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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 IC 50 of NFEPP to displace bound [ 3 H]-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.

The non-selective activation of central and peripheral opioid receptors is a major shortcoming of currently available opioids. Targeting peripheral opioid receptors is a promising strategy to preclude side effects. Recently, we showed that fentanyl-derived μ-opioid receptor (MOR) agonists with reduced acid dissociation constants (pK a ) due to introducing single fluorine atoms produced injury-restricted antinociception in rat models of inflammatory, postoperative and neuropathic pain. Here, we report that a new double-fluorinated compound (FF6) and fentanyl show similar pK a , MOR affinity and [ 35 S]-GTPγS binding at low and physiological pH values. In vivo , FF6 produced antinociception in injured and non-injured tissue, and induced sedation and constipation. The comparison of several fentanyl derivatives revealed a correlation between pK a values and pH-dependent MOR activation, antinociception and side effects. An opioid ligand’s pK a value may be used as discriminating factor to design safer analgesics.

N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide is a newly-designed pain killer selectively activating G-protein-coupled mu-opioid receptors (MOR) in acidic injured tissues, and therefore devoid of central side effects which are typically elicited at normal pH values in healthy tissues. However, the neuronal mechanisms underlying NFEPP’s antinociceptive effects were not examined in detail so far. Voltage-dependent Ca 2+ channels (VDCCs) in nociceptive neurons play a major role in the generation and inhibition of pain. In this study, we focused on the effects of NFEPP on calcium currents in rat dorsal root ganglion (DRG) neurons. The inhibitory role of the G-protein subunits G i/o and Gβγ on VDCCs was investigated using the blockers pertussis toxin and gallein, respectively. GTPγS binding, calcium signals and MOR phosphorylation were also investigated. All experiments were performed at acidic and normal pH values using NFEPP in comparison to the conventional opioid agonist fentanyl. At low pH, NFEPP produced more efficient G-protein activation in transfected HEK293 cells and significantly reduced VDCCs in depolarized DRG neurons. The latter effect was mediated by Gβγ subunits, and NFEPP-mediated MOR phosphorylation was pH-dependent. Fentanyl’s responses were not affected by pH changes. Our data indicate that NFEPP-induced MOR signaling is more effective at low pH and that the inhibition of calcium channels in DRG neurons underlies NFEPP’s antinociceptive actions.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The sensory ion channel transient receptor potential vanilloid 1 (TRPV1) is mainly expressed in small to medium sized dorsal root ganglion neurons, which are involved in the transfer of acute noxious thermal and chemical stimuli. The Ankyrin-rich membrane spanning protein (ARMS) interaction with TRPV1 is modulated by protein kinase A (PKA) mediating sensitization. Here, we hypothesize that PKA phosphorylation sites of ARMS are crucial for the modulation of TRPV1 function, and that the phosphorylation of ARMS is facilitated by the A-kinase anchoring protein 79 (AKAP79). We used transfected HEK293 cells, immunoprecipitation, calcium flux, and patch clamp experiments to investigate potential PKA phosphorylation sites in ARMS and in ARMS-related peptides. Additionally, experiments were done to discriminate between PKA and protein kinase D (PKD) phosphorylation. We found different interaction ratios for TRPV1 and ARMS mutants lacking PKA phosphorylation sites. The degree of TRPV1 sensitization by ARMS mutants is independent on PKA phosphorylation. AKAP79 was also involved in the TRPV1/ARMS/PKA signaling complex. These data show that ARMS is a PKA substrate via AKAP79 in the TRPV1 signaling complex and that all four proteins interact physically, regulating TRPV1 sensitization in transfected HEK293 cells. To assess the physiological and/or therapeutic significance of these findings, similar investigations need to be performed in native neurons and/or in vivo.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The non-selective activation of central and peripheral opioid receptors is a major shortcoming of currently available opioids. Targeting peripheral opioid receptors is a promising strategy to preclude side effects. Recently, we showed that fentanyl-derived μ-opioid receptor (MOR) agonists with reduced acid dissociation constants (pK ) due to introducing single fluorine atoms produced injury-restricted antinociception in rat models of inflammatory, postoperative and neuropathic pain. Here, we report that a new double-fluorinated compound (FF6) and fentanyl show similar pK , MOR affinity and [ S]-GTPγS binding at low and physiological pH values. In vivo, FF6 produced antinociception in injured and non-injured tissue, and induced sedation and constipation. The comparison of several fentanyl derivatives revealed a correlation between pK values and pH-dependent MOR activation, antinociception and side effects. An opioid ligand's pK value may be used as discriminating factor to design safer analgesics.

Introduction The prerequisite for transoral microsurgery of laryngeal lesions is an uninterrupted line of sight to the operative field. Patients with cervical stiffness or anatomical variations that prevent adequate laryngeal exposure are typically unsuitable for this procedure. In such cases, a curved video laryngoscope may facilitate improved access to the larynx. However, conventional suspension laryngoscopy setups are incompatible with standard video laryngoscopes. Objective This study evaluates three attachment methods for integrating a curved video laryngoscope into a surgical setup, focusing on their resistance to external forces. Methods This study assessed three different attachment methods (3D‐printed clamp vs. metal bracket vs. articulated stand) for a video laryngoscope in a surgical setup. External forces, both lateral and rotational (torque), were applied and continuously measured until laryngeal visualization was compromised by displacement of the video laryngoscope. Results The metal bracket demonstrated significantly (p < 0.001) higher resistance to lateral forces (median 184.49 N, 95% CI [181.59–189.61 N]) compared to the articulated stand (median 88.16 N, 95% CI [76.73–88.98 N]) and the 3D‐printed clamp (median 55.59 N, 95% CI [54.74–57.58 N]). The articulated stand exhibited significantly (p < 0.005) greater torque resistance (median 9.57 N m, 95% CI [5.65–9.87 N m]) compared to the metal bracket (median 1.58 N m, 95% CI [1.57–2.13 N m]) and the 3D‐printed clamp (median 2.46 N m, 95% CI [2.24–2.79 N m]). Conclusion Overall, the articulated stand outperformed the other attachment methods, displaying robust resistance to lateral forces and superior rotational stability. Level of Evidence Level 4. The study presents a systematic evaluation of innovative attachment methods for integrating a curved video laryngoscope into surgical setups, addressing a significant clinical need for improving laryngeal exposure in patients with complex anatomical or mobility challenges. In this work, we assessed the performance of three attachment systems—3D‐printed clamp, metal bracket, and articulated stand—under conditions simulating external surgical forces.