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The development of analgesic tolerance to opioids is an important limitation in the management of chronic pain. Spinal cord glial cell activation appears to play a pivotal role in the development and maintenance of opioid tolerance, indicating the presence of an opioid-induced neuronal-glial interaction; however, how opioids drive this cross-talk is still elusive. In search of treatments to attenuate morphine analgesic tolerance, our research focused on the role of Notch signaling pathway, one of the most important mechanisms of cell-to-cell interactions, in the spinal dorsal horn after morphine repeated exposure and whether Notch inhibition attenuates morphine analgesic tolerance. Double immunofluorescence experiments on spinal sections from morphine-tolerant mice showed a neuronal localization of Notch-1 receptor whereas the Notch ligand Jagged was localized on neighboring astrocytes. Morphine-induced μ opioid receptor (MOR) stimulation triggered Notch-1 signaling activation and this event was mediated by astrocyte JNK activation. Notch-1 activation selectively reduced the expression of histone deacetylase (HDAC)-1, resulting in an overphosphorylation of PKC and ERK, kinases involved in MOR phosphorylation and internalization after repeated morphine exposure. Notch-1 signaling inhibition, through intrathecal administration of the γ-secretase inhibitor, DAPT, counteracted PKC and ERK overphosphorylation, MOR internalization, and analgesic tolerance. Conversely, the HDAC-1 inhibitor, LG325, further aggravated MOR internalization, PKC overphosphorylation, and analgesic tolerance.Our findings implicate the MOR-triggered Notch-1 signaling in promoting MOR internalization and morphine analgesic tolerance by epigenetic regulation mechanisms. These data suggest that Notch-1 inhibitors could represent an innovative therapeutic perspective for the management of opioid tolerance in chronic pain therapy.
Learn More >Chronic itch is a highly debilitating symptom among patients with inflammatory skin diseases. Recent studies have revealed that gastrin-releasing peptide (GRP) and its receptor (gastrin-releasing peptide receptor [GRPR]) in the spinal dorsal horn (SDH) play a central role in itch transmission.
Learn More >Migraine is a complex brain disorder that involves abnormal activation of the trigeminocervical complex (TCC). Since an increase of oxytocin concentration has been found in cerebrospinal fluid in migrainous patients and intranasal oxytocin seems to relieve migrainous pain, some studies suggest that the hypothalamic neuropeptide oxytocin may play a role in migraine pathophysiology. However, it remains unknown whether oxytocin can interact with the trigeminovascular system at TCC level. The present study was designed to test the above hypothesis in a well-established electrophysiological model of migraine. Using anesthetized rats, we evaluated the effect of oxytocin on TCC neuronal activity in response to dural nociceptive trigeminovascular activation. We found that spinal oxytocin significantly reduced TCC neuronal firing evoked by meningeal electrical stimulation. Furthermore, pretreatment with L-368,899 (a selective oxytocin receptor antagonist, OTR) abolished the oxytocin-induced inhibition of trigeminovascular neuronal responses. This study provides the first direct evidence that oxytocin, probably by OTR activation at TCC level inhibited dural nociceptive-evoked action potential in this complex. Thus, targeting OTR at TCC could represent a new avenue to treat migraine.
Learn More >Chemotherapy-induced peripheral neuropathy is a severe side effect of chemotherapeutic agents. Vagus nerve stimulation attenuates neuroinflammation by activating the cholinergic anti-inflammatory pathway and thus may attenuate CIPN.
Learn More >Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic urological condition characterised by urinary urgency, frequency and pelvic pain, that significantly impacts the quality of life for ∼5% of women. Bladder sensation is coordinated by primary afferent sensory neurons that innervate the bladder wall, translating bladder stretch into signals that travel to the brain via the spinal cord. Whilst the pathophysiology of IC/BPS remains unknown, an increase in the permeability of the bladder urothelium has been proposed as an initiating cause. Here we experimentally increased bladder permeability and tracked bladder afferent sensitivity for up to 28 days. We found that one day after increasing bladder epithelial permeability with bladder infusion of protamine sulfate, mechanosensitive bladder afferents exhibited significant hypersensitivity to bladder filling. This mechanical hypersensitivity was characterised by significantly increased peak afferent firing rates and a decrease in the activation threshold of individual afferents. Bladder afferent hypersensitivity occurred in the absence of inflammation and changes in bladder muscle compliance, indicating a direct sensitisation of peripheral afferent endings. Bladder afferent mechanosensitive responses to distension returned to control levels by day 7 post-protamine sulfate treatment and remained at control levels at 28-days post-treatment. Here we demonstrate, contrary to the prevailing hypothesis, that increased bladder permeability alone does not induce chronic bladder afferent sensitisation. Whilst experimentally induced changes in bladder permeability are able to induce transient bladder afferent hypersensitivity in the absence of inflammation, highly regulated homeostatic mechanisms exist to rapidly repair the urothelial barrier and normalise bladder afferent mechanosensitivity. Together, these data suggest that additional pathophysiology is required to induce chronic bladder dysfunction.
Learn More >The exposure of the nucleus pulposus (NP) causes an immune and inflammatory response, which is intrinsically linked to the pathogenesis of radicular pain. As a newly discovered pro-resolving lipid mediator, maresin 1 (MaR1) could exert powerful inflammatory resolution, neuroprotection, and analgesic activities. In the present research, the analgesic effect of MaR1 was observed. Then, the potential mechanism by which MaR1 attenuated radicular pain was also analyzed in a rat model.
