Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain

Alexander T. Podolsky, Alexander Sandweiss, Jackie Hu, Edward J. Bilsky, Jim P. Cain, Vlad K. Kumirov, Yeon Sun Lee, Victor J Hruby, Ruben S Vardanyan, Todd W Vanderah

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids have highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors. Aims: Here we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors. Main methods: Mice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats. Key findings: RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment. Significance This is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists.

Original languageEnglish (US)
Pages (from-to)1010-1016
Number of pages7
JournalLife Sciences
Volume93
Issue number25-26
DOIs
StatePublished - Dec 18 2013

Fingerprint

Acute Pain
Fentanyl
Chronic Pain
Opioid Analgesics
delta Opioid Receptor
mu Opioid Receptor
Pain
Prescriptions
Rats
Therapeutics
Spinal Nerves
kappa Opioid Receptor
Narcotic Antagonists
Enkephalins
Opioid Receptors
Neuralgia
Morphine
Formaldehyde
Ligation
Rodentia

Keywords

  • Allodynia
  • Chronic pain
  • Delta opioid
  • Fentanyl
  • Formalin flinch
  • Hyperalgesia
  • Inflammatory
  • Mice
  • mu opioid
  • Naloxone
  • Rat
  • Spinal nerve ligation

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Podolsky, A. T., Sandweiss, A., Hu, J., Bilsky, E. J., Cain, J. P., Kumirov, V. K., ... Vanderah, T. W. (2013). Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain. Life Sciences, 93(25-26), 1010-1016. https://doi.org/10.1016/j.lfs.2013.09.016

Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain. / Podolsky, Alexander T.; Sandweiss, Alexander; Hu, Jackie; Bilsky, Edward J.; Cain, Jim P.; Kumirov, Vlad K.; Lee, Yeon Sun; Hruby, Victor J; Vardanyan, Ruben S; Vanderah, Todd W.

In: Life Sciences, Vol. 93, No. 25-26, 18.12.2013, p. 1010-1016.

Research output: Contribution to journalArticle

Podolsky, AT, Sandweiss, A, Hu, J, Bilsky, EJ, Cain, JP, Kumirov, VK, Lee, YS, Hruby, VJ, Vardanyan, RS & Vanderah, TW 2013, 'Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain', Life Sciences, vol. 93, no. 25-26, pp. 1010-1016. https://doi.org/10.1016/j.lfs.2013.09.016
Podolsky AT, Sandweiss A, Hu J, Bilsky EJ, Cain JP, Kumirov VK et al. Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain. Life Sciences. 2013 Dec 18;93(25-26):1010-1016. https://doi.org/10.1016/j.lfs.2013.09.016
Podolsky, Alexander T. ; Sandweiss, Alexander ; Hu, Jackie ; Bilsky, Edward J. ; Cain, Jim P. ; Kumirov, Vlad K. ; Lee, Yeon Sun ; Hruby, Victor J ; Vardanyan, Ruben S ; Vanderah, Todd W. / Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain. In: Life Sciences. 2013 ; Vol. 93, No. 25-26. pp. 1010-1016.
@article{684fba28dbaf4a0f807510e17e25083d,
title = "Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain",
abstract = "Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids have highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors. Aims: Here we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors. Main methods: Mice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats. Key findings: RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment. Significance This is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists.",
keywords = "Allodynia, Chronic pain, Delta opioid, Fentanyl, Formalin flinch, Hyperalgesia, Inflammatory, Mice, mu opioid, Naloxone, Rat, Spinal nerve ligation",
author = "Podolsky, {Alexander T.} and Alexander Sandweiss and Jackie Hu and Bilsky, {Edward J.} and Cain, {Jim P.} and Kumirov, {Vlad K.} and Lee, {Yeon Sun} and Hruby, {Victor J} and Vardanyan, {Ruben S} and Vanderah, {Todd W}",
year = "2013",
month = "12",
day = "18",
doi = "10.1016/j.lfs.2013.09.016",
language = "English (US)",
volume = "93",
pages = "1010--1016",
journal = "Life Sciences",
issn = "0024-3205",
publisher = "Elsevier Inc.",
number = "25-26",

}

TY - JOUR

T1 - Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain

AU - Podolsky, Alexander T.

AU - Sandweiss, Alexander

AU - Hu, Jackie

AU - Bilsky, Edward J.

AU - Cain, Jim P.

AU - Kumirov, Vlad K.

AU - Lee, Yeon Sun

AU - Hruby, Victor J

AU - Vardanyan, Ruben S

AU - Vanderah, Todd W

PY - 2013/12/18

Y1 - 2013/12/18

N2 - Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids have highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors. Aims: Here we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors. Main methods: Mice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats. Key findings: RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment. Significance This is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists.

AB - Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids have highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors. Aims: Here we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors. Main methods: Mice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats. Key findings: RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment. Significance This is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists.

KW - Allodynia

KW - Chronic pain

KW - Delta opioid

KW - Fentanyl

KW - Formalin flinch

KW - Hyperalgesia

KW - Inflammatory

KW - Mice

KW - mu opioid

KW - Naloxone

KW - Rat

KW - Spinal nerve ligation

UR - http://www.scopus.com/inward/record.url?scp=84889094221&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84889094221&partnerID=8YFLogxK

U2 - 10.1016/j.lfs.2013.09.016

DO - 10.1016/j.lfs.2013.09.016

M3 - Article

C2 - 24084045

AN - SCOPUS:84889094221

VL - 93

SP - 1010

EP - 1016

JO - Life Sciences

JF - Life Sciences

SN - 0024-3205

IS - 25-26

ER -