Activation of µ receptors by SR-17018 through a distinctive mechanism.

Agonists at µ opioid receptors relieve acute pain, however, their long-term use is limited by side effects, which may involve ß-arrestin2. Agonists biased against ß-arrestin2 recruitment may be advantageous. However, the classification of bias may be compromised by assays utilising overexpressed µ receptors which overestimate efficacy for G-protein activation. There is a need for re-evaluation with restricted receptor availability to determine accurate agonist efficacies. We depleted µ receptor availability in PathHunter CHO cells using the irreversible antagonist, ß-funaltrexamine (ß-FNA), and compared efficacies and apparent potencies of twelve agonists, including several previously reported as biased, in ß-arrestin2 recruitment and cAMP assays. With full receptor availability all agonists had partial efficacy for stimulating ß-arrestin2 recruitment relative to DAMGO, while only TRV130 and buprenorphine were partial agonists as inhibitors of cAMP accumulation. Limiting receptor availability by prior exposure to ß-FNA (100 nM) revealed morphine, oxycodone, PZM21, herkinorin, U47700, tianeptine and U47931e are also partial agonists in the cAMP assay. The efficacies of all agonists, except SR-17018, correlated between ß-arrestin2 recruitment and cAMP assays, with depleted receptor availability in the latter. Furthermore, naloxone and cyprodime exhibited non-competitive antagonism of SR-17018 in the ß-arrestin2 recruitment assay. Limited antagonism by naloxone was also non-competitive in the cAMP assay, while cyprodime was competitive. Furthermore, SR-17018 only negligibly diminished ß-arrestin2 recruitment stimulated by DAMGO (1 µM), whereas fentanyl, morphine and TRV130 all exhibited the anticipated competitive inhibition. The data suggest that SR-17018 achieves bias against ß-arrestin2 recruitment through interactions with µ receptors outside the orthosteric agonist site. This article is part of the Special Issue on "Ligand Bias".

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

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 shown 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-naive 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 first-line treatment due to negative side effects. Compared with 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 with ZH853. Chronic morphine, but not chronic ZH853, elevated markers of activation/inflammation of astrocytes (glial fibrillary acidic protein), microglia (ionized calcium-binding adapter molecule 1), the proinflammatory cytokine tumor necrosis factor-α, and phosphorylated mitogen-activated protein (MAP) kinase p38 (pp38). By contrast, chronic ZH853 reduced ionized calcium-binding adapter molecule 1 and tumor necrosis factor-α relative to both morphine and vehicle, suggesting anti-inflammatory properties with respect to these markers. Glial fibrillary acidic protein 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 with morphine, potentially due to reductions in spinal glial activation. PERSPECTIVE: Neuropathic pain is generally undertreated and resistant to medication, and side-effects limit opioid treatment. Here, we show that, compared with an equiantinociceptive dose of 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.

Aniquinazoline B, a Fungal Natural Product, Activates the µ-Opioid Receptor.

The development of new µ-opioid receptor (MOR) agonists without the undesirable side effects, such as addiction or respiratory depression, has been a difficult challenge over the years. In the search for new compounds, we screened our chemical database of over 40.000 substances and further assessed the best 100 through molecular docking. We selected the top 10 compounds and evaluated them for their biological activity and potential to influence cyclic adenosine monophosphate (cAMP) levels. From the tested compounds, compound 7, called aniquinazoline B, belonging to the quinazolinone alkaloids class and isolated from the marine fungus Aspergillus nidulans, showed promising results, by inhibiting cAMP levels and in vitro binding to MOR, verified through microscale thermophoresis. Transcriptomic data investigation profiled the genes affected by compound 7 and discovered activation of different pathways compared to opioids. The western blot analysis revealed compound 7 as a balanced ligand, activating both p-ERK1/2 and ß-arrestin1/2 pathways, showing this is a favorable candidate to be further tested.

Tegileridine: First Approval.