Learn More >In the search for safer, non-addictive analgesics, kappa opioid receptor (KOPr) agonists are a potential target, as unlike mu-opioid analgesics, they do not have abuse potential. Salvinorin A (SalA) is a potent and selective KOPr agonist, however, clinical utility is limited by the short duration of action and aversive side effects. Biasing KOPr signaling toward G-protein activation has been highlighted as a key cellular mechanism to reduce the side effects of KOPr agonists. The present study investigated KOPr signaling bias and the acute antinociceptive effects and side effects of two novel analogs of SalA, 16-Bromo SalA and 16-Ethynyl SalA. 16-Bromo SalA showed G-protein signaling bias, whereas 16-Ethynyl SalA displayed balanced signaling properties. In the dose-response tail-withdrawal assay, SalA, 16-Ethynyl SalA and 16-Bromo SalA were more potent than the traditional KOPr agonist U50,488, and 16-Ethynyl SalA was more efficacious. 16-Ethynyl SalA and 16-Bromo SalA both had a longer duration of action in the warm water tail-withdrawal assay, and 16-Ethynyl had greater antinociceptive effect in the hot-plate assay, compared to SalA. In the intraplantar 2% formaldehyde test, 16-Ethynyl SalA and 16-Bromo SalA significantly reduced both nociceptive and inflammatory pain-related behaviors. Moreover, 16-Ethynyl SalA and 16-Bromo SalA had no anxiogenic effects in the marble burying task, and 16-Bromo SalA did not alter behavior in the elevated zero maze. Overall, 16-Ethynyl SalA significantly attenuated acute pain-related behaviors in multiple preclinical models, while the biased KOPr agonist, 16-Bromo SalA, displayed modest antinociceptive effects, and lacked anxiogenic effects.
Learn More >The transient receptor potential vanilloid 1 (TRPV1) ion channel is a member of the family of Transient Receptor Potential (TRP) channels that acts as a molecular detector of noxious signals in primary sensory neurons. Activated by capsaicin, heat, voltage and protons, it is also well known for its desensitization, which led to the medical use of topically applied TRPV1 agonist capsaicin for its long-lasting analgesic effects. Here we report three novel small molecules, which were identified using a Structure-Based Virtual Screening for TRPV1 from the ZINC database. The three compounds were tested using electrophysiological assays, which confirmed their capsaicin-like agonist activity. von Frey filaments were used to measure the analgesic effects of the compounds applied topically on tactile allodynia induced by intra-plantar carrageenan. All compounds had anti-nociceptive activity, but two of them showed faster and longer lasting analgesic effects than capsaicin. The present results suggest that TRPV1 agonists different from capsaicin could be used to develop topical analgesics with faster onset and more potent effects.
Learn More >Patients with cholestatic liver diseases, such as primary biliary cirrhosis, usually suffer from pruritus. However, the pathogenesis of cholestatic pruritus is unclear, and there is no current effective treatment for it. In order to find a treatment for the condition, an appropriate mouse model should be developed. Therefore, here, we established a surgically-induced mouse model of cholestatic pruritus. The bile duct was ligated in order to block bile secretion from the anterior, right, and left lobes, with the exception of the caudate lobe. Serum levels of total bile acid increased after bile duct ligation (BDL). The spontaneous hind paw scratching was also increased in BDL mice. Spontaneous scratching was reduced in BDL mice by naloxone (µ-opioid receptor antagonist), U-50,488H (κ-opioid receptor agonist), and clonidine (α2-adrenoceptor agonist). Azelastine (H receptor antagonist with membrane-stabilizing activity) slightly reduced scratching. However, terfenadine (H receptor antagonist), methysergide (serotonin (5-HT) receptor antagonist), ondansetron (5-HT receptor antagonist), proteinase-activated receptor 2-neutralizing antibody, fluvoxamine (selective serotonin reuptake inhibitor), milnacipran (serotonin-noradrenalin reuptake inhibitor), and cyproheptadine (H and 5-HT receptor antagonist) did not affect scratching. These results suggested that partial obstruction of bile secretion in mice induced anti-histamine-resistant itching and that central opioid system is involved in cholestatic itching.
Learn More >As a chemotherapeutic agent, bortezomib (BTZ) is used for the treatment of multiple myeloma with adverse effect of painful peripheral neuropathy. Our current study was to determine the inhibitory effects of blocking microRNA-155 (miR-155) signal on BTZ-induced neuropathic pain and the underlying mechanisms. We employed real time RT-PCR and western blot analysis to examine the miR-155 and expression of – tumor necrosis factor-α receptor (TNFR1) in the dorsal horn of the spinal cord. Its downstream signals p38-MAPK and JNK and transient receptor potential ankyrin 1 (TRPA1) were also determined. Mechanical pain and cold sensitivity were assessed by behavioral test. In result, inhibition of miR-155 significantly attenuated mechanical allodynia and thermal hyperalgesia in BTZ rats, which was accompanied with decreasing expression of TNFR1, p38-MAPK, JNK, and TRPA1. In contrast, miRNA-155 mimics amplified TNFR1-TRPA1 pathway and augmented mechanical pain and cold sensitivity. In addition, mechanical and thermal hypersensitivity induced by miRNA-155 mimics were attenuated after blocking TNFR1, p38-MAPK, JNK, and TRPA1. Overall, we show the key role of miR-155 in modifying BTZ-induced neuropathic pain through TNFR1-TRPA1 pathway, suggesting that miR-155 is a potential target in preventing neuropathic pain development during intervention of BTZ.
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