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Calcitonin gene-related peptide (CGRP) plays an important role in migraine pathophysiology. CGRP acts primarily by activating a receptor composed of 3 proteins: calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and receptor component protein (RCP). We tested the hypothesis that sex differences exist in protein levels of two key components of this CGRP receptor: CLR and RCP.
Learn More >Chemotherapy-induced painful peripheral neuropathy (CIPN) is a significant clinical problem that is associated with widely used chemotherapeutics. Unfortunately, the molecular mechanisms by which CIPN develops has remained elusive. The proteasome inhibitor, bortezomib, has been shown to induce aerobic glycolysis in sensory neurons. This altered metabolic phenotype leads to the extrusion of metabolites which sensitize primary afferents and cause pain. Hypoxia-inducible factor alpha (HIF1A) is a transcription factor that is known to reprogram cellular metabolism. Furthermore, HIF1A protein is constantly synthesized and undergoes proteasomal degradation in normal conditions. However, metabolic stress or hypoxia stabilize the expression of HIF1A leading to the transcription of genes that reprogram cellular metabolism. This study demonstrates that treatment of mice with bortezomib stabilize the expression of HIF1A. Moreover, knockdown of HIF1A, inhibition of HIF1A binding to its response element or limiting its translation by using metformin prevent the development of bortezomib-induced neuropathic pain. Strikingly, the blockade of HIF1A expression does not attenuate mechanical allodynia in mice with existing bortezomib-induced neuropathic pain. These results establish the stabilization of HIF1A expression as the molecular mechanism by which bortezomib initiates CIPN. Crucially these findings reveal that the initiation and maintenance of bortezomib-induced neuropathic pain are regulated by distinct mechanisms.
Learn More >Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. Patients with MS typically present with visual, motor, and sensory deficits. However, an additional complication of MS in large subset of patients is neuropathic pain. To study the underlying immune-mediated pathophysiology of pain in MS we employed the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis (EAE) model in mice. Since sensory neurons are crucial for nociceptive transduction, we investigated the effect of this disease on sensory neurons of the lumbar dorsal root ganglia (DRG). Here, we report the disease was associated with activation of the complement system and the NLRP3 inflammasome in the DRG. We further observe a transient increase in the number of complement component 5a receptor 1-positive (C5aR1+) immune cells, CD4+ T-cells, and Iba1+ macrophages in the DRG. The absence of any significant change in the levels of mRNA for myelin proteins in the DRG and the sciatic nerve suggests that demyelination in the PNS is not a trigger for the immune response in the DRG. However, we did observe an induction of activating transcription factor 3 (ATF3) at disease onset and chronic disruption of cytoskeletal proteins in the DRG demonstrating neuronal injury in the PNS in response to the disease. Electrophysiological analysis revealed the emergence of hyperexcitability in medium-to-large (≥26 µm) diameter neurons, especially at the onset of MOG-EAE signs. These results provide conclusive evidence of immune activation, neuronal injury, and peripheral sensitization in MOG-EAE, a model classically considered to be centrally mediated.
Learn More >Management of bone cancer pain (BCP) is difficult because of its complex mechanisms, which has a major impact on the quality of patients' daily life. Recent studies have indicated that endoplasmic reticulum (ER) stress is involved in many neurological and inflammatory pathways associated with pain. However, the factors that contribute to ER stress and its causes in bone cancer pain are still unknown. In this study, we examined whether the ER stress response is involved in caspase signaling pathway-dependent apoptosis in neurons in the spinal dorsal horn of tumor-38 bearing rats and whether it thereby induces bone cancer pain.
Learn More >Headache disorders are highly prevalent and debilitating, with limited treatment options. Previous studies indicate that many pro-inflammatory immune cells contribute to headache pathophysiology. Given the well-recognized role of regulatory T (Treg) cells in maintaining immune homeostasis, we hypothesized that enhancing Treg function may be effective to treat multiple headache disorders. In a mouse model of chronic migraine, we observed that repeated nitroglycerin (NTG, a reliable trigger of migraine in patients) administration doubled the number of CD3 T cells in the trigeminal ganglia without altering the number of Treg cells, suggesting a deficiency in Treg-mediated immune homeostasis. We treated mice with low-dose interleukin-2 (ld-IL2) to preferentially expand and activate endogenous Treg cells. This not only prevented the development of NTG-induced persistent sensitization, but also completely reversed the established facial skin hyper-sensitivity resulting from repeated NTG administration. The effect of ld-IL2 was independent of mouse sex and/or strain. Importantly, ld-IL2 treatment did not alter basal nociceptive responses, and repeated usage did not induce tolerance. The therapeutic effect of ld-IL2 was abolished by Treg depletion and was recapitulated by Treg adoptive transfer. Furthermore, treating mice with ld-IL2 1-7 days after mild traumatic brain injury effectively prevented as well as reversed the development of behaviors related to acute and chronic post-traumatic headache. In a model of medication overuse headache, Ld-IL2 completely reversed the cutaneous hyper-sensitivity induced by repeated administration of sumatriptan. Collectively, the present study identifies ld-IL2 as a promising prophylactic for multiple headache disorders with a mechanism distinct from the existing treatment options.
