TY - JOUR
T1 - A large animal neuropathic pain model in sheep
T2 - A strategy for improving the predictability of preclinical models for therapeutic development
AU - Wilkes, Denise
AU - Li, Guangwen
AU - Angeles, Carmina F.
AU - Patterson, Joel T.
AU - Huang, Li Yen Mae
PY - 2012
Y1 - 2012
N2 - Background: Evaluation of analgesics in large animals is a necessary step in the development of better pain medications or gene therapy prior to clinical trials. However, chronic neuropathic pain models in large animals are limited. To address this deficiency, we developed a neuropathic pain model in sheep, which shares many anatomical similarities in spine dimensions and cerebrospinal fluid volume as humans. Methods: A neuropathic pain state was induced in sheep by tight ligation and axotomy of the common peroneal nerve. The analgesic effect of intrathecal (IT) morphine was investigated. Interspecies comparison was conducted by analyzing the ceiling doses of IT morphine for humans, sheep, and rats. Results: Peroneal nerve injury (PNI) produced an 86% decrease in von-Frey filament-evoked withdrawal threshold on postsurgery day 3 and the decrease lasted for the 8-week test period. Compared to the pre-injury, sham, and contralateral hindlimb, the IT morphine dose that produces 50% of maximum analgesia (ED50) for injured PNI hindlimb was 1.8-fold larger and Emax, the dose that produces maximal analgesia, was 6.1-fold lower. The sheep model closely predicts human IT morphine ceiling dose by allometric scaling. This is in contrast to the approximately 10-fold lower morphine ceiling dose predicted by the rat spinal nerve ligated or spared nerve injury models. Conclusion: PNI sheep model has a fast onset and shows stable and long-lasting pain behavioral characteristics. Since the antinociceptive properties of IT morphine are similar to those observed in humans, the PNI sheep model will be a useful tool for the development of analgesics. Its large size and consistent chronic pain behavior will facilitate the development and evaluation of surgical intervention and gene therapy. The PNI sheep pain model provides us with the opportunity for multi-species testing, which will improve the success of clinical trials.
AB - Background: Evaluation of analgesics in large animals is a necessary step in the development of better pain medications or gene therapy prior to clinical trials. However, chronic neuropathic pain models in large animals are limited. To address this deficiency, we developed a neuropathic pain model in sheep, which shares many anatomical similarities in spine dimensions and cerebrospinal fluid volume as humans. Methods: A neuropathic pain state was induced in sheep by tight ligation and axotomy of the common peroneal nerve. The analgesic effect of intrathecal (IT) morphine was investigated. Interspecies comparison was conducted by analyzing the ceiling doses of IT morphine for humans, sheep, and rats. Results: Peroneal nerve injury (PNI) produced an 86% decrease in von-Frey filament-evoked withdrawal threshold on postsurgery day 3 and the decrease lasted for the 8-week test period. Compared to the pre-injury, sham, and contralateral hindlimb, the IT morphine dose that produces 50% of maximum analgesia (ED50) for injured PNI hindlimb was 1.8-fold larger and Emax, the dose that produces maximal analgesia, was 6.1-fold lower. The sheep model closely predicts human IT morphine ceiling dose by allometric scaling. This is in contrast to the approximately 10-fold lower morphine ceiling dose predicted by the rat spinal nerve ligated or spared nerve injury models. Conclusion: PNI sheep model has a fast onset and shows stable and long-lasting pain behavioral characteristics. Since the antinociceptive properties of IT morphine are similar to those observed in humans, the PNI sheep model will be a useful tool for the development of analgesics. Its large size and consistent chronic pain behavior will facilitate the development and evaluation of surgical intervention and gene therapy. The PNI sheep pain model provides us with the opportunity for multi-species testing, which will improve the success of clinical trials.
KW - Interspecies drug scaling
KW - Neuropathic pain model
KW - Ovine
KW - Ovine pain model
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UR - http://www.scopus.com/inward/citedby.url?scp=84874976029&partnerID=8YFLogxK
U2 - 10.2147/JPR.S34977
DO - 10.2147/JPR.S34977
M3 - Article
C2 - 23166445
AN - SCOPUS:84874976029
SN - 1178-7090
VL - 5
SP - 415
EP - 424
JO - Journal of Pain Research
JF - Journal of Pain Research
ER -