Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats

Lazenka, Matthew F.; Moerke, Megan J.; Townsend, E. Andrew; Freeman, Kevin B.; Carroll, F. Ivy; Negus, S. Stevens

doi:10.1007/s00213-017-4758-7

Cited by 44 publications

(43 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…uremic pruritus) resulted in biased ERK1/2 activation compared to p38MAPK induction in hKOPr-expressing HEK-293 cells and displayed antinociceptive effects in the tail immersion test (Schattauer et al, 2017) as well as in other species and preclinical pain models (Endoh et al, 2000); thus, further sustaining interest in developing KOPr agonists that result in limited p38MAPK phosphorylation (e.g., LOR17). However, it should be noted that nalfurafine was recently demonstrated not to be effective in relieving pain-depressed behaviors (Lazenka et al, 2018); consistently, nalfurafine is not indicated as analgesic drug not even in Japan (where it is marketed as an anti-itch drug). These limited effects displayed by nalfurafine may be related to a G protein signaling bias not high enough to produce a desirable profile of antinociceptive efficacy and safety (Lazenka et al, 2018); thus, pointing at the magnitude of bias factor as another element to be considered when developing new KOPr biased agonists.…”

Section: Discussionmentioning

confidence: 99%

“…However, it should be noted that nalfurafine was recently demonstrated not to be effective in relieving pain-depressed behaviors (Lazenka et al, 2018); consistently, nalfurafine is not indicated as analgesic drug not even in Japan (where it is marketed as an anti-itch drug). These limited effects displayed by nalfurafine may be related to a G protein signaling bias not high enough to produce a desirable profile of antinociceptive efficacy and safety (Lazenka et al, 2018); thus, pointing at the magnitude of bias factor as another element to be considered when developing new KOPr biased agonists. LOR17 displayed a bias factor of 853 as compared to U50,488, thus emerging as a candidate compound that is worthy of further characterization.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist

et al. 2020

View full text Add to dashboard Cite

Kappa opioid receptor (KOPr) agonists represent alternative analgesics for their low abuse potential, although relevant adverse effects have limited their clinical use. Functionally selective KOPr agonists may activate, in a pathway-specific manner, G protein-mediated signaling, that produces antinociception, over b-arrestin 2-dependent induction of p38MAPK, which preferentially contributes to adverse effects. Thus, functionally selective KOPr agonists biased toward G protein-coupled intracellular signaling over barrestin-2-mediated pathways may be considered candidate therapeutics possibly devoid of many of the typical adverse effects elicited by classic KOPr agonists. Nonetheless, the potential utility of functionally selective agonists at opioid receptors is still highly debated; therefore, further studies are necessary to fully understand whether it will be possible to develop more effective and safer analgesics by exploiting functional selectivity at KOPr. In the present study we investigated in vitro functional selectivity and in vivo antinociceptive effects of LOR17, a novel KOPr selective peptidic agonist that we synthesized. LOR17mediated effects on adenylyl cyclase inhibition, ERK1/2, p38MAPK phosphorylation, and astrocyte cell proliferation were studied in HEK-293 cells expressing hKOPr, U87-MG glioblastoma cells, and primary human astrocytes; biased agonism was investigated via cAMP ELISA and b-arrestin 2 recruitment assays. Antinociception and antihypersensitivity were assessed in mice via warm-water tail-withdrawal test, intraperitoneal acid-induced writhing, and a model of oxaliplatin-induced neuropathic cold hypersensitivity. Effects of LOR17 on locomotor activity, exploratory activity, and forced-swim behavior were also assayed. We found that LOR17 is a selective, G protein biased KOPr agonist that inhibits adenylyl cyclase and activates early-phase ERK1/2 phosphorylation. Conversely to classic KOPr agonists as U50,488, LOR17 neither induces p38MAPK phosphorylation nor increases KOPr-dependent, p38MAPK-mediated cell proliferation in astrocytes. Moreover, LOR17 counteracts, in a concentration-dependent manner, U50,488induced p38MAPK phosphorylation and astrocyte cell proliferation. Both U50,488 and LOR17 display potent antinociception in models of acute nociception, whereas LOR17 counteracts oxaliplatin-induced thermal hypersensitivity better than U50,488, and it is effective after single or repeated s.c. administration. LOR17 administered at a dose that fully alleviated oxaliplatin-induced thermal hypersensitivity did not alter motor coordination, locomotor and exploratory activities nor induced pro-depressant-like behavior. LOR17, therefore, may emerge as a novel KOPr agonist displaying functional selectivity toward G protein signaling and eliciting antinociceptive/antihypersensitivity effects in different animal models, including oxaliplatin-induced neuropathy.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Our result is well consistent with many early studies in rodents with similar dose ranges of nalfurafine, but different from many “classic” KOP‐r agonists with several side effects. Specifically, low doses of nalfurafine (<40 μ g/kg) do not produce conditioned place aversion, sedation, anxiety‐like, or depression‐like behaviors (Inan et al., ; Liu et al., ; Nagase et al., ; Suzuki et al., ), though high doses (>80 μ g/kg) were reported to induce aversion (Lazenka et al., ). In humans, unlike other KOP‐r agonists, nalfurafine does not produce strong hallucinogenic or dysphoric effects (Kamimura et al., ; Kozono et al., ; Kumagai et al., , ; Pongcharoen and Fleischer, ).…”

