Abstract
BackgroundPreemptive 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.MethodsThe 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.ResultsPreemptive 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.ConclusionsOur 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.
Highlights
Preemptive administration of analgesic drugs reduces perceived pain and prolongs duration of antinociceptive action
Preemptive intrathecal administration of EM-1 and EM-2 robustly reduced the development of mechanical allodynia Intraplantar injection of complete Freund’s adjuvant (CFA) induced a strong mechanical allodynia during the whole experimental period
To investigate whether mitogen-activated protein kinase (MAPK) signaling is involved in the preemptive analgesia of endomorphins in inflammatory pain model, we further examined the effects of EM-1 and EM-2 on CFA-induced activation of p38 MAPK and ERK1/2 in dorsal root ganglion (DRG) neurons
Summary
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. We evaluated the anti-allodynic activities of endomorphins and explored their mechanisms of action after preemptive administration in a mouse model of inflammatory pain. It has been demonstrated that both EM-1 and EM-2 produced potent analgesic actions in inflammatory pain, which were reversed by the opioid receptor antagonist naloxone or β-funaltrexamine (β-FNA) [2,3,4]. Histological studies elucidated that both EM-1 and EM-2 were expressed in macrophages and monocytes in lymph nodes during peripheral inflammation, suggesting the involvement of endomorphins in inflammatory pain [8]
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