Tegileridine () is a small molecule µ-opioid receptor biased agonist developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd for the treatment of postoperative pain. Tegileridine selectively activates the G-protein-coupled pathway, which mediates strong central analgesic effects and only weakly activates the ß-arrestin-2 pathway implicated in adverse events like respiratory depression and gastrointestinal dysfunction. In January 2024, tegileridine received its first approval in China for the treatment of moderate to severe pain after abdominal surgery. This article summarizes the milestones in the development of tegileridine leading to this first approval for the treatment of moderate to severe pain after abdominal surgery.

All-Hydrocarbon Stapled Peptide Multifunctional Agonists at Opioid and Neuropeptide FF Receptors: Highly Potent, Long-Lasting Brain Permeant Analgesics with Diminished Side Effects.

Our previous study reported the multifunctional agonist for opioid and neuropeptide FF receptors DN-9, along with its cyclic peptide analogues c[D-Cys2, Cys5]-DN-9 and c[D-Lys2, Asp5]-DN-9. These analogues demonstrated potent antinociceptive effects with reduced opioid-related side effects. To develop more stable and effective analgesics, we designed, synthesized, and evaluated seven hydrocarbon-stapled cyclic peptides based on DN-9. In vitro calcium mobilization assays revealed that most of the stapled peptides, except 3, displayed multifunctional agonistic activities at opioid and neuropeptide FF receptors. Subcutaneous administration of all stapled peptides resulted in effective and long-lasting antinociceptive activities lasting up to 360 min. Among these stapled peptides, 1a and 1b emerged as the optimized compounds, producing potent central antinociception following subcutaneous, intracerebroventricular, and oral administrations. Additionally, subcutaneous administration of 1a and 1b caused nontolerance antinociception, with limited occurrence of constipation and addiction. Furthermore, 1a was selected as the final optimized compound due to its wider safety window compared to 1b.

Identification and Pharmacological Characterization of a Low-Liability Antinociceptive Bifunctional MOR/DOR Cyclic Peptide.

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED50 (and 95% confidence interval) of 0.70 (0.52-0.97) mg/kg i.p. mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p.) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED50 value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics.

Effects of the novel selective κ-opioid receptor agonist NP-5497-KA on morphine-induced reward-related behaviors.

Opioid addiction and the opioid overdose epidemic are becoming more serious, and the development of therapeutic agents is essential for the pharmacological treatment of substance use disorders. The κ-opioid receptor (KOP) is a member of the opioid receptor system that has been gaining attention as a promising molecular target for the treatment of numerous human disorders, including pain, depression, anxiety, and drug addiction. Here, we biologically and pharmacologically evaluated a novel azepane-derived ligand, NP-5497-KA, as a selective KOP agonist. NP-5497-KA had 1000-fold higher selectivity for the KOP over the µ-opioid receptor (MOP), which was higher than nalfurafine (KOP/MOP: 65-fold), and acted as a selective KOP full agonist in the 3',5'-cyclic adenosine monophosphate assay. The oral administration of NP-5497-KA (1-10 mg/kg) dose-dependently suppressed morphine-induced conditioned place preference in C57BL/6 J mice, and its effects were comparable to an intraperitoneal injection of nalfurafine (1-10 µg/kg). Nalfurafine (10 µg/kg) significantly inhibited rotarod performance, whereas NP-5497-KA (10 mg/kg) exerted no effect on rotarod performance. These results indicate that NP-5497-KA may be a novel option for the treatment of opioid use disorder with fewer side effects.

CYX-5, a G-protein biassed MOP receptor agonist, DOP receptor antagonist and KOP receptor agonist, evokes constipation but not respiratory depression relative to morphine in rats.

