title: A preclinical physiological assay to test modulation of knee joint pain in the spinal cord: effects of oxycodone and naproxen.
abstract: Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain.
authors.affiliation: Neusentis Research Unit, Pfizer, Cambridge, United Kingdom.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Miranda
authors.affiliation: Research Statistics, Clinical Research, Pfizer, Cambridge, United Kingdom.
authors.forename: Phil
authors.initials: P
authors.lastname: Stanley
authors.affiliation: Research Statistics, Clinical Research, Pfizer, Cambridge, United Kingdom.
authors.forename: Katrina
authors.initials: K
authors.lastname: Gore
authors.affiliation: Neusentis Research Unit, Pfizer, Cambridge, United Kingdom.
authors.forename: Jamie
authors.initials: J
authors.lastname: Turner
authors.affiliation: Neusentis Research Unit, Pfizer, Cambridge, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dias
authors.affiliation: Neusentis Research Unit, Pfizer, Cambridge, United Kingdom.
authors.forename: Huw
authors.initials: H
authors.lastname: Rees
mesh_terms: D000200:Action Potentials; D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018771:Arthralgia / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D007719:Knee Joint / Q000473:pathology*; D008297:Male; D009288:Naproxen / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010098:Oxycodone / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058748:Pain Perception; D017207:Rats, Sprague-Dawley; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000503:physiopathology
chemical_list: D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009288:Naproxen; D010098:Oxycodone