Section: Discussionmentioning

confidence: 99%

Combination of Clinically Utilized Kappa‐Opioid Receptor Agonist Nalfurafine With Low‐Dose Naltrexone Reduces Excessive Alcohol Drinking in Male and Female Mice

Zhou

Kreek

2019

Alcoholism Clin & Exp Res

View full text Add to dashboard Cite

Background: Nalfurafine is the first clinically approved kappa-opioid receptor (KOP-r) agonist as an antipruritus drug with few side effects in humans (e.g., sedation, depression, and dysphoria). No study, however, has been done using nalfurafine on alcohol drinking in rodents or humans.Methods: We investigated whether nalfurafine alone or in combination with mu-opioid receptor (MOP-r) antagonist naltrexone changed excessive alcohol drinking in male and female C57BL/6J (B6) mice subjected to a chronic intermittent-access drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Neuronal proopiomelanocortin enhancer (nPE) knockout mice with brain-specific deficiency of beta-endorphin (endogenous ligand of MOP-r) were used as a genetic control for the naltrexone effects.Results: Single administration of nalfurafine decreased alcohol intake and preference in both male and female B6 mice in a dose-dependent manner. Pretreatment with nor-BNI (a selective KOP-r antagonist) blocked the nalfurafine effect on alcohol drinking, indicating a KOP-r-mediated mechanism. Pharmacological effects of a 5-dosing nalfurafine regimen were further evaluated: The repeated nalfurafine administrations decreased alcohol consumption without showing any blunted effects, suggesting nalfurafine did not develop a tolerance after the multidosing regimen tested. Nalfurafine did not produce any sedation (spontaneous locomotor activity), anhedonia-like (sucrose preference test), anxietylike (elevated plus maze test), or dysphoria-like (conditioned place aversion test) behaviors, suggesting that nalfurafine had few side effects. Investigating synergistic effects between low-dose naltrexone and nalfurafine, we found that single combinations of nalfurafine and naltrexone, at doses lower than individual effective dose, profoundly decreased excessive alcohol intake in both sexes. The effect of nalfurafine on decreasing alcohol consumption was confirmed in nPEÀ/À mice, suggesting independent mechanisms by which nalfurafine and naltrexone reduced alcohol drinking.Conclusion: The clinically utilized KOP-r agonist nalfurafine in combination with low-dose naltrexone has potential in alcoholism treatment.

