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Papers of the Week

Papers: 15 Jun 2024 - 21 Jun 2024

2024 Jun 15

J Pain


Comparison of Morphine and Endomorphin Analog ZH853 for Tolerance and Immunomodulation in a Rat Model of Neuropathic Pain.


Hunter TJ, Videlefsky ZM, Nakatani LF, Zadina JE


µ-Opioid receptor agonists, the gold standard for analgesia, come with significant side effects when used chronically. Tolerance, defined as the decrease in analgesic activity after repeated use, remains a vital therapeutic obstacle as it increases the likelihood of dose escalation and potentially lethal side effects like respiratory depression. Previous experiments have indicated that the endomorphin-1 analog, ZH853, is a specific µ-opioid receptor agonist with reduced side effects like tolerance and glial activation following chronic central administration in pain-naïve animals. Here we investigated the effects of chronic, peripheral administration of µ-opioid receptor agonists following neuropathic injury. Though µ-opioids are effective at reducing neuropathic pain, they are not recommended for 1 line treatment due to negative side effects. Compared to chronic morphine, chronic ZH853 treatment led to decreased tolerance and reduced glial activation. Following twice daily intravenous injections, morphine was less potent and had a shorter duration of antinociception compared to ZH853. Chronic morphine, but not chronic ZH853, elevated markers of activation/inflammation of astrocytes (GFAP), microglia (Iba1), the proinflammatory cytokine TNFα and phosphorylated MAP kinase pp38. By contrast, chronic ZH853 reduced Iba1 and TNFα relative to both morphine and vehicle, suggesting anti-inflammatory properties with respect to these markers. GFAP and pp38 were not significantly different from vehicle but were significantly lower than morphine. This study demonstrates the effectiveness of chronic ZH853 for providing analgesia in a neuropathic pain state with reduced tolerance compared to morphine, potentially due to reductions in spinal glial activation. PERSPECTIVE: Neuropathic pain is generally undertreated, resistant to available medications, and opioid treatment is limited by side-effects. Here, we show that, compared to an equiantinociceptive dose of a stereotypical µ-opioid receptor agonist, morphine, chronic intravenous administration of endomorphin analog ZH853 led to prolonged antiallodynia, reduced tolerance, and inhibition of spinal cord neuroinflammation in male spared nerve-injured rats.