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

Life sciences (2013-10-03)
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
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. 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. 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. RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment. 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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Fentanyl solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Sigma-Aldrich
Naloxone hydrochloride dihydrate, ≥98% (TLC and titration), powder
Sigma-Aldrich
Fentanyl citrate salt
Supelco
Fentanyl solution, 100 μg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Supelco
Naloxone solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Supelco
Naltrexone solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®