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The underlying mechanism of interstitial cystitis/bladder pain syndrome (IC/BPS) is not well understood and evaluation of current therapeutic interventions has not identified any generally effective treatments. Physical activity has shown beneficial effects on individuals suffering from chronic pain. Anxiety-prone rats exposed to water avoidance stress (WAS) develop urinary frequency and lower bladder sensory thresholds with high face and construct validity for the study of IC/BPS. The aim of this study was to evaluate the role of chronic voluntary exercise on urinary frequency, voiding function, and hyperalgesia in animals exposed to WAS.
Learn More >Chronic constriction injury of the sciatic nerve is frequently considered as a cause of chronic neuropathic pain. Marked activation of microglia in the posterior horn (PH) has been well established with regard to this pain. However, microglial activation in the anterior horn (AH) is also strongly induced in this process. Therefore, in this study, we compared the differential activation modes of microglia in the AH and PH of the lumbar cord 7 days after chronic constriction injury of the left sciatic nerve in Wistar rats. Microglia in both the ipsilateral AH and PH demonstrated increased immunoreactivity of the microglial markers Iba1 and CD11b. Moreover, abundant CD68 phagosomes were observed in the cytoplasm. Microglia in the AH displayed elongated somata with tightly surrounding motoneurons, whereas cells in the PH displayed a rather ameboid morphology and were attached to myelin sheaths rather than to neurons. Microglia in the AH strongly expressed NG2 chondroitin sulfate proteoglycan. Despite the tight attachment to neurons in the AH, a reduction in synaptic proteins was not evident, suggesting engagement of the activated microglia in synaptic stripping. Myelin basic protein immunoreactivity was observed in the phagosomes of activated microglia in the PH, suggesting the phagocytic removal of myelin. CCI caused both motor deficit and hyperalgesia that were evaluated by applying BBB locomotor rating scale and von Frey test, respectively. Motor defict was the most evident at postoperative day1, and that became less significant thereafter. By contrast, hyperalgesia was not severe at day 1 but it became worse at least by day 7. Collectively, the activation modes of microglia were different between the AH and PH, which may be associated with the difference in the course of motor and sensory symptoms.
Learn More >Most centrally-acting migraine preventive drugs suppress frequency and velocity of cortical spreading depression (CSD). The purpose of the current study was to determine how the new class of peripherally acting migraine preventive drug (i.e., the anti-CGRP-mAbs) affect CSD – an established animal model of migraine aura, which affects about 1/3 of people with migraine – when allowed to cross the blood brain barrier (BBB). Using standard electrocorticogram recording techniques and rats in which the BBB was intentionally compromised, we found that when the BBB was opened, the anti-CGRP-mAb fremanezumab did not prevent the induction, occurrence or propagation of a single wave of CSD induced by a pinprick, but that both fremanezumab and its isotype were capable of slowing down the propagation velocity of CSD and shortening the period of profound depression of spontaneous cortical activity that followed the spreading depolarization. Fremanezumab's inability to completely block the occurrence of CSD in animals in which the BBB was compromised suggests that CGRP may not be involved in the initiation of CSD, at least not to the extent that it can prevent its occurrence. Similarly, we cannot conclude that CGRP is involved in the propagation velocity or the neuronal silencing period (also called cortical recovery period) that follows the CSD because similar effects were observed when the isotype was used. These finding call for caution with interpretations of studies that claim to show direct CNS effects of anti-CGRP-mAbs.
Learn More >Both inhibiting ascending nociceptive transmission and activating descending inhibition are involved in the opioid analgesic effect. The spinal dorsal horn is a critical site for modulating nociceptive transmission by descending pathways elicited by opioids in the brain. μ-Opioid receptors (MORs, encoded by Oprm1) are highly expressed in primary sensory neurons and their central terminals in the spinal cord. In the present study, we tested the hypothesis that MORs expressed in primary sensory neurons contribute to the descending inhibition and supraspinal analgesic effect induced by centrally administered opioids. We generated Oprm1 conditional knockout (Oprm1-cKO) mice by crossing Advillin mice with Oprm1 mice. Immunocytochemcal labeling in Oprm1-cKO mice showed that MORs are completely ablated from primary sensory neurons and are profoundly reduced in the superficial spinal dorsal horn. Intracerebroventricular injection of morphine or fentanyl produced a potent analgesic effect in wild-type mice, but such an effect was significantly attenuated in Oprm1-cKO mice. Furthermore, the analgesic effect produced by morphine or fentanyl microinjected into the periaqueductal gray was significantly greater in wild-type mice than in Oprm1-cKO mice. Blocking MORs at the spinal cord level diminished the analgesic effect of morphine and fentanyl microinjected into the periaqueductal gray in both groups of mice. Our findings indicate that MORs expressed at primary afferent terminals in the spinal cord contribute to the supraspinal opioid analgesic effect. These presynaptic MORs in the spinal cord may serve as an interface between ascending inhibition and descending modulation that are involved in opioid analgesia.
Learn More >Low-dose interleukin-2 (LD-IL-2) treatment has been shown to effectively reverse chronic migraine-related behaviors and the sensitization of trigeminal ganglion (TG) neurons through expansion and activation of peripheral regulatory T cells (Tregs) in mice. In this study, we investigated the molecular mechanisms underlying the effects of LD-IL-2 and Treg cells. LD-IL-2 treatment increases the production of cytokines interleukin-10 (IL-10) and transforming growth factor beta-1 (TGFβ1) in T cells, especially Treg cells, suggesting that they may mediate the therapeutic effect of LD-IL-2. Indeed, neutralizing antibodies against either IL-10 or TGFβ completely blocked the effects of LD-IL-2 on the facial mechanical hypersensitivity as well as the sensitization of TG neurons resulting from repeated nitroglycerin (NTG, a reliable trigger of migraine in patients) administration in mice, indicating that LD-IL-2 and Treg cells engage both peripheral IL-10 and TGFβ signaling pathways to reverse chronic-migraine related sensitizations. In an assay, incubation of TG culture with exogenous IL-10 or TGFβ1 fully reversed NTG-induced sensitization of TG neurons, suggesting that the IL-10 and TGFβ1 signaling in TG neurons contribute to LD-IL-2's therapeutic effects. Collectively, these results not only elucidate the molecular mechanisms through which LD-IL-2 and Treg cells reverse chronic-migraine related sensitizations, but also suggest that the IL-10 and TGFβ1 signaling pathways in TG neurons are potential targets for chronic migraine therapy.
Learn More >Obesity is a global concern and affects millions of Americans who consume poor-quality diets. Diets directly affect the gut microbiota, which can have subsequent effects on inflammation and contribute to other chronic states. Previously we have shown that a Standard American Diet (SAD) increased immune cell activation and prolonged recovery and that a beneficial diet could reduce these negative effects. Here, male and female mice were given access to regular chow (REG), SAD, our Anti-Inflammatory Diet (AID) or a combination of SAD and AID. This latter group was modeled on the commonplace dietary pattern of healthy eating during the week (AID: Monday-Friday) and relaxed eating patterns on the weekend (SAD: Saturday-Sunday). After 14 weeks of diet consumption and an inflammatory injury, we found that the SAD prolonged and the AID promoted recovery. However, recovery was significantly delayed in those mice consuming the AID-SAD, regardless of weekly healthy diet access. In addition, fecal samples taken during the study revealed dramatic differences in microbial community composition, relative abundance of abundant bacterial phyla and alpha diversity. These data confirm the impact of diet on gut microbiota and suggest a relation between abundance of specific bacterial taxa and susceptibility to prolonged recovery from injury.
