Background & Aims
The Preclinical Screening Platform for Pain (PSPP) was developed as part of the National Institutes of Health Helping to End Addiction LongtermSM Initiative, or NIH HEAL InitiativeSM, with the goal of accelerating the discovery and development of non-opioid, non-addictive pain therapeutics. Toward this goal, the PSPP program accepts small molecules, biologics, natural products, and devices from industry, academic, or government asset owners worldwide for preclinical evaluation at no cost to the asset owner. Additionally, the PSPP program aims to disseminate information regarding best practices and to share data, enabling rigorous preclinical research in the development of potential pain therapeutics. Toward this goal, the PSPP program has developed a public-facing website featuring information about the program, methods for assays, models, and endpoints used in the program, and data generated for clinically used drugs and CNS active compounds.
Methods
In collaboration with PsychoGenics Inc. (PGI), carbamazepine (3-300 mg/kg, PO), celecoxib (3-100 mg/kg, PO), diazepam (1-30 mg/kg, PO), diclofenac sodium (1-100 mg/kg, PO), duloxetine hydrochloride (3-100 mg/kg, PO), gabapentin (10-300 mg/kg, PO), ketoprofen (0.3-10 mg/kg, PO), morphine sulfate (0.3-10 mg/kg, SC), naproxen sodium (1-100 mg/kg, PO), nalfurafine hydrochloride (1-3,000 µg/kg, SC), pregabalin (10-100 mg/kg, PO), and resatorvid (1-100 mg/kg, SC) were evaluated using the PSPP workflow, including in vitro assessment of safety and abuse liability and protein binding and in vivo assessment of pharmacokinetics, side effect profile, efficacy in pain-related models, and/or abuse liability. All in vivo studies were completed using male and female Sprague Dawley rats (Envigo), in fully powered groups. Experimenters were blinded to treatment, each study included vehicle and positive control groups, and pre-determined inclusion criteria were applied for each endpoint assessed.
Results
Data from clinically used drugs and CNS active compounds listed above and assessed in the PSPP workflow have been published on our interactive, publicly accessible website and data from representative examples will be presented. One such example, morphine, was assessed in in vitro functional activity screens and showed agonist activity at human mu opioid receptor. In a pharmacokinetics study, morphine (6 mg/kg, SC) plasma levels peaked at 0.25 h with a Cmax of approximately 7 µM. Using 1-10 mg/kg, the Irwin functional behavior assay showed dose-dependent sedative effects in both sexes, and males showed decreased latency to fall in the rotarod. Dose- and time-dependent analgesic efficacy was demonstrated after assessing the effects of 0.3-6 mg/kg in 2 endpoints each in of 5 validated pain-related models, including acute, chronic, and disease-specific pain models. Full data sets are available for 12 compounds, including in vivo abuse liability evaluated for selected drugs.
Conclusions
The PSPP program and public-facing website (https://pspp.ninds.nih.gov/) are resources available to the global community developing potential pain therapeutics with the goal of accelerating the development of new, non-opioid, non-addictive pain therapeutics. The program website details the optimized and validated methods for the assays, models, and endpoints used within the program and outlines how assets move through the PSPP workflow. Further, through the website, the PSPP program is sharing the rigorously collected data for clinically used and CNS active drugs. The data represent different classes of drugs and demonstrate the various profiles of efficacy taking into consideration potential side effects and exposure.
References
https://pspp.ninds.nih.gov/