Preclinical Assessment of the Analgesic Pharmacology of NKTR-181 in Rodents.
Antinociception
Efficacy
Mice
NKTR-181
Opioid
Potency
Rats
Journal
Cellular and molecular neurobiology
ISSN: 1573-6830
Titre abrégé: Cell Mol Neurobiol
Pays: United States
ID NLM: 8200709
Informations de publication
Date de publication:
Jul 2021
Jul 2021
Historique:
received:
05
11
2019
accepted:
16
02
2020
pubmed:
29
2
2020
medline:
15
12
2021
entrez:
29
2
2020
Statut:
ppublish
Résumé
Pharmacological evaluation of the mu-opioid receptor (MOR) agonist properties of NKTR-181 in rodent models. Graded noxious stimulus intensities were used in rats to establish the antinociceptive potency and efficacy of NKTR-181 relative to morphine, fentanyl, and oxycodone. Characteristics of MOR agonist actions, as measured by antinociceptive tolerance and cross-tolerance, as well as opioid-induced hyperalgesia (OIH) and naloxone-precipitated withdrawal in NKTR-181- and morphine-dependent in mice, were compared. NKTR-181 showed dose- and time-related antinociception with similar maximal effects to morphine in the rat and mouse hot-water tail-flick test. No sex or species differences were observed in NKTR-181 or morphine antinociception. Rats treated with NKTR-181 and morphine exhibited decreases in both potency and maximal efficacy as nociceptive stimulus intensity was increased from a water temperature of 50 °C to 54 °C. Evaluation of antinociception at a high stimulus intensity revealed that oxycodone and fentanyl exhibited greater efficacy than either NKTR-181 or morphine. The relative potency difference between NKTR-181 and morphine across all tail-flick studies was determined to be 7.6-fold (90% confidence interval, 2.6, 21.5). The peak antinociceptive effect of NKTR-181 was delayed compared to that of the other opioids and cumulative drug effects were not observed. Repeated treatment with escalating, approximately equi-analgesic doses of NKTR-181 or morphine, produced antinociceptive tolerance and cross-tolerance. Under these pharmacological conditions, OIH and naloxone-precipitated physical dependence were similar for NKTR-181 and morphine. NKTR-181 had a slower onset, but similar efficacy, to morphine in the models studied supporting reduced abuse potential while maintaining analgesic effect in comparison with current opioids.
Identifiants
pubmed: 32107752
doi: 10.1007/s10571-020-00816-3
pii: 10.1007/s10571-020-00816-3
doi:
Substances chimiques
Analgesics, Opioid
0
Morphinans
0
NKTR-181
0
Receptors, Opioid, mu
0
Morphine
76I7G6D29C
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
949-960Références
Abreu ME, Bigelow GE, Fleisher L, Walsh SL (2001) Effect of intravenous injection speed on responses to cocaine and hydromorphone in humans. Psychopharmacology 154:76–84
pubmed: 11292009
doi: 10.1007/s002130000624
Anantharamu T, Sharma S, Gupta AK, Dahiya N, Singh Brashier DB, Sharma AK (2015) Naloxegol: First oral peripherally acting mu opioid receptor antagonists for opioid-induced constipation. J Pharmacol Pharmacother 6:188–192
pubmed: 26312011
pmcid: 4544149
doi: 10.4103/0976-500X.162015
Angst MS, Clark JD (2006) Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 104:570–587
pubmed: 16508405
doi: 10.1097/00000542-200603000-00025
Bohnert ASB, Ilgen MA (2019) Understanding Links among opioid use, overdose, and suicide. N Engl J Med 380:71–79
pubmed: 30601750
doi: 10.1056/NEJMra1802148
Brat GA, Agniel D, Beam A et al (2018) Postsurgical prescriptions for opioid naive patients and association with overdose and misuse: retrospective cohort study. BMJ 360:j5790
pubmed: 29343479
pmcid: 5769574
doi: 10.1136/bmj.j5790
Bryant CD, Roberts KW, Byun JS, Fanselow MS, Evans CJ (2006) Morphine analgesic tolerance in 129P3/J and 129S6/SvEv mice. Pharmacol Biochem Behav 85:769–779
pubmed: 17196637
pmcid: 1905890
doi: 10.1016/j.pbb.2006.11.012
Chan HCS, McCarthy D, Li J, Palczewski K, Yuan S (2017) Designing safer analgesics via mu-opioid receptor pathways. Trends Pharmacol Sci 38:1016–1037
pubmed: 28935293
