 is derived from the (+)-naltrexone pharmacophore. Moreover, (+)-1 significantly increased and prolonged morphine analgesia . The efficacy of (+)-1 is long lasting. This is the first report showing enantioselective modulation of the innate immune TLR signaling.-Zhang, X., Peng, Y., Grace, P. M., Metcalf, M. D., Kwilasz, A. J., Wang, Y., Zhang, T., Wu, S., Selfridge, B. R., Portoghese, P. S., Rice, K. C., Watkins, L. R., Hutchinson, M. R., Wang, X. Stereochemistry and innate immune recognition: (+)-norbinaltorphimine targets myeloid differentiation protein 2 and inhibits toll-like receptor 4 signaling.
Spinal cord injury (SCI) results in not only motor dysfunction but also chronic neuropathic pain. Allodynia, an abnormal sensation that evokes pain against non-noxious stimuli, is a major symptom of post-SCI neuropathic pain. Astrocytic activation is a cause of post-SCI neuropathic pain and is considered a key treatment target. However, no effective treatment for these problems is available to date. ONO-2506 is a novel agent that suppresses astrocytic activation by inhibition of S100B production from astrocytes. Recently, it has been demonstrated that ONO-2506 inhibits secondary injury and improves motor function after SCI.
The spinal administration of opioids can cause intense pruritisInteractions between specific μ-opioid receptor isoforms and the gastrin releasing peptide receptor in spinal tissues likely mediate morphine-induced pruritus WHAT THIS ARTICLE TELLS US THAT IS NEW: Human spinal cord tissue expresses the 1Y isoform of the μ-opioid receptor, and that isoform functionally interacts with the gastrin releasing peptide receptor to cause cellular calcium influxBlocking interactions between the 1Y isoform and the gastrin releasing peptide receptor does not reduce opioid analgesiaEliminating interactions between the 1Y isoform and the gastrin releasing peptide receptor or reducing 1Y isoform activation may reduce opioid-induced pruritis BACKGROUND:: Although spinal opioids are safe and effective, pruritus is common and distressing. The authors previously demonstrated in mouse spinal cord that interactions between μ-opioid receptor isoform 1D and gastrin releasing peptide receptor mediate morphine-induced scratch. The C-terminal of 1D inhibits morphine-induced scratch without affecting analgesia. The authors hypothesize that human spinal cord also contains itch-specific μ-opioid receptor isoforms which interact with gastrin releasing peptide receptor.
Animal experiment: a rat model of lumbar disc herniation (LDH) induced painful radiculopathies.
Excitatory interneurons account for the majority of dorsal horn neurons, and are required for perception of normal and pathological pain. We have identified largely non-overlapping populations in laminae I-III, based on expression of substance P, gastrin-releasing peptide, neurokinin B and neurotensin. Cholecystokinin (CCK) is expressed by many dorsal horn neurons, particularly in the deeper laminae. Here we have used immunocytochemistry and in situ hybridisation to characterise the CCK cells. We show that they account for ~7% of excitatory neurons in laminae I-II, but between a third and a quarter of those in lamina III. They are largely separate from the neurokinin B, neurotensin and gastrin-releasing peptide populations, but show limited overlap with the substance P cells. Laminae II-III neurons with protein kinase Cγ (PKCγ) have been implicated in mechanical allodynia following nerve injury, and we found that around 50% of CCK cells were PKCγ-immunoreactive. Neurotensin is also expressed by PKCγ cells, and among neurons with moderate to high levels of PKCγ, ~85% expressed CCK or neurotensin. A recent transcriptomic study (Häring et al, Nat. Neurosci., 2018) identified mRNA for thyrotropin-releasing hormone (TRH) in a specific subpopulation of CCK neurons, and we show that these account for half of the CCK/PKCγ cells. These findings indicate that CCK cells are distinct from other excitatory interneuron populations that we have defined. They also show that PKCγ cells can be assigned to different classes based on neuropeptide expression, and it will be important to determine the differential contribution of these classes to neuropathic allodynia. This article is protected by copyright. All rights reserved.