Learn More >Aldosterone is believed to be synthesized exclusively in the adrenal gland through the processing enzyme aldosterone synthaseMineralocorticoid receptors are predominantly expressed in peripheral nociceptive neurons whose activation leads to increased neuronal excitability and mechanical sensitivity WHAT THIS ARTICLE TELLS US THAT IS NEW: Extra-adrenal production of aldosterone by aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity via intrinsic activation of neuronal mineralocorticoid receptorsIntrathecally-applied aldosterone synthase inhibitor reduced aldosterone content in peripheral sensory neurons and subsequently attenuated enhanced mechanical hypersensitivity resulting from local inflammation BACKGROUND:: Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons.
Learn More >Cortical spreading depression (CSD) is a wave of transient network hyperexcitability leading to long lasting depolarization and block of firing, which initiates focally and slowly propagates in the cerebral cortex. It causes migraine aura and it has been implicated in the generation of migraine headache. Cortical excitability can be modulated by cholinergic actions, leading in neocortical slices to the generation of rhythmic synchronous activities (UP/DOWN states). We investigated the effect of cholinergic activation with the cholinomimetic agonist carbachol on CSD triggered with 130 mM KCl pulse injections in acute mouse neocortical brain slices, hypothesizing that the cholinergic-induced increase of cortical network excitability during UP states could facilitate CSD. We observed instead an inhibitory effect of cholinergic activation on both initiation and propagation of CSD, through the action of muscarinic receptors. In fact, carbachol-induced CSD inhibition was blocked by atropine or by the preferential M1 muscarinic antagonist telenzepine; the preferential M1 muscarinic agonist McN-A-343 inhibited CSD similarly to carbachol, and its effect was blocked by telenzepine. Recordings of spontaneous excitatory and inhibitory post-synaptic currents in pyramidal neurons showed that McN-A-343 induced overall a decrease of the excitatory/inhibitory ratio. This inhibitory action may be targeted for novel pharmacological approaches in the treatment of migraine with muscarinic agonists.
Learn More >Growing evidence suggests a critical role of astrocytes for pain regulation. The water channel protein aquaporin 4 (AQP4), a functional regulator of astrocytes, is involved in various neurological disorders. However, the pathophysiological roles of AQP4 in pain conditions remain unclear. In the present study, we investigated the effect of AQP4 gene knockout in central sensitization induced by complete Freund's adjuvant (CFA). The behavioral analysis revealed that mechanical allodynia and thermal hyperalgesia were more severe in AQP4 null mice than those of wild-type controls over the course of 11 days following CFA intraplantar injection. CFA caused activation of astrocytes with upregulated expression levels of AQP4 and glutamate transporter 1 (GLT1) in the dorsal horn of the spinal cord. AQP4 deficiency reduced GLT1 up-regulation, causing persistent expression of the neuronal activation marker Fos within superficial dorsal horn neurons, including glutamatergic neurons. However, AQP4 deletion did not affect CFA-evoked proinflammatory cytokine expression in the spinal cord. Together, these results have shown that AQP4 absence intensifies CFA-induced spinal central sensitization, which is associated with reduced compensatory up-regulation of GLT1, subsequently increasing glutamatergic overexcitation. Therefore, targeting spinal cord AQP4 may serve as a potential strategy for treatment of peripheral inflammation-evoked hyperalgesia.
Learn More >Neuropathy is major source of chronic pain that can be caused by mechanically or chemically induced nerve injury. Intraplantar formalin injection produces local necrosis over a two-week period and has been used to model neuropathy in rats. To determine whether neuropathy alters dopamine (DA) receptor responsiveness in mesolimbic brain regions, we examined dopamine D-like and D-like receptor (DR) signaling and expression in male rats 14 days after bilateral intraplantar formalin injections into both rear paws. DR-mediated G-protein activation and expression of the DR long, but not short, isoform were reduced in nucleus accumbens (NAc) core, but not in NAc shell, caudate-putamen or ventral tegmental area of formalin-compared to saline-treated rats. In addition, DR-stimulated adenylyl cyclase activity was also reduced in NAc core, but not in NAc shell or prefrontal cortex, of formalin-treated rats, whereas DR expression was unaffected. Other proteins involved in dopamine neurotransmission, including dopamine uptake transporter and tyrosine hydroxylase, were unaffected by formalin treatment. In behavioral tests, the potency of a DR agonist to suppress intracranial self-stimulation (ICSS) was decreased in formalin-treated rats, whereas DR agonist effects were not altered. The combination of reduced DR expression and signaling in NAc core with reduced suppression of ICSS responding by a DR agonist suggest a reduction in D autoreceptor function. Altogether, these results indicate that intraplantar formalin produces attenuation of highly specific DA receptor signaling processes in NAc core of male rats and suggest the development of a neuropathy-induced allostatic state in both pre- and post-synaptic DA receptor function.
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