Building a Better Analgesic: Multifunctional Compounds that Address Injury-Induced Pathology to Enhance Analgesic Efficacy while Eliminating Unwanted Side Effects

Abstract

The most highly abused prescription drugs are opioids used for the treatment of pain. Physician-reported drug-seeking behavior has resulted in a significant health concern among doctors trying to adequately treat pain while limiting the misuse or diversion of pain medications. In addition to abuse liability, opioid use is associated with unwanted side effects that complicate pain management, including opioid-induced emesis and constipation. This has resulted in restricting long-term doses of opioids and inadequate treatment of both acute and chronic debilitating pain, demonstrating a compelling need for novel analgesics. Recent reports indicate that adaptations in endogenous substance P/neurokinin-1 receptor (NK 1 ) are induced by chronic pain and sustained opioid exposure, and these changes may contribute to processes responsible for opioid abuse liability, emesis, and analgesic tolerance. Here, we describe a multifunctional mu-/delta-opioid agonist/NK 1 antagonist compound [Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bn(CF 3 ) 2 (TY027)] that has a preclinical profile of excellent antinociceptive efficacy, low abuse liability, and no opioid-related emesis or constipation. In rodent models of acute and neuropathic pain, TY027 demonstrates analgesic efficacy following central or systemic administration with a plasma half-life of more than 4 hours and central nervous system penetration. These data demonstrate that an innovative opioid designed to contest the pathology created by chronic pain and sustained opioids results in antinociceptive efficacy in rodent models, with significantly fewer side effects than morphine. Such rationally designed, multitargeted compounds are a promising therapeutic approach in treating patients who suffer from acute and chronic pain.

A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors

“…Unlike our previous studies demonstrating that morphine (i.c.v. dosing) results in a positive condition place preference indicative of the potential of rewarding behavior, 47 tat-CBD3 and myr-tat-CBD3 (10 μg in 5 μL, i.c.v.) did not produce a significant increase in total time per chamber (45.7% ± 7.1% and 46.5% ± 5.9%, respectively; P = 0.76) nor a decrease suggesting lack of conditioned place aversion.…”

“…47 Three-chambered rat-conditioned place preference/aversion (CPP/CPA) apparatus (San Diego Instruments, San Diego, CA) with the following modifications were used: (1) end chamber of horizontal black and white striped walls, smooth floor; (2) end chamber of black walls, rough floor; and (3) middle chamber of neutral gray walls and metal rod flooring. Male Sprague-Dawley rats (200–225 g, Harlan) were implanted with intracerebroventricular cannula (i.c.v.…”

“…Male Sprague-Dawley rats (200–225 g, Harlan) were implanted with intracerebroventricular cannula (i.c.v. 47 ). Although we have previously observed penetration of tat-CBD3 into the brain after an intraperitoneal injection, 9 here we chose the i.c.v.…”

Design of Multivalent Ligands that Cross the Blood Brain Barrier for the Treatment of Neuropathic Pain Without Toxicities

“…In addition, we have demonstrated that these ligands have none of the toxicities associated with morphine long term use including: 1) no motor impairment; 2) no development of tolerance after several days of administration of drug; 3) no development of place preference, an assay for addiction potential after several days of administration; and 4) no inhibition of gut transit (constipation) as well as others [3,4,5].…”

“…To summarize, our 3 compounds show potent analgesic effects in both acute and neuropathic pain models given i.p. or given i.v., and all three compounds cross the blood brain barrier.In addition, we have demonstrated that these ligands have none of the toxicities associated with morphine long term use including: 1) no motor impairment; 2) no development of tolerance after several days of administration of drug; 3) no development of place preference, an assay for addiction potential after several days of administration; and 4) no inhibition of gut transit (constipation) as well as others [3,4,5].We are very excited about these findings which strongly suggest that this multivalent approach to drug has great potential for the development of novel drugs for the treatment of prolonged pain without toxicities or the development of tolerance, and our approach can find applications to other degenerative diseases. …”