Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain

Rodríguez‐Gaztelumendi, Antonio; Spahn, Viola; Łabuz, Dominika; Machelska, Halina; Stein, Christoph

doi:10.1097/j.pain.0000000000001328

Cited by 57 publications

(47 citation statements)

References 43 publications

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“…Both fiber types express opioid receptors (44)(45)(46)(47) and transmit mechanical and heat stimuli (48,49). Consistently, exogenous opioid receptor agonists applied at the CCI site attenuated mechanical and heat hypersensitivity (40,46,(50)(51)(52). However, here we found that endogenous opioid peptides, derived from IL-4-induced M2 macrophages, attenuated mechanical but not heat hypersensitivity.…”

Section: Discussionsupporting

confidence: 77%

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

Celik¹,

Łabuz²,

Keye³

et al. 2020

JCI Insight

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Section: Discussionsupporting

confidence: 77%

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

Celik¹,

Łabuz²,

Keye³

et al. 2020

JCI Insight

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“…Similar binding characteristics of NFEPP were recently demonstrated in homogenates of MOR-transfected human embryonic kidney (HEK) 293 cells 14 and rat brain 15 . Here, we examined mouse brain membranes by comparing the effects of NFEPP and fentanyl on the binding of the selective MOR agonist [ 3 H]-DAMGO to MOR.…”

Section: Discussionsupporting

confidence: 74%

A low pKa ligand inhibits cancer-associated pain in mice by activating peripheral mu-opioid receptors

Baamonde

Menéndez

González-Rodríguez

et al. 2020

Sci Rep

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The newly designed fentanyl derivative [( ±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide] (NFEPP) was recently shown to produce analgesia selectively via peripheral mu-opioid receptors (MOR) at acidic pH in rat inflamed tissues. Here, we examined the pH-dependency of NFEPP binding to brain MOR and its effects on bone cancer-induced pain in mice. The IC50 of NFEPP to displace bound [3H]-DAMGO was significantly higher compared to fentanyl at pH 7.4, but no differences were observed at pH 5.5 or 6.5. Intravenous NFEPP (30–100 nmol/kg) or fentanyl (17–30 nmol/kg) inhibited heat hyperalgesia in mice inoculated with B16-F10 melanoma cells. The peripherally-restricted opioid receptor antagonist naloxone-methiodide reversed the effect of NFEPP (100 nmol/kg), but not of fentanyl (30 nmol/kg). The antihyperalgesic effect of NFEPP was abolished by a selective MOR- (cyprodime), but not delta- (naltrindole) or kappa- (nor-binaltorphimine) receptor antagonists. Ten-fold higher doses of NFEPP than fentanyl induced maximal antinociception in mice without tumors, which was reversed by the non-restricted antagonist naloxone, but not by naloxone-methiodide. NFEPP also reduced heat hyperalgesia produced by fibrosarcoma- (NCTC 2472) or prostate cancer-derived (RM1) cells. These data demonstrate the increased affinity of NFEPP for murine MOR at low pH, and its ability to inhibit bone cancer-induced hyperalgesia through peripheral MOR. In mice, central opioid receptors may be activated by ten-fold higher doses of NFEPP.

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“…Indeed, in vitro experiments confirmed that NFEPP bound to and activated μ-receptors only at acidic pH, whereas fentanyl was active at both acidic and physiological pH. Importantly, unlike fentanyl, intravenously applied NFEPP produced analgesia by activation of opioid receptors exclusively in peripheral injured tissue in rat models of unilateral hind paw inflammation or surgical incision ( Spahn et al, 2017 ), sciatic nerve injury-induced neuropathy, and abdominal pain ( Rodriguez-Gaztelumendi et al, 2018 ). Furthermore, NFEPP did not induce respiratory depression, sedation, motor impairment, reward (assessed by conditioned place preference; CPP), and constipation, even at doses 10-fold higher than the most effective analgesic doses ( Spahn et al, 2017 ) (Table 2 ).…”

Section: Targeting Opioid Receptors In Painful Tissuementioning

confidence: 98%

Advances in Achieving Opioid Analgesia Without Side Effects

2018

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Opioids are the most effective drugs for the treatment of severe pain, but they also cause addiction and overdose deaths, which have led to a worldwide opioid crisis. Therefore, the development of safer opioids is urgently needed. In this article, we provide a critical overview of emerging opioid-based strategies aimed at effective pain relief and improved side effect profiles. These approaches comprise biased agonism, the targeting of (i) opioid receptors in peripheral inflamed tissue (by reducing agonist access to the brain, the use of nanocarriers, or low pH-sensitive agonists); (ii) heteromers or multiple receptors (by monovalent, bivalent, and multifunctional ligands); (iii) receptor splice variants; and (iv) endogenous opioid peptides (by preventing their degradation or enhancing their production by gene transfer). Substantial advancements are underscored by pharmaceutical development of new opioids such as peripheral κ-receptor agonists, and by treatments augmenting the action of endogenous opioids, which have entered clinical trials. Additionally, there are several promising novel opioids comprehensively examined in preclinical studies, but also strategies such as biased agonism, which might require careful rethinking.

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Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain

Abstract: Supplemental Digital Content is Available in the Text.The newly designed, pH-dependent opioid agonist NFEPP induced analgesia exclusively through peripheral opioid receptors in models of neuropathic and abdominal pain.

Cited by 57 publications

References 43 publications

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

A low pKa ligand inhibits cancer-associated pain in mice by activating peripheral mu-opioid receptors

Advances in Achieving Opioid Analgesia Without Side Effects

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