Measuring Behavior 2005: Bilsky

Targeting pain-suppressed behaviors in preclinical assays of pain and analgesia

E.J. Bilsky

Department of Pharmacology, University of New England, Biddeford, ME, USA

Effective management of pain continues to be a clinical challenge. Industry and academic laboratories have invested significant resources into identifying novel targets, synthesizing small molecule drug candidates, and performing preclinical/clinical assessments of lead candidates. The introduction of novel pharmacotherapies has, however, been rather limited, with several advanced-stage candidates failing in phase III clinical trials. One potential limitation in the drug discovery process is the manner in which drug candidates are tested in preclinical models of nociception, with an emphasis being placed on pain-evoked behaviors in rodents. Our laboratories are developing assays that focus on pain-suppressed behaviors that may complement traditional methods. Here we present results that compare the effects of i.p. acetic acid on a pain-evoked behavior (writhing) and a pain-suppressed behavior (locomotor activity-LMA and feeding) in two strains of mice (ICR and C57BL/6J). Acetic acid (0.18-0.56%) produced concentration- and time-dependent increases in writhing and decreases in LMA and feeding. The potency of acetic acid was similar for producing these effects, but decreases in LMA and feeding lasted longer than increases in writhing. Interestingly, a high concentration of acetic acid (1% acid) produced less writhing than lower concentrations, whereas the highest concentrations of acetic acid tested produced maximal suppression of LMA and feeding. Morphine produced dose-related restoration of feeding at doses that did not significantly affect feeding in control animals. This effect was selectively reversed by the opioid antagonist naltrexone. For the LMA measure, the effects of morphine were confounded by the drug’s propensity to stimulate LMA by itself. When comparing baseline levels of activity for the respective controls, morphine produced an upward and leftward shift in the LMA dose-response curve under pain conditions. The doses of morphine tested also reduced the number of abdominal writhes in a dose-dependent fashion. We are currently testing a number of other analgesic drugs, along with drugs that produce false positives, in this assay. These studies of pain-suppressed behaviors may help improve the predicative reliability of preclinical antinociceptive assays.

Paper presented at Measuring Behavior 2005 , 5^th International Conference on Methods and Techniques in Behavioral Research, 30 August - 2 September 2005, Wageningen, The Netherlands.