pmcid: 5690544
doi: 10.1016/j.tips.2017.08.004
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63
pubmed: 7990513
doi: 10.1016/0165-0270(94)90144-9
Comer SD, Ashworth JB, Sullivan MA, Vosburg SK, Saccone PA, Foltin RW (2009) Relationship between rate of infusion and reinforcing strength of oxycodone in humans. J Opioid Manag 5:203–212
pubmed: 19736900
doi: 10.5055/jom.2009.0022
Compton WM, Jones CM, Baldwin GT (2016) Relationship between nonmedical prescription-opioid use and heroin use. N Engl J Med 374:154–163
pubmed: 26760086
doi: 10.1056/NEJMra1508490
Del Vecchio G, Spahn V, Stein C (2017) Novel Opioid analgesics and side effects. ACS Chem Neurosci 8:1638–1640
pubmed: 28603962
doi: 10.1021/acschemneuro.7b00195
Drewes AM, Jensen RD, Nielsen LM et al (2013) Differences between opioids: pharmacological, experimental, clinical and economical perspectives. Br J Clin Pharmacol 75:60–78
pubmed: 22554450
doi: 10.1111/j.1365-2125.2012.04317.x
Dumas EO, Pollack GM (2008) Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J 10:537–551
pubmed: 18989788
pmcid: 2628209
doi: 10.1208/s12248-008-9056-1
Farre M, Cami J (1991) Pharmacokinetic considerations in abuse liability evaluation. Br J Addict 86:1601–1606
pubmed: 1786493
doi: 10.1111/j.1360-0443.1991.tb01754.x
Fields HL, Margolis EB (2015) Understanding opioid reward. Trends Neurosci 38:217–225
pubmed: 25637939
pmcid: 4385443
doi: 10.1016/j.tins.2015.01.002
Grosser T, Woolf CJ, FitzGerald GA (2017) Time for nonaddictive relief of pain. Science 355:1026–1027
pubmed: 28280170
doi: 10.1126/science.aan0088
Gudin J, Rauck R, Argoff C et al (2019) Long-term safety and tolerability of NKTR-181 in patients with moderate to severe chronic low back pain or chronic noncancer pain: a phase 3 multicenter, open-label, 52-week study (SUMMIT-08 LTS). Pain Med. https://doi.org/10.1093/pm/pnz169
doi: 10.1093/pm/pnz169
pmcid: 7372935
Heimer R, Hawk K, Vermund SH (2018) Prevalent misconceptions about opioid use disorders in the United States produce failed policy and public health responses. Clin Infect Dis 69:546–551
pmcid: 6637277
doi: 10.1093/cid/ciy977
Hooten WM, Lamer TJ, Twyner C (2015) Opioid-induced hyperalgesia in community-dwelling adults with chronic pain. Pain 156:1145–1152
pubmed: 25815431
pmcid: 4431900
doi: 10.1097/j.pain.0000000000000170
Kanof PD, Handelsman L, Aronson MJ, Ness R, Cochrane KJ, Rubinstein KJ (1992) Clinical characteristics of naloxone-precipitated withdrawal in human opioid-dependent subjects. J Pharmacol Exp Ther 260:355–363
pubmed: 1731046
Kest B, Palmese CA, Hopkins E, Adler M, Juni A, Mogil JS (2002) Naloxone-precipitated withdrawal jumping in 11 inbred mouse strains: evidence for common genetic mechanisms in acute and chronic morphine physical dependence. Neuroscience 115:463–469
pubmed: 12421612
doi: 10.1016/S0306-4522(02)00458-X
King TE, Joynes RL, Grau JW (1997) Tail-flick test: II. The role of supraspinal systems and avoidance learning. Behav Neurosci 111:754–767
pubmed: 9267652
doi: 10.1037/0735-7044.111.4.754
Kousik SM, Napier TC, Carvey PM (2012) The effects of psychostimulant drugs on blood brain barrier function and neuroinflammation. Front Pharmacol 3:121
pubmed: 22754527
pmcid: 3386512
doi: 10.3389/fphar.2012.00121
Leppert W, Woron J (2016) The role of naloxegol in the management of opioid-induced bowel dysfunction. Ther Adv Gastroenterol 9:736–746
doi: 10.1177/1756283X16648869
Markman J, Gudin J, Rauck R et al (2019) Summit-07: A randomized trial of NKTR-181, a new molecular entity, full mu-opioid receptor agonist for chronic low-back pain. Pain 160:1374–1382
pubmed: 30747908
pmcid: 6553961
doi: 10.1097/j.pain.0000000000001517
Marsch LA, Bickel WK, Badger GJ et al (2001) Effects of infusion rate of intravenously administered morphine on physiological, psychomotor, and self-reported measures in humans. J Pharmacol Exp Ther 299:1056–1065
pubmed: 11714895
Miyazaki T, Choi IY, Rubas W et al (2017) NKTR-181: a novel mu-opioid analgesic with inherently low abuse potential. J Pharmacol Exp Ther 363:104–113
