Background & Aims
The National Institutes of Health Helping to End Addiction Long-termSM Initiative, or NIH HEAL InitiativeSM, Preclinical Screening Platform for Pain (PSPP) program aims to accelerate the discovery and development of novel non-opioid, non-addictive pain therapeutics. The PSPP program accepts small molecules, biologics, natural products and devices from industry, academia or government asset owners. In collaboration with PsychoGenics, Inc., assets are evaluated to determine in vitro functional properties, pharmacokinetics, side effect profile, abuse liability, and efficacy in preclinical pain models. Efforts in the PSPP program are also focused on the characterization and optimization of disease-specific models to provide support for specific pain indications. Here, we describe one such effort to characterize the behavioral pain phenotype and pharmacology of the rat monoiodoacetate (MIA) model of osteoarthritis pain.
Methods
Adult male and female Sprague Dawley rats (n=10, each sex) were used in these studies. For the MIA model, MIA (1 – 4.5 mg) was injected intraarticularly into the left hindlimb knee joint. Behavioral pain endpoints included examination of hind paw mechanical allodynia, knee joint mechanical allodynia and dynamic weight bearing deficits. Behavioral pain phenotype in these studies was evaluated for 4-6 weeks following the induction of osteoarthritis. Pharmacology was examined by evaluating dose-dependent effects of the reference analgesics morphine sulfate (0.3 – 6 mg/kg, SC), ketoprofen (0.3 – 6 mg/kg, PO), celecoxib (3 – 30 mg/kg, PO), gabapentin (10 – 100 mg/kg, PO, pregabalin (10 – 60 mg/kg, PO) and duloxetine (3 – 60 mg/kg, PO). Effects of reference analgesics on hind paw mechanical allodynia and dynamic weight bearing deficits were determined following single and repeated administration during Week 1. Data were analyzed using two-way repeated measures ANOVA with Bonferroni’s or
Results
Intraarticular injection of MIA (1- 4.5 mg) into the hindlimb knee joint produced unilateral hind paw mechanical allodynia in male and female rats which was maximal by Weeks 1-2. Unilateral knee joint mechanical allodynia to a pressure stimulus was observed in female, but not male, rats at Weeks 1-2. Dynamic hind paw weight bearing deficits associated with the affected hind limb were maximal at Week 1, and weight bearing deficits in male rats were observed during Weeks 1-6, whereas weight bearing deficits in female rats were no longer observed by Week 4. In Week 1, single administration of morphine, gabapentin, and pregabalin reduced mechanical allodynia, whereas single administration of morphine and celecoxib reduced dynamic weight bearing deficits. Repeated administration of ketoprofen, duloxetine, gabapentin, and pregabalin reduced mechanical allodynia, whereas repeated administration of ketoprofen, celecoxib, and duloxetine reduced dynamic weight bearing deficits
Conclusions
The behavioral phenotype data from these studies demonstrate that hind paw mechanical allodynia and dynamic weight bearing deficits can be reliably measured in male and female Sprague Dawley rats, whereas knee joint mechanical allodynia is less robust and not apparent in male rats. The reference analgesic data from these studies demonstrate different pharmacology when comparing effects on mechanical allodynia and weight bearing deficits and support the use of both endpoints for pharmacological characterization of novel assets. Additionally, reference analgesics exhibited generally greater efficacy following repeated administration in comparison to single administration. Characterization of the pharmacology and behavioral phenotype associated with the rat MIA model of osteoarthritis will support the use of this model to accelerate the development of novel treatments for osteoarthritis pain.
References
Pomonis JD, Boulet JM, Gottshall SL, Phillips S, Sellers R, Bunton T and Walker K (2005) Development and pharmacological characterization of a rat model of osteoarthritis pain. Pain 114:339.
Presenting Author
Mark Urban
Poster Authors
Taleen Hanania
PhD
Psychogenics Inc.
Lead Author
Yangmiao Zhang
Ph.D.
PsychoGenics, Inc.
Lead Author
Tolga Berkman
B.S.
PsychoGenics, Inc.
Lead Author
Elizabeth Dugan
Ph.D.
PsychoGenics, Inc.
Lead Author
Katelyn Buban
M.S.
PsychoGenics, Inc.
Lead Author
Jennifer Hagedorn
B.S.
PsychoGenics, Inc.
Lead Author
Menarva Matar
PsychoGenics
Lead Author
Lynn Zhao
PsychoGenics
Lead Author
Kyle Krozser
PsychoGenics
Lead Author
Morgan Woods
PsychoGenics
Lead Author
Matia Ciklic
PsychoGenics
Lead Author
Sarah Woller
Ph.D.
NINDS/NIH
Lead Author
Smriti Iyengar
PhD.
NINDS
Lead Author
Mark Urban
Ph.D.
Psychogenics Inc.
Lead Author
Topics
- Models: Musculoskeletal