BACKGROUND: Strong opioid analgesics such as morphine alleviate moderate to severe acute nociceptive pain (e.g. post-surgical or post-trauma pain) as well as chronic cancer pain. However, they evoke many adverse effects and so there is an unmet need for opioid analgesics with improved tolerability. Recently, a prominent hypothesis has been that opioid-related adverse effects are mediated by ß-arrestin2 recruitment at the µ-opioid (MOP) receptor and this stimulated research on discovery of G-protein biassed opioid analgesics. In other efforts, opioids with MOP agonist and δ-opioid (DOP) receptor antagonist profiles are promising for reducing side effects c.f. morphine. Herein, we report on the in vivo pharmacology of a novel opioid peptide (CYX-5) that is a G-protein biassed MOP receptor agonist, DOP receptor antagonist and kappa opioid (KOP) receptor agonist. METHODS: Male Sprague-Dawley received intracerebroventricular bolus doses of CYX-5 (3, 10, 20 nmol), morphine (100 nmol) or vehicle, and antinociception (tail flick) was assessed relative to constipation (charcoal meal and castor oil-induced diarrhoea tests) and respiratory depression (whole body plethysmography). RESULTS: CYX-5 evoked naloxone-sensitive, moderate antinociception, at the highest dose tested. Although CYX-5 did not inhibit gastrointestinal motility, it reduced stool output markedly in the castor oil-induced diarrhoea test. In contrast to morphine that evoked respiratory depression, CYX-5 increased tidal volume, thereby stimulating respiration. CONCLUSION: Despite its lack of recruitment of ß-arrestin2 at MOP, DOP and KOP receptors, CYX-5 evoked constipation, implicating a mechanism other than ß-arrestin2 recruitment at MOP, DOP and KOP receptors, mediating constipation evoked by CYX-5 and potentially other opioid ligands.

Synergistic interaction between DAMGO-NH2 and NOP01 in peripherally acting antinociception in two mouse models of formalin pain.

The most commonly used opioid analgesics are limited by their severe side-effects in the clinical treatment of pain. Preliminary reports indicate that the combination of classical opioids and N/OFQ receptor (NOP) ligands may be an effective strategy to reduce unwanted side-effects and improve antinociception. But the interaction of these two receptor ligands in pain regulation at the peripheral level remains unclear. In this study, the antinociception of a designed amide analogue of the mu opioid receptor (MOP) peptide agonist DAMGO, DAMGO-NH2, and its antinociceptive interaction with the peripherally limited NOP peptide agonist NOP01 was investigated in two mouse models of formalin pain. Our results showed that DAMGO-NH2 acted as a MOP agonist in in vitro functional assays. Moreover, local subcutaneous or intraplantar injection of DAMGO-NH2 exerted dose-related antinociception in both phases of the formalin orofacial and intraplantar pain, which could be mediated by the classical opioid receptor. Peripheral but not central pretreatment with the peripherally restricted opioid antagonist naloxone methiodide inhibited local DAMGO-NH2-induced antinociception, supporting the involvement of the peripheral opioid receptor in local DAMGO-NH2-induced antinociception. Furthermore, co-administration of the inactive doses of DAMGO-NH2 and NOP01 produced effective antinociception. More importantly, isobolographic analysis indicates that the combination of DAMGO-NH2 and NOP01 elicited supra-additive antinociception in these two models of formalin pain. In addition, the combination of DAMGO-NH2 and NOP01 did not change motor function of mice in rotarod test. In conclusion, these data suggest that peripheral DAMGO-NH2 and particularly its combination therapy with NOP01 may be effective for pain management.

Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors.

Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH2 (RP-170), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH2, a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH2 (KW-495) and RP-170-Gly3-RYYRIK-NH2 (KW-496). In vitro, the chimeric KW-496 gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while KW-495 behaved as a mixed MOP/NOP agonist with low nM affinity. Hence, KW-495 was selected for further in vivo experiments. Intrathecal administration of this peptide in mice elicited antinociceptive effects in the hot-plate test; this action was sensitive to both the universal opioid receptor antagonist naloxone and the selective NOP antagonist SB-612111. The rotarod test revealed that KW-495 administration did not alter the mice motor coordination performance. Computational studies have been conducted on the two chimeras to investigate the structural determinants at the basis of the experimental activities, including any role of the Gly3 spacer.

