Interleukin‐33 (IL‐33) and its receptor ST2 contribute to spinal glial activation and chronic pain. A recent study showed that peripheral IL‐33 plays a pivotal role in the pathogenesis of chronic ...itch induced by poison ivy. However, how IL‐33/ST2 signaling in the spinal cord potentially mediates chronic itch remains elusive. Here, we determined that St2−/− substantially reduced scratching behaviors in 2,4‐dinitrofluorobenzene (DNFB)‐induced allergic contact dermatitis (ACD) as well as acetone and diethylether followed by water‐induced dry skin in mice. Intrathecal administration of the neutralizing anti‐ST2 or anti‐IL‐33 antibody remarkably decreased the scratching response in DNFB‐induced ACD mice. Expression of spinal IL‐33 and ST2 significantly increased in ACD mice, as evidenced by increased mRNA and protein levels. Immunofluorescence and in situ hybridization demonstrated that increased expression of spinal IL‐33 was predominant in oligodendrocytes and astrocytes, whereas ST2 was mainly expressed in astrocytes. Further studies showed that in ACD mice, the activation of astrocytes and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) were markedly attenuated by St2−/−. Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice. rIL‐33 pretreatment exacerbated gastrin‐releasing peptide (GRP)‐evoked scratching behaviors. This increased gastrin‐releasing peptide receptor (GRPR) expression was abolished by St2−/−. Tnf‐α upregulation was suppressed by St2−/−. Our results indicate that the spinal IL‐33/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2‐STAT3 cascade activation, promoting TNF‐α release to regulate the GRP/GRPR signaling‐related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.
The spinal astroglial JAK2‐STAT3 cascade participates in IL‐33/ST2 signaling mediated chronic itch.
Spinal IL‐33 regulates GRP/GRPR signaling‐related itch and TNF‐α expression.
There is current interest in understanding the molecular mechanisms of tumor-induced bone pain. Accumulated evidence shows that endogenous formaldehyde concentrations are elevated in the blood or ...urine of patients with breast, prostate or bladder cancer. These cancers are frequently associated with cancer pain especially after bone metastasis. It is well known that transient receptor potential vanilloid receptor 1 (TRPV1) participates in cancer pain. The present study aims to demonstrate that the tumor tissue-derived endogenous formaldehyde induces bone cancer pain via TRPV1 activation under tumor acidic environment.
Endogenous formaldehyde concentration increased significantly in the cultured breast cancer cell lines in vitro, in the bone marrow of breast MRMT-1 bone cancer pain model in rats and in tissues from breast cancer and lung cancer patients in vivo. Low concentrations (1 approximately 5 mM) of formaldehyde induced pain responses in rat via TRPV1 and this pain response could be significantly enhanced by pH 6.0 (mimicking the acidic tumor microenvironment). Formaldehyde at low concentrations (1 mM to 100 mM) induced a concentration-dependent increase of Ca(2+)i in the freshly isolated rat dorsal root ganglion neurons and TRPV1-transfected CHO cells. Furthermore, electrophysiological experiments showed that low concentration formaldehyde-elicited TRPV1 currents could be significantly potentiated by low pH (6.0). TRPV1 antagonists and formaldehyde scavengers attenuated bone cancer pain responses.
Our data suggest that cancer tissues directly secrete endogenous formaldehyde, and this formaldehyde at low concentration induces metastatic bone cancer pain through TRPV1 activation especially under tumor acidic environment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The chronic neuropathic pain-associated psychiatric disorders have seriously disturbed the quality of patients' life, such as depression and anxiety. Neuroinflammation in the hippocampus plays an ...important role in the neuropathic pain-associated depressive and anxiety disorders, but the underlying mechanism has not been thoroughly elucidated to date. The Nod-like receptor protein (NLRP)-1 inflammasome, which controls the production of pro-inflammatory cytokines, was broadly involved in the neuroinflammation-related diseases. In the present study, we show that the NLRP1 inflammasome is significantly activated in the hippocampus of rats subjected to the chronic constriction injury (CCI)-induced neuropathic pain. Inhibiting the product of NLRP1 inflammasome not only attenuated the depression-like behaviors but also suppressed the production of mature IL-1β in the hippocampus of CCI rats. The double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) has been recently shown to be a pivotal regulator for the activation of inflammasome. In the rats subjected to CCI neuropathic pain, the PKR was simultaneously activated in hippocampus. Functional inhibition of PKR suppressed the NLRP1 inflammasome activation and effectively attenuated the CCI-induced depression-like behaviors. These results indicate that the hippocampal PKR/NLRP1 inflammasome pathway play an important role in the development of the depressive behaviors after chronic neuropathic pain. Thus, interrupting this pathway might provide a novel therapeutic strategy for neuropathic pain-associated depressive disorders.
•The NLRP1 inflammasome is activated in the hippocampus of CCI rats.•Hippocampal PKR regulates the activation of NLRP1 inflammasome.•The PKR/NLRP1 inflammasome pathway contributes to the depressive behaviors in CCI rats.
Itch, a common somatic sensation, serves as a crucial protective system. Recent studies have unraveled the neural mechanisms of itch at peripheral, spinal cord as well as cerebral levels. However, a ...comprehensive understanding of the central mechanism governing itch transmission and regulation remains elusive. Here, we report the role of the medial septum (MS), an integral component of the basal forebrain, in modulating the acute itch processing. The increases in c-Fos+ neurons and calcium signals within the MS during acute itch processing were observed. Pharmacogenetic activation manipulation of global MS neurons suppressed the scratching behaviors induced by chloroquine or compound 48/80. Microinjection of GABA into the MS or pharmacogenetic inhibition of non-GABAergic neurons markedly suppressed chloroquine-induced scratching behaviors. Pharmacogenetic activation of the MS-ACC GABAergic pathway attenuated chloroquine-induced acute itch. Hence, our findings reveal that MS has a regulatory role in the chloroquine-induced acute itch through local increased GABA to inhibit non-GABAergic neurons and the activation of MS-ACC GABAergic pathway.
•MS neurons are activated during pruritogens-induced acute itch.•Pharmacogenetic activation of MS neurons suppressed pruritogens-induced scratching behaviors.•Pharmacogenetic inhibition of MS non-GABAergic neurons reduced chloroquine-induced scratching behavior.•Pharmacogenetic activation of MS-ACC GABAergic pathway suppressed chloroquine-induced acute itch behavior.
As one of the most important complementary and alternative modalities, acupuncture has been used worldwide in pain relief at bedside. Substantial and accumulating clinical evidences show that ...acupuncture produces analgesic effects in various acute/chronic pain conditions. In this chapter, we will summarize the clinical research of acupuncture-induced analgesic effects on various pain disorders, especially headaches, chronic low back pain, knee osteoarthritis, chronic neck pain, neuropathic pain, motor system injuries, fibromyalgia, cancer pain, dental pain, and phantom limb pain. Furthermore, the clinical designs and acupuncture approaches for pain relief will also be discussed in terms of appropriate use of acupuncture. Finally, we will briefly comment on several problematic issues in acupuncture studies, and present a prospective view in terms of future research to improve the clinical application of acupuncture to make it more beneficial to patients.
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