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<p>Burn injury-induced chronic pain is a highly debilitating condition that profoundly impacts the well-being of military veterans and the general population. Current pain management for burn injured patients mainly relies on central opioids, often causing sedation, addiction, and physical dependence. This study aims to investigate the effects of Dermorphin [D-Arg2, Lys4] (1–4) amide (DALDA), a peripherally acting μ-opioid receptor (MOR) agonist in an animal model of burn injury-induced chronic pain while unravelling the underlying mechanisms. Soldering apparatus was used to induce burn pain in Sprague Dawley rats followed by testing for both evoked and ongoing pain behaviours. Molecular investigations were performed for TRPV1, NR2B, neuro-inflammatory and glia cell markers (TNF-α, IL-6, Iba-1 &amp; ICAM-1), and neuropeptides (CGRP), using western blotting and RT-PCR analysis. Burn-injured rats exhibited significant hypersensitivity to mechanical, thermal, and cold stimuli, along with severe ongoing pain. Systemic administration of DALDA significantly reduced evoked pain behaviour in a dose-dependent manner (1, 3, and 10&#xa0;mg/kg), with the 10&#xa0;mg/kg s.c. dose effectively alleviating spontaneous pain without causing drug addiction. DALDA also restored antioxidant enzyme levels in the sciatic nerve and downregulated burn injury-induced molecular changes, including TRPV1, NR2B, and CGRP, as well as neuroinflammatory markers such as TNF-α and IL-6 in the DRG and spinal cord of rats. Activation of peripheral μ-opioid receptors efficiently mitigates both evoked and spontaneous pain in burn-injured rats, without causing central nervous system (CNS)-related side effects. Findings from the present study demonstrate a promising approach to mitigate burn pain, overcoming the limitations associated with centrally acting opioids.</p> Graphical Abstract <p><b>Peripheral μ-opioid receptor activation mitigates burn injury-induced chronic pain</b>. Burn injuries activate various nociceptors and inflammatory mediators at the site of injury, including TRP channels. DALDA, a preferential μ-opioid receptor agonist, inhibits CGRP release and NMDA receptor activity while increasing levels of Fibulin-5&#xa0;in response to burn injury. Oxidative stress, exacerbated following burn injury, drives the generation of pro-inflammatory mediators and the activation of microglia. A reduction in pro-inflammatory cytokines and glial cell activation following DALDA administration suppresses central sensitization and contributes to the inhibition of chronic pain.</p> <p></p>

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Dermorphin [D-Arg2, Lys4] (1–4) Amide Attenuates Burn Pain by Inhibiting TRPV1/NR2B Mediated Neuroinflammatory Signalling

  • 期刊论文

  • 发表日期：

    2025年5月29日

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  • Ajay Modi,
  • Ankit Uniyal,
  • Akhilesh,
  • Vineeta Tiwari,
  • Deepak Chouhan,
  • Somesh Agrawal,
  • Obulapathi Ummadisetty,
  • Vinod Tiwari

摘要

Burn injury-induced chronic pain is a highly debilitating condition that profoundly impacts the well-being of military veterans and the general population. Current pain management for burn injured patients mainly relies on central opioids, often causing sedation, addiction, and physical dependence. This study aims to investigate the effects of Dermorphin [D-Arg2, Lys4] (1–4) amide (DALDA), a peripherally acting μ-opioid receptor (MOR) agonist in an animal model of burn injury-induced chronic pain while unravelling the underlying mechanisms. Soldering apparatus was used to induce burn pain in Sprague Dawley rats followed by testing for both evoked and ongoing pain behaviours. Molecular investigations were performed for TRPV1, NR2B, neuro-inflammatory and glia cell markers (TNF-α, IL-6, Iba-1 & ICAM-1), and neuropeptides (CGRP), using western blotting and RT-PCR analysis. Burn-injured rats exhibited significant hypersensitivity to mechanical, thermal, and cold stimuli, along with severe ongoing pain. Systemic administration of DALDA significantly reduced evoked pain behaviour in a dose-dependent manner (1, 3, and 10 mg/kg), with the 10 mg/kg s.c. dose effectively alleviating spontaneous pain without causing drug addiction. DALDA also restored antioxidant enzyme levels in the sciatic nerve and downregulated burn injury-induced molecular changes, including TRPV1, NR2B, and CGRP, as well as neuroinflammatory markers such as TNF-α and IL-6 in the DRG and spinal cord of rats. Activation of peripheral μ-opioid receptors efficiently mitigates both evoked and spontaneous pain in burn-injured rats, without causing central nervous system (CNS)-related side effects. Findings from the present study demonstrate a promising approach to mitigate burn pain, overcoming the limitations associated with centrally acting opioids.

Graphical Abstract

Peripheral μ-opioid receptor activation mitigates burn injury-induced chronic pain. Burn injuries activate various nociceptors and inflammatory mediators at the site of injury, including TRP channels. DALDA, a preferential μ-opioid receptor agonist, inhibits CGRP release and NMDA receptor activity while increasing levels of Fibulin-5 in response to burn injury. Oxidative stress, exacerbated following burn injury, drives the generation of pro-inflammatory mediators and the activation of microglia. A reduction in pro-inflammatory cytokines and glial cell activation following DALDA administration suppresses central sensitization and contributes to the inhibition of chronic pain.