pubmed: 28778859
doi: 10.1124/jpet.117.243030
Nath C, Gupta MB, Patnaik GK, Dhawan KN (1994) Morphine-induced straub tail response: mediated by central mu2-opioid receptor. Eur J Pharmacol 263:203–205
pubmed: 7821354
doi: 10.1016/0014-2999(94)90543-6
Nemmani KV, Grisel JE, Stowe JR, Smith-Carliss R, Mogil JS (2004) Modulation of morphine analgesia by site-specific N-methyl-D-aspartate receptor antagonists: dependence on sex, site of antagonism, morphine dose, and time. Pain 109:274–283
pubmed: 15157688
doi: 10.1016/j.pain.2004.01.035
Ossipov MH, Lai J, King T et al (2004) Antinociceptive and nociceptive actions of opioids. J Neurobiol 61:126–148
pubmed: 15362157
doi: 10.1002/neu.20091
Ossipov MH, Dussor GO, Porreca F (2010) Central modulation of pain. J Clin Invest 120:3779–3787
pubmed: 21041960
pmcid: 2964993
doi: 10.1172/JCI43766
Porreca F, Ossipov MH (2009) Nausea and vomiting side effects with opioid analgesics during treatment of chronic pain: mechanisms, implications, and management options. Pain Med 10:654–662
pubmed: 19302436
doi: 10.1111/j.1526-4637.2009.00583.x
Roeckel LA, Le Coz GM, Gaveriaux-Ruff C, Simonin F (2016) Opioid-induced hyperalgesia: cellular and molecular mechanisms. Neuroscience 338:160–182
pubmed: 27346146
doi: 10.1016/j.neuroscience.2016.06.029
Rosen SF, Ham B, Haichin M et al (2019) Increased pain sensitivity and decreased opioid analgesia in T-cell-deficient mice and implications for sex differences. Pain 160:358–366
pubmed: 30335680
doi: 10.1097/j.pain.0000000000001420
Rutkow L, Vernick JS (2017) Emergency Legal authority and the opioid crisis. N Engl J Med 377:2512–2514
pubmed: 29140760
doi: 10.1056/NEJMp1710862
Schaefer CP, Tome ME, Davis TP (2017) The opioid epidemic: a central role for the blood brain barrier in opioid analgesia and abuse. Fluids Barriers CNS 14:32
pubmed: 29183383
pmcid: 5706290
doi: 10.1186/s12987-017-0080-3
Shah A, Hayes CJ, Martin BC (2017) Factors Influencing long-term opioid use among opioid naive patients: an examination of initial prescription characteristics and pain etiologies. J Pain 18:1374–1383
pubmed: 28711636
pmcid: 5660650
doi: 10.1016/j.jpain.2017.06.010
Skolnick P, Volkow ND (2016) Re-energizing the Development of pain therapeutics in light of the opioid epidemic. Neuron 92:294–297
pubmed: 27764663
doi: 10.1016/j.neuron.2016.09.051
Stein C (2016) Opioid receptors. Annu Rev Med 67:433–451
pubmed: 26332001
doi: 10.1146/annurev-med-062613-093100
Tompkins DA, Campbell CM (2011) Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon? Curr Pain Headache Rep 15:129–136
pubmed: 21225380
pmcid: 3165032
doi: 10.1007/s11916-010-0171-1
Treillet E, Laurent S, Hadjiat Y (2018) Practical management of opioid rotation and equianalgesia. J Pain Res 11:2587–2601
pubmed: 30464578
pmcid: 6211309
doi: 10.2147/JPR.S170269
US Food and Drug Administration (2015) Guidance for industry: abuse-deterrent opioids–evaluation and labeling. US Department of Health and Human Services website. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm334743.pdf . Accessed: 2019
Vander Weele CM, Porter-Stransky KA, Mabrouk OS et al (2014) Rapid dopamine transmission within the nucleus accumbens: dramatic difference between morphine and oxycodone delivery. Eur J Neurosci 40:3041–3054
pubmed: 25208732
pmcid: 4358739
doi: 10.1111/ejn.12709
Walker G (2018) The opioid crisis: a 21st century pain. Drugs Today (Barc) 54:283–286
doi: 10.1358/dot.2018.54.4.2812620
Webster LR, Bath B, Medve RA, Marmon T, Stoddard GJ (2012) Randomized, double-blind, placebo-controlled study of the abuse potential of different formulations of oral oxycodone. Pain Med 13:790–801
pubmed: 22568663
doi: 10.1111/j.1526-4637.2012.01380.x
Webster L, Henningfield J, Buchhalter AR et al (2018) Human abuse potential of the new opioid analgesic molecule NKTR-181 compared with oxycodone. Pain Med 19:307–318
pubmed: 28340145
doi: 10.1093/pm/pnw344
Zollner C, Stein C (2007) Opioids. Handb Exp Pharmacol 177:31–63
doi: 10.1007/978-3-540-33823-9_2