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Sickle cell disease is a hemoglobinopathy that causes sickling of red blood cells, resulting in vessel blockage, stroke, anemia, inflammation, and extreme pain. The development and treatment of pain, in particular, neuropathic pain in sickle cell disease patients is poorly understood and impedes our progress toward the development of novel therapies to treat pain associated with sickle cell disease. The orexin/hypocretin system offers a novel approach to treat chronic pain and hyperalgesia. These neuropeptides are synthesized in three regions: perifornical area (PFA), lateral hypothalamus (LH), and dorsomedial hypothalamus (DMH). Data suggest that orexin-A neuropeptide has an analgesic effect on inflammatory pain and may affect mechanisms underlying the maintenance of neuropathic pain. The purpose of this study was to determine whether there are neuronal activation differences in the orexin system as a result of neuropathic pain testing in a mouse model of sickle cell disease. Female transgenic sickle mice that express exclusively (99%) human sickle hemoglobin (HbSS-BERK) and age-/gender-matched controls (HbAA-BERK mice; = 10/group, 20-30 g) expressing normal human hemoglobin A were habituated to each test protocol and environment before collecting baseline measurements and testing. Four measures were used to assess pain-related behaviors: thermal/heat hyperalgesia, cold hyperalgesia, mechanical hyperalgesia, and deep-tissue hyperalgesia. Hypothalamic brain sections from HbAA-BERK and HbSS-BERK mice were processed to visualize orexin and c-Fos immunoreactivity and quantified. The percentage of double labeled neurons in the PFA was significantly higher than the percentage of double labeled neurons in the LH orexin field of HbAA-BERK mice ( < 0.05). The percentages of double labeled neurons in PFA and DMH orexin fields are significantly higher than those neurons in the LH of HbSS-BERK mice ( < 0.05). These data suggest that DMH orexin neurons were preferentially recruited during neuropathic pain testing and a more diverse distribution of orexin neurons may be required to produce analgesia in response to pain in the HbSS-BERK mice. Identifying specific orexin neuronal populations that are integral in neuropathic pain processing will allow us to elucidate mechanisms that provide a more selective, targeted approach in treating of neuropathic pain in sickle cell disease.
Learn More >Migraine is one of the most disabling neurological diseases worldwide; however, the mechanisms underlying migraine headache are still not fully understood and current therapies for such pain are inadequate. It has been suggested that inflammation and neuroimmune modulation in the gastrointestinal tract could play an important role in the pathogenesis of migraine headache, but how gut microbiomes contribute to migraine headache is unclear. In the present study, we investigated the effect of gut microbiota dysbiosis on migraine-like pain using broad-spectrum antibiotics and germ-free (GF) mice. We observed that antibiotics treatment-prolonged nitroglycerin (NTG)-induced acute migraine-like pain in wild-type (WT) mice and the pain prolongation was completely blocked by genetic deletion of tumor necrosis factor-alpha (TNFα) or intra-spinal trigeminal nucleus caudalis (Sp5C) injection of TNFα receptor antagonist. The antibiotics treatment extended NTG-induced TNFα upregulation in the Sp5C. Probiotics administration significantly inhibited the antibiotics-produced migraine-like pain prolongation. Furthermore, NTG-induced migraine-like pain in GF mice was markedly enhanced compared to that in WT mice and gut colonization with fecal microbiota from WT mice robustly reversed microbiota deprivation-caused pain enhancement. Together, our results suggest that gut microbiota dysbiosis contributes to chronicity of migraine-like pain by upregulating TNFα level in the trigeminal nociceptive system.
Learn More >The pathogenesis of cancer induced bone pain (CIBP) is extremely complex, and glutamate receptor dysfunction plays an important role in the formation of CIBP. Synapse-associated protein 102 (SAP102) anchors glutamate receptors in the postsynaptic membrane. However, its effect on hyperalgesia formation in CIBP has not been clarified. This study investigated the role of SAP102 in the formation of hyperalgesia in rats with CIBP SAP102 is present in spinal dorsal horn neurons, but not in astrocytes or microglia. NMDAR-NR2B is localized with neurons. In addition, SAP102 and NMDAR-NR2B expression levels in spinal dorsal horn tissues were detected by Western blot and co-immunoprecipitation. Intrathecal injection of lentiviral vector of RNAi to knockdown SAP102 expression in the spinal dorsal horn significantly attenuated abnormal mechanic pain when compared to non-coding lentiviral vector. These findings indicate that SAP102 can anchor NMDA receptors to affect hyperalgesia formation in bone cancer pain.
Learn More >Chronic pain is one of the most common complications of postmenopausal osteoporosis. Since oxidative stress is involved in the pathogenesis of postmenopausal osteoporosis, we explored whether oxidative stress contributes to postmenopausal osteoporotic pain.
