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Preemptive intrathecal administration of endomorphins relieves inflammatory pain in male mice via inhibition of p38 MAPK signaling and regulation of inflammatory cytokines.

ABSTRACT: BACKGROUND:Preemptive administration of analgesic drugs reduces perceived pain and prolongs duration of antinociceptive action. Whereas several lines of evidence suggest that endomorphins, the endogenous mu-opioid agonists, attenuate acute and chronic pain at the spinal level, their preemptive analgesic effects remain to be determined. In this study, we evaluated the anti-allodynic activities of endomorphins and explored their mechanisms of action after preemptive administration in a mouse model of inflammatory pain. METHODS:The anti-allodynic activities of preemptive intrathecal administration of endomorphin-1 and endomorphin-2 were investigated in complete Freund's adjuvant (CFA)-induced inflammatory pain model and paw incision-induced postoperative pain model. The modulating effects of endomorphins on the expression of p38 mitogen-activated protein kinase (p38 MAPK) and inflammatory mediators in dorsal root ganglion (DRG) of CFA-treated mice were assayed by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, or immunofluorescence staining. RESULTS:Preemptive intrathecal injection of endomorphins dose-dependently attenuated CFA-induced mechanical allodynia via the mu-opioid receptor and significantly reversed paw incision-induced allodynia. In addition, CFA-caused increase of phosphorylated p38 MAPK in DRG was dramatically reduced by preemptive administration of endomorphins. Repeated intrathecal application of the specific p38 MAPK inhibitor SB203580 reduced CFA-induced mechanical allodynia as well. Further RT-PCR assay showed that endomorphins regulated the mRNA expression of inflammatory cytokines in DRGs induced by peripheral inflammation. CONCLUSIONS:Our findings reveal a novel mechanism by which preemptive treatment of endomorphins attenuates inflammatory pain through regulating the production of inflammatory cytokines in DRG neurons via inhibition of p38 MAPK phosphorylation.

SUBMITTER: Zhang T

PROVIDER: S-EPMC6236886 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Preemptive intrathecal administration of endomorphins relieves inflammatory pain in male mice via inhibition of p38 MAPK signaling and regulation of inflammatory cytokines.

Zhang Ting T Zhang Nan N Zhang Run R Zhao Weidong W Chen Yong Y Wang Zilong Z Xu Biao B Zhang Mengna M Shi Xuerui X Zhang Qinqin Q Guo Yuanyuan Y Xiao Jian J Chen Dan D Fang Quan Q

Journal of neuroinflammation 20181115 1

<h4>Background</h4>Preemptive administration of analgesic drugs reduces perceived pain and prolongs duration of antinociceptive action. Whereas several lines of evidence suggest that endomorphins, the endogenous mu-opioid agonists, attenuate acute and chronic pain at the spinal level, their preemptive analgesic effects remain to be determined. In this study, we evaluated the anti-allodynic activities of endomorphins and explored their mechanisms of action after preemptive administration in a mou ...[more]

PMID: 30442166

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Project description:Current pain therapeutics offer inadequate relief to patients with chronic pain. A growing literature supports that pro-inflammatory cytokine signaling between immune, glial, and neural cells is integral to the development of pathological pain. Modulation of these communications may hold the key to improved pain management. In this review we first offer an overview of the relationships between pro-inflammatory cytokine and chemokine signaling and pathological pain, with a focus on the actions of cytokines and chemokines in communication between glia (astrocytes and microglia), immune cells (macrophages and T cells), and neurons. These interactions will be discussed in relation to both peripheral and central nervous system locations. Several novel non-neuronal drug targets for controlling pain are emerging as highly promising, including non-viral IL-10 gene therapy, which offer the potential for substantial pain relief through localized modulation of targeted cytokine pathways. Preclinical investigation of the mechanisms underlying the success of IL-10 gene therapy revealed the unexpected discovery of the powerful anti-nociceptive anti-inflammatory properties of D-mannose, an adjuvant in the non-viral gene therapeutic formulation. This review will include gene therapeutic approaches showing the most promise in controlling pro-inflammatory signaling via increased expression of anti-inflammatory cytokines like interleukin-10 (IL-10) or IL-4, or by directly limiting the bioavailability of specific pro-inflammatory cytokines, as with tumor necrosis factor (TNF) by the TNF soluble receptor (TNFSR). Approaches that increase endogenous anti-inflammatory signaling may offer additional opportunities for pain therapeutic development in patients not candidates for gene therapy. Promising novel avenues discussed here include the disruption of lymphocyte function-associated antigen (LFA-1) activity, antagonism at the cannabinoid 2 receptor (CB2R), and toll-like receptor 4 (TLR4) antagonism. Given the partial efficacy of current drugs, new strategies to manipulate neuroimmune and cytokine interactions hold considerable promise.

Dataset Information

Preemptive intrathecal administration of endomorphins relieves inflammatory pain in male mice via inhibition of p38 MAPK signaling and regulation of inflammatory cytokines.

Publications

Preemptive intrathecal administration of endomorphins relieves inflammatory pain in male mice via inhibition of p38 MAPK signaling and regulation of inflammatory cytokines.

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