OFP011 Cyclic Peptide as a Multifunctional Agonist for Opioid/Neuropeptide FF Receptors with Improved Blood-Brain Barrier Penetration.

Mounting evidence indicates that the neuropeptide FF (NPFF) system is involved in the side effects of opioid usage, including antinociceptive tolerance, hyperalgesia, abuse, constipation, and respiratory depression. Our group recently discovered that the multitarget opioid/NPFF receptor agonist DN-9 exhibits peripheral antinociceptive activity. To improve its metabolic stability, antinociceptive potency, and duration, in this study, we designed and synthesized a novel cyclic disulfide analogue of DN-9, OFP011, and examined its bioactivity through in vitro cyclic adenosine monophosphate (cAMP) functional assays and in vivo behavioral experiments. OFP011 exhibited multifunctional agonistic effects at the µ-opioid and the NPFF1 and NPFF2 receptors and partial agonistic effects at the δ- and κ-opioid in vitro, as determined via the cAMP functional assays. Pharmacokinetic and pharmacological experiments revealed improvement in its blood-brain barrier permeability after systemic administration. In addition, subcutaneous OFP011 exhibited potent and long-lasting antinociceptive activity via the central µ- and κ-opioid receptors, as observed in different physiological and pathological pain models. At the highest antinociceptive doses, subcutaneous OFP011 exhibited limited tolerance, gastrointestinal transit, motor coordination, addiction, reward, and respiration depression. Notably, OFP011 exhibited potent oral antinociceptive activities in mouse models of acute, inflammatory, and neuropathic pain. These results suggest that the multifunctional opioid/NPFF receptor agonists with improved blood-brain barrier penetration are a promising strategy for long-term treatment of moderate to severe nociceptive and pathological pain with fewer side effects.

Benzo[b]thiophene-2-carboxamides as novel opioid receptor agonists with potent analgesic effect and reduced constipation.

Currently, there is a significant unmet need for novel analgesics with fewer side effects. In this study, we carried out structural modification of a hit compound previously identified in an artificial-intelligence (AI) virtual screening and discovered the potent analgesic, benzo[b]thiophene-2-carboxamide analog (compound 25) with new structural scaffold. We investigated the signaling pathways of opioid receptors mediated by compound 25, and found this racemic compound activated mu-opioid receptor through the cyclic adenosine monophosphate (cAMP) and ß-arrestin-2-mediated pathways with strong potency and efficacy, and accompanying nociceptin-orphanin FQ opioid peptide and delta-opioid receptors through the cAMP pathway with weak potencies. Compound 25 elicited potent antinociception in thermal-stimulated pain (ED50 value of 127.1 ± 34.65 µg/kg) and inflammatory-induced allodynia models with less gastrointestinal transit inhibition and antinociceptive tolerance than morphine. Overall, this study revealed a novel analgesic with reduced risks of side effects.

Discovery of pyrazole-1-carboxamide derivatives as novel Gi-biased µ-opioid receptor agonists.

µ-Opioid receptor (MOR) Gi-biased agonists with no recruitment of ß-arrestin were introduced as a new analgesic strategy to overcome the conventional undesirable side effects of opioid receptor-targeted drugs, such as tolerance, addiction, respiratory depression, and constipation. For the development of novel Gi-biased MOR agonists, the design, synthesis, and structure-activity relationship (SAR) analysis of the aminopyrazole core skeleton were conducted according to the current SAR data of PZM21 (2a) and its derivatives. New derivatives were biologically evaluated for their agonistic effects on cyclic adenosine monophosphate (cAMP) levels for the Gi pathway and ß-arrestin recruitment in MOR/κ-opioid receptor/δ opioid receptor. An optimized selective Gi-biased agonist, Compound 17a, was discovered with potent cAMP inhibitory activities, with a 50% efficacy concentration value of 87.1 nM and no activity in the MOR ß-arrestin pathway and other subtypes. The in vivo pain relief efficacy of Compound 17a was confirmed in a dose-dependent manner with spinal nerve ligation and cisplatin-induced peripheral neuropathy rodent neuropathic pain models.

