Prescription opioid analgesics and non-steroidal anti-inflammatory drugs are frontline treatments for chronic pain. However, inconsistent therapeutic effects and/or side effects limit their use. Development of better analgesics requires predictive and reliable preclinical (animal) models for pain. Although pain is typically associated with pain-evoked behaviors (e.g. withdrawal responses), and pain-suppressed behaviors (e.g. decreases in normally adaptive behaviors like feeding, locomotion, exercise), current preclinical pain models rely almost exclusively on pain-evoked behaviors. This approach has at least two limitations. First, although assays of pain-evoked behavior are thought to be predictive of many acute pain states, they may lack clinical relevance as models of chronic pain. In support of this, assessment of chronic pain in clinical medicine (both human and veterinary) relies heavily on measurement of pain-suppressed behavior to assess the presence and impact of pain, and the effectiveness of treatment. Second, drugs may decrease pain-evoked behaviors not only by reducing the sensory experience of pain (true analgesia), but also by producing motor impairment, which results in """"""""false positive"""""""" effects. A primary goal of this Academic Research Enhancement Award (AREA) application is to address these limitations by developing and validating new animal models that can assess preclinical analgesic efficacy using measures of pain-suppressed behaviors in rodents. A secondary goal of this application is to help facilitate the new PI's career as an independent scientist, and to help further strengthen the undergraduate research environment at the University of New England. It is hypothesized that models of pain-suppressed behavior may capture clinically important aspects of pain that can be missed using standard assays of pain-evoked behaviors. It is also hypothesized that drugs producing motor impairment would not produce """"""""false positive"""""""" analgesic effects in such models. In support of these hypotheses, preliminary data are presented demonstrating that locomotor activity can be reliably suppressed by a standard sub-acute noxious stimulus (i.p. injection of acetic acid), and that pain-suppressed locomotor activity can be selectively restored by a prototype analgesic drug (morphine). I will further validate and extend these findings according to 2 specific aims: (1) Evaluate the effects of osteoarthritis-induced pain on locomotor activity and wheel running and (2) Assess analgesic and non-analgesic drugs on the observed pain-suppressed behaviors in an effort to validate the model. The successful development and validation of the proposed model will facilitate the discovery of more effective drugs for osteoarthritis. Furthermore, the research is likely applicable to the study of all chronic pain states and will help advance our understanding of the broad impact pain has on higher order mammals including humans. This grant proposes a new preclinical strategy for assessing pain and the effectiveness of analgesic drug candidates in rodents that is congruent with current methods of pain assessment in human and veterinary populations. This strategy will complement the more traditional procedures for assessing pain and antinociceptive activity, and help in the development of safer and more effective treatments for chronic pain. ? ? ?
