Rosa Maria A Simmons1, Beth Forster2, Wenhong Guo3, Kelly L Knopp4. 1. Neuroscience Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: simmons-rma@lilly.com. 2. Neuroscience Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: forster_beth_marie@lilly.com. 3. Neuroscience Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: guo_wenhong@lilly.com. 4. Neuroscience Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: knopp_kelly_l@lilly.com.
Abstract
BACKGROUND: The rat L5/L6 spinal nerve ligation model (SNL) has been widely used to investigate putative analgesics. Pursuit of novel therapies in preclinical settings requires models with consistent and reproducible phenotypes. NEW METHOD: We assessed the effects of repetitive stimulation of the hindpaws of SNL and Sham surgery rats during the 2 weeks immediately after surgery on the overall rate of achieving tactile hypersensitivity, as well as the magnitude of the hypersensitivity compared to unprimed rats. Beginning on day 2 post-surgery, and continuing on alternate days for a total of seven sessions, animals underwent light brushing/tapping (termed priming) of the hindpaws ipsilateral and contralateral to surgery. RESULTS: Priming the ipsilateral hindpaw enhanced the magnitude of tactile hypersensitivity such that the baseline withdrawal threshold (BWT) for primed SNL animals was significantly lower than unprimed SNL animals over post-surgical days 15-29. BWT was not different between primed and unprimed Sham rats. The percentage of SNL primed animals meeting the a priori criterion for tactile hypersensitivity of paw withdrawal threshold less than 2.0 grams was 98.9%±1.1%. COMPARISON WITH EXISTING METHOD: SNL rats that did not receive stimulation (unprimed) showed significantly higher baseline hypersensitivity when evaluated on days 15-29, exemplified by only 34.5%±7.2% meeting the established <2.0g criterion. CONCLUSION: Our data indicate that tactile priming during the 2 weeks immediately after SNL surgery enhances the magnitude of tactile hypersensitivity in the SNL model, and provide an optimized assay for evaluating putative analgesics.
BACKGROUND: The rat L5/L6 spinal nerve ligation model (SNL) has been widely used to investigate putative analgesics. Pursuit of novel therapies in preclinical settings requires models with consistent and reproducible phenotypes. NEW METHOD: We assessed the effects of repetitive stimulation of the hindpaws of SNL and Sham surgery rats during the 2 weeks immediately after surgery on the overall rate of achieving tactile hypersensitivity, as well as the magnitude of the hypersensitivity compared to unprimed rats. Beginning on day 2 post-surgery, and continuing on alternate days for a total of seven sessions, animals underwent light brushing/tapping (termed priming) of the hindpaws ipsilateral and contralateral to surgery. RESULTS: Priming the ipsilateral hindpaw enhanced the magnitude of tactile hypersensitivity such that the baseline withdrawal threshold (BWT) for primed SNL animals was significantly lower than unprimed SNL animals over post-surgical days 15-29. BWT was not different between primed and unprimed Sham rats. The percentage of SNL primed animals meeting the a priori criterion for tactile hypersensitivity of paw withdrawal threshold less than 2.0 grams was 98.9%±1.1%. COMPARISON WITH EXISTING METHOD: SNL rats that did not receive stimulation (unprimed) showed significantly higher baseline hypersensitivity when evaluated on days 15-29, exemplified by only 34.5%±7.2% meeting the established <2.0g criterion. CONCLUSION: Our data indicate that tactile priming during the 2 weeks immediately after SNL surgery enhances the magnitude of tactile hypersensitivity in the SNL model, and provide an optimized assay for evaluating putative analgesics.
Authors: J M Witkin; R Cerne; P G Davis; K B Freeman; J M do Carmo; J K Rowlett; K R Methuku; A Okun; S D Gleason; X Li; M J Krambis; M Poe; G Li; J M Schkeryantz; R Jahan; L Yang; W Guo; L K Golani; W H Anderson; J T Catlow; T M Jones; F Porreca; J L Smith; K L Knopp; J M Cook Journal: Pharmacol Biochem Behav Date: 2019-02-27 Impact factor: 3.533