show abstract

“…In addition, while nalfurafine was shown to reduce acetic acid-induced writhing in mice (a pain-stimulated behavior), it did not restore ICSS thresholds depressed by acetic acid administration (a pain-suppressed behavior) (Lazenka et al, 2018). Furthermore, nalfurafine alone suppressed ICSS thresholds in the absence of a painful stimulus (Lazenka et al, 2018). These results seem to indicate that nalfurafine alone does not alleviate the negative affect produced by pain, unlike traditional opioid analgesics (Altarifi et al, 2014;Porreca and Navratilova, 2017b), and nalfurafine may prevent this positive effect of traditional opioid analgesics when co-administered.…”

Section: -Future Directionsmentioning

confidence: 98%

“…Other therapeutically limiting effects must also be investigated, such as constipation, a side effect of MOR agonists prevalent enough to prompt the development of naloxegol (a peripherally restricted MOR antagonist) and diuresis, a side effect of KOR agonism (Leander et al, 1985;Webster, 2015). In addition, while nalfurafine was shown to reduce acetic acid-induced writhing in mice (a pain-stimulated behavior), it did not restore ICSS thresholds depressed by acetic acid administration (a pain-suppressed behavior) (Lazenka et al, 2018). Furthermore, nalfurafine alone suppressed ICSS thresholds in the absence of a painful stimulus (Lazenka et al, 2018).…”

Section: -Future Directionsmentioning

confidence: 99%

Genetic and Pharmacologic Studies Towards Prevention of opioid use disorder

Kaski¹

View full text Add to dashboard Cite

Genetic and Pharmacologic Studies Towards Prevention of opioid use disorder Shane West Kaski Endogenous opioids mediate both analgesic and affective responses to stress. While the mu opioid receptor (MOR) produces the reinforcing euphoric effects responsible for the high abuse potential of traditional opioid analgesics, the kappa opioid receptor (KOR) is hypothesized to mediate the dysphoric component of stress. With increasing rates of opioid addiction, extensive research efforts are focused on better understanding each of these systems and how they interact, with the goal of developing less addictive pain management strategies and better approaches to addiction treatment. With this in mind, we conducted both clinical and preclinical studies aimed at developing better treatment strategies for opioid use and the management of patients with opioid use disorder (OUD). First, we assessed a local cohort of patients with (OUD) for a collection of single nucleotide polymorphisms (SNPs) related to reward processing, with the goal of furthering efforts to develop a gene-based screening mechanism for OUD risk assessment. Second, we conducted preclinical assessments of the G protein-biased KOR agonist nalfurafine as a potential adjuvant medication for increasing the therapeutic efficacy of opioid-based analgesia. Genetic analysis of OUD patients identified two SNPs within the gene encoding the mu opioid receptor, one SNP within the gene encoding the serotonin 2B (5-HT2B) receptor, and one SNP within the gene encoding Regulator of G protein Signaling 2 (RGS2), with the frequency of each SNP varying significantly from that observed in reference populations of European descent. Preclinical investigations with nalfurafine use in mice demonstrated a greater analgesic synergy when co-administered with morphine than morphine co-administered with the unbiased KOR agonist U50,488. As G protein-biased KOR agonists are hypothesized to produce less dysphoria (a therapeutically limiting side effect of KOR agonists), they may present a viable method for reducing the dose of MOR-targeting analgesic necessary for adequate pain relief, thereby reducing the likelihood of developing OUD. Further research is necessary to identify any antitherapeutic effects of co-administering these two classes of drugs, as well as the range of pain modalities for which this approach is efficacious.

show abstract

Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats

Cited by 44 publications

References 57 publications

Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist

Functional Selectivity and Antinociceptive Effects of a Novel KOPr Agonist

Combination of Clinically Utilized Kappa‐Opioid Receptor Agonist Nalfurafine With Low‐Dose Naltrexone Reduces Excessive Alcohol Drinking in Male and Female Mice

Genetic and Pharmacologic Studies Towards Prevention of opioid use disorder

Contact Info

Product

Resources

About