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation.

Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

Novel Opioid Analgesics for the Development of Transdermal Opioid Patches That Possess Morphine-Like Pharmacological Profiles Rather Than Fentanyl: Possible Opioid Switching Alternatives Among Patch Formula.

BACKGROUND: Transdermal fentanyl is widely used in the treatment of severe pain because of convenience, safety, and stable blood concentrations. Nevertheless, patients often develop tolerance to fentanyl, necessitating the use of other opioids; transdermal buprenorphine patch is widely used as an analgesic agent, though available formulation does not provide comparable analgesic effect as transdermal fentanyl patch. Opioids bind to the opioid receptor (OR) to activate both G protein-mediated and ß-arrestin-mediated pathways. We synthesized morphine-related compounds with high transdermal absorbability (N1 and N2) and evaluated their OR activities pharmacologically in comparison with fentanyl and morphine. METHODS: In cells stably expressing µ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), G protein-mediated pathways were assessed using the CellKey and an intracellular cyclic adenosine monophosphate (cAMP) assay, while ß-arrestin-mediated pathways were analyzed with ß-arrestin recruitment and receptor internalization assays. Furthermore, analgesic effects were evaluated using a tail-flick test in mice, and the analgesic effect on fentanyl-tolerant mice was evaluated. RESULTS: In the CellKey and cAMP assays, both N1 and N2 showed the highest affinity for MOR and acted as full agonists as well as partial agonists for DOR and KOR. In the ß-arrestin and internalization assays, only fentanyl acted as a full agonist; N1 and N2 acted as partial agonists of MOR. In the mouse tail-flick test, N1 and N2 showed analgesic effects equivalent to those of fentanyl and morphine. In fentanyl-tolerant mice, fentanyl showed a diminished analgesic effect, whereas N1 and N2 as well as morphine retained their analgesic effects. CONCLUSIONS: While N1 and N2 have higher transdermal absorbability than fentanyl, they also have analgesic effects comparable to those of morphine, suggesting that they may be attractive compounds for the development of novel opioid patches for transitioning from fentanyl patches.

Analgesic Opioid Ligand Discovery Based on Nonmorphinan Scaffolds Derived from Natural Sources.

Strong opioid analgesics, including morphine, are the mainstays for treating moderate to severe acute pain and alleviating chronic cancer pain. However, opioid-related adverse effects, including nausea or vomiting, sedation, respiratory depression, constipation, pruritus (itch), analgesic tolerance, and addiction and abuse liability, are problematic. In addition, the use of opioids to relieve chronic noncancer pain is controversial due to the "opioid crisis" characterized by opioid misuse or abuse and escalating unintentional death rates due to respiratory depression. Hence, considerable research internationally has been aimed at the "Holy Grail" of the opioid analgesic field, namely the discovery of novel and safer opioid analgesics with improved opioid-related adverse effects. In this Perspective, medicinal chemistry strategies are addressed, where structurally diverse nonmorphinan-based opioid ligands derived from natural sources were deployed as lead molecules. The current state of play, clinical or experimental status, and novel opioid ligand discovery approaches are elaborated in the context of retaining analgesia with improved safety and reduced adverse effects, especially addiction liability.

Tapentadol shows lower intrinsic efficacy at µ receptor than morphine and oxycodone.

Tapentadol is a centrally acting analgesic with a dual mechanism of action. It acts as an agonist at the µ receptor and inhibitor of noradrenaline reuptake. Clinical trials suggest similar analgesic efficacy of tapentadol, oxycodone, and morphine in acute and chronic pain. Given the limited information about the molecular actions of tapentadol at the µ receptor, we investigated the intrinsic efficacy of tapentadol and compared it with other opioids. ß-chlornaltrexamine (ß-CNA, 100 nM, 20 min) was used to deplete spare receptors in AtT20 cells stably transfected with human µ receptor wild-type (WT). Opioid-mediated changes in membrane potential were measured in real-time using a membrane potential-sensitive fluorescent dye. Using Black and Leff's operational model, intrinsic efficacy relative to DAMGO was calculated for each opioid. Tapentadol (0.05 ± 0.01) activated the GIRK channel with lesser intrinsic efficacy than morphine (0.17 ± 0.02) and oxycodone (0.16 ± 0.02). We further assessed the signaling of tapentadol in the common µ receptor variants (N40D and A6V) which are associated with altered receptor signaling. We found no difference in the response of tapentadol between these receptor variants.