Learn More >Alcohol use disorder (AUD) is a chronic, relapsing psychiatric disorder that is characterized by the emergence of negative affective states. The transition from recreational, limited intake to uncontrolled, escalated intake is proposed to involve a transition from positive to negative reinforcement mechanisms for seeking alcohol. Past work has identified the emergence of significant hyperalgesia/allodynia in alcohol-dependent animals, which may serve as a key negative reinforcement mechanism. Chronic pain has been associated with enhanced extracellular signal-regulated kinase (ERK) activity in cortical and subcortical nociceptive areas. Additionally, both pain and AUD have been associated with increased activity of the glucocorticoid receptor (GR), a key mediator of stress responsiveness. The objectives of the current study were to first determine relationships between thermal nociceptive sensitivity and alcohol drinking in male Wistar rats. While inflammatory pain induced by complete Freund's adjuvant (CFA) administration did not modify escalation of home cage drinking in animals over four weeks, the relationship between drinking levels and hyperalgesia symptoms reversed between acute (1 week) and chronic (3-4 week) periods post-CFA administration, suggesting that either the motivational or analgesic effects of alcohol may be altered over the time course of chronic pain. We next examined ERK and GR phosphorylation in pain-related brain areas (including the central amygdala and prefrontal cortex subregions) in animals experiencing acute withdrawal from binge alcohol administration (2 g/kg, 6 h withdrawal) and CFA administration (four weeks) to model the neurobiological consequences of binge alcohol exposure in the context of pain. We observed a significant interaction between alcohol and pain state, whereby alcohol withdrawal increased ERK phosphorylation across all four frontocortical areas examined, although this effect was absent in animals experiencing chronic inflammatory pain. Alcohol withdrawal also increased GR phosphorylation across all four frontocortical areas, but these changes were not altered by CFA. Interestingly, we observed significant inter-brain regional correlations in GR phosphorylation between the insula and other regions investigated only in animals exposed to both alcohol and CFA, suggesting coordinated activity in insula circuitry and glucocorticoid signaling in this context. The results of these studies provide a greater understanding of the neurobiology of AUD and will contribute to the development of effective treatment strategies for comorbid AUD and pain.
Learn More >Activation of glial cells has been shown to play an important role in chronic itch. However, whether glial cells play an important role in the development of psoriasis-induced chronic itch has not been fully elucidated. This study investigated the role of spinal glial cells in psoriasis-induced chronic itch. To develop a mouse model of psoriasis-induce chronic itch, we used 5% imiquimod cream to receive a daily topical application on the shaved back skin for seven consecutive days. The results showed that the expression of microglial marker ionized calcium binding adaptor molecule-1 was significantly increased after 5% imiquimod treatment in cervical spinal cord dorsal horn (C3-C4), and the intrathecal microglial inhibitor minocycline or PLX5622 diet suppressed both spontaneous itch and microglial activation. Furthermore, we found that the number of scratches and alloknesis score in female mice was significantly greater than in male mice after 5% imiquimod treatment. Our results indicate that microglia mediate chronic psoriatic itch induced by imiquimod.
Learn More >Morphine is the most commonly used drug for treating physical and psychological suffering caused by advanced cancer. Although morphine is known to elicit multiple supraspinal analgesic effects, its behavioral correlates with respect to the whole brain metabolic activity during cancer-induced bone pain have not been elucidated. We injected 4T1 mouse breast cancer cells into the left femur bone marrow cavity of BALB/c mice. All mice developed limb use deficits, mechanical allodynia, and hypersensitivity to cold, which were effectively suppressed with morphine. Serial 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was performed for each mouse before cancer induction (0 d), after cancer-induced bone pain was established (14 d), and during effective morphine treatment (16 d). The longitudinal FDG-PET imaging analysis demonstrated that cancer-induced bone pain increased glucose uptake in the insular cortex and hypothalamus and decreased the activity of the retrosplenial cortex. Morphine reversed the activation of the insular cortex and hypothalamus. Furthermore, morphine activated the amygdala and rostral ventromedial medulla and suppressed the activity of anterior cingulate cortex. Our findings of hypothalamic and insular cortical activation support the hypothesis that cancer-induced bone pain has strong inflammatory and affective components in freely moving animals. Morphine may provide descending inhibitory and facilitatory actions in the treatment of cancer-induced bone pain in a clinical setting.
Learn More >The glutamate type 1 transporter (GLT1) plays a major role in glutamate homeostasis in the brain. Although alterations of GLT1 activity have been linked to persistent pain, the significance of these changes is poorly understood. Focusing on the rostral ventromedial medulla, a key site in pain modulation, we examined the expression and function of GLT1 and related transcription factor kappa B-motif binding phosphoprotein (KBBP) in rats after adjuvant-induced hind paw inflammation.
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