Learn More >In the lumbar spinal cord dorsal horn, release of afferent nerve glutamate activates the neurons that relay information about injury pain. Here, we examined the effects of protein tyrosine kinase (PTK) inhibition on NMDA receptor NR1 subunit protein expression and subcellular localization in an acute experimental arthritis model. PTK inhibitors genistein and lavendustin A reduced cellular histological translocation of NMDA NR1 in the spinal cord occurring after the inflammatory insult and the nociceptive behavioral responses to heat. The PTK inhibitors were administered into lumbar spinal cord by microdialysis, and secondary heat hyperalgesia was determined using the Hargreaves test. NMDA NR1 cellular protein expression and nuclear translocation were determined by immunocytochemical localization with light and electron microscopy, as well as with Western blot analysis utilizing both C- and N-terminal antibodies. Genistein and lavendustin A (but not inactive lavendustin B or diadzein) effectively reduced (i) pain related behavior, (ii) NMDA NR1 subunit expression increases in spinal cord, and (iii) the shift of NR1 from a cell membrane to a nuclear localization. Genistein pre-treatment reduced these events that occur within 4 h after inflammatory insult to the knee joint with kaolin and carrageenan (k/c). Cycloheximide reduced glutamate activated upregulation of NR1 content confirming synthesis of new protein in response to the inflammatory insult. In addition to this data, genistein or staurosporin inhibited upregulation of NMDA NR1 protein and nuclear translocation after treatment of human neuroblastoma clonal cell cultures (SH-SY5Y) with glutamate or NMDA (4 h). These studies provide evidence that inflammatory activation of peripheral nerves initiates increase in NMDA NR1 in the spinal cord coincident with development of pain related behaviors through glutamate non-receptor, PTK dependent cascades.
Learn More >Cerebrospinal fluid (CSF) and brain tissue sodium levels increase during migraine. However, little is known regarding the underlying mechanisms of sodium homeostasis disturbance in the brain during the onset and propagation of migraine. Exploring the cause of sodium dysregulation in the brain is important, since correction of the altered sodium homeostasis could potentially treat migraine. Under the hypothesis that disturbances in sodium transport mechanisms at the blood-CSF barrier (BCSFB) and/or the blood-brain barrier (BBB) are the underlying cause of the elevated CSF and brain tissue sodium levels during migraines, we developed a mechanistic, differential equation model of a rat's brain to compare the significance of the BCSFB and the BBB in controlling CSF and brain tissue sodium levels. The model includes the ventricular system, subarachnoid space, brain tissue and blood. Sodium transport from blood to CSF across the BCSFB, and from blood to brain tissue across the BBB were modeled by influx permeability coefficients and , respectively, while sodium movement from CSF into blood across the BCSFB, and from brain tissue to blood across the BBB were modeled by efflux permeability coefficients and , respectively. We then performed a global sensitivity analysis to investigate the sensitivity of the ventricular CSF, subarachnoid CSF and brain tissue sodium concentrations to pathophysiological variations in , , and . Our results show that the ventricular CSF sodium concentration is highly influenced by perturbations of , and to a much lesser extent by perturbations of . Brain tissue and subarachnoid CSF sodium concentrations are more sensitive to pathophysiological variations of and than variations of and within 30 min of the onset of the perturbations. However, is the most sensitive model parameter, followed by and , in controlling brain tissue and subarachnoid CSF sodium levels within 3 h of the perturbation onset.
Learn More >Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a disorder that is characterized by persistent pelvic pain in men of any age. Although several studies suggest that the transient receptor potential vanilloid 1 (TRPV1) channel is involved in various pathways of chronic pain, the TRPV1 channel has not been implicated in chronic pelvic pain associated with CP/CPPS.
Learn More >Considerable effort has recently been directed at developing multifunctional opioid drugs to minimize the unwanted side-effects of opioid analgesics. We developed a novel multifunctional agonist named DN-9. Here, we studied the analgesic profiles and related side-effects of peripheral DN-9 in various pain models.
Learn More >To evaluate the anti-inflammatory and analgesic effect of sepiapterin reductase (SPR) inhibition in a mouse model of inflammatory joint disease and to evaluate sepiapterin as a non-invasive, translational biomarker of SPR inhibition/target engagement in mice and healthy human volunteers.
Learn More >Central post-stroke pain (CPSP) can occur after stroke in the somatosensory pathway that includes the posterolateral region of the thalamus. Tactile allodynia, in which innocuous tactile stimuli are perceived as painful, is common in patients with CPSP. Previous brain imaging studies have reported plastic changes in brain activity in patients with tactile allodynia after stroke, but a causal relationship between such changes and the symptoms has not been established. We recently developed a non-human primate (macaque) model of CPSP based on thalamic lesions, in which the animals show behavioral changes consistent with the occurrence of tactile allodynia. Here we performed functional magnetic resonance imaging under propofol anesthesia to investigate the changes in brain activation associated with the allodynia in this CPSP model. Before the lesion, innocuous tactile stimuli significantly activated the contralateral sensorimotor cortex. When behavioral changes were observed after the thalamic lesion, equivalent stimuli significantly activated pain-related brain areas, including the posterior insular cortex (PIC), secondary somatosensory cortex (SII), anterior cingulate cortex (ACC), and amygdala. Moreover, when either PIC/SII or ACC was pharmacologically inactivated, the signs of tactile allodynia were dampened. Our results show that increased cortical activity plays a role in CPSP-induced allodynia.
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