Sucrose drinking mimics effects of nucleus accumbens µ-opioid receptor stimulation on fat intake and brain c-Fos-expression.

Objectives: We have previously shown that the combined consumption of fat and a sucrose solution induces overeating, and there is evidence indicating that sucrose drinking directly stimulates fat intake. One neurochemical pathway by which sucrose may enhance fat intake is through the release of endogenous opioids in the nucleus accumbens (NAC).Methods: To test this hypothesis, we provided rats with a free-choice high-fat diet for two weeks. During the second week, rats had access to an additional bottle of water or a 30% sucrose solution for five minutes per day. After these two weeks, we infused vehicle or the µ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) into the NAC 30 min after their daily access to the additional bottle of water or the sucrose solution.Results: Sucrose drinking had two effects, (1) it stimulated fat intake in the absence of DAMGO infusion, (2) it diminished sensitivity to DAMGO, as it prevented the rapid increase in fat intake typically seen upon DAMGO infusion in the nucleus accumbens. In a second experiment, we confirmed that these results are not due to the ingested calories of the sucrose solution. Lastly, we investigated which brain areas are involved in the observed effects on fat intake by assessing c-Fos-expression in brain areas previously linked to DAMGO's effects on food intake. Both intra-NAC DAMGO infusion and sucrose consumption in the absence of DAMGO infusion had no effect on c-Fos-expression in orexin neurons and the central amygdala but increased c-Fos-expression in the NAC as well as the basolateral amygdala.Discussion: In conclusion, we confirm that sucrose drinking stimulates fat intake, likely through the release of endogenous opioids.

Synthesis, biological, and structural explorations of a series of µ-opioid receptor (MOR) agonists with high G protein signaling bias.

Biased agonism refers to the ability of compounds to drive preferred signaling pathways and avoid adverse signaling pathways in a ligand-dependent manner for some G-protein-coupled receptors. It is thought that the separation of therapeutic efficacy (e.g., analgesia) from adverse effects (e.g., respiration depression) can be achieved through the design of biased MOR agonists and one example is the recently approved MOR biased agonist oliceridine (TRV130). However, oliceridine only demonstrates modest beneficial effects as compared to other opioids in terms of therapeutic/adverse effect balance. One possibility attributable to the modest success of oliceridine is its limited bias, and as such developing MOR ligands with a more biased agonism profile could in theory further improve the beneficial effects of the ligands. Here, we rationally designed and synthesized a series of derivatives as potent highly biased MOR agonists (19a-v) through the modification and structure-activity relationship study of TRV130. This novel synthetic molecule, LPM3480392 (19m), demonstrated improved in vitro biased agonism (EC50 = 0.35 nM, Emax = 91.4%) with no measured ß-arrestin recruitment (EC50 > 30000 nM, Emax = 1.6%), good brain penetration (B/P ratio = 4.61, 0.25 h post-IV dosing 2.0 mg/kg), a favorable pharmacokinetic profile (distribution volume = 10766 mL/kg, t1/2 = 1.9 h) and produced potent antinociceptive effect with reduced respiratory suppression (sO2(%) = 92.17, 0.32 mg/kg, SC) as compared to TRV130. LPM3480392 has completed preclinical studies and is currently under clinical development (CTR20210370) as an analgesic for the treatment of moderate to severe pain.

Shedding Light on the Pharmacological Interactions between µ-Opioid Analgesics and Angiotensin Receptor Modulators: A New Option for Treating Chronic Pain.

The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia.