Experimental models of peripheral nerve injury have been developed to study mechanisms of neuropathic pain. In the spared nerve injury (SNI) model in rats, the common peroneal and tibial nerves are injured, producing consistent and reproducible pain hypersensitivity in the territory of the spared sural nerve. In this study, we investigated whether SNI in mice is also a valid model system for neuropathic pain. SNI results in a significant decrease in withdrawal threshold in SNI-operated mice. The effect is very consistent between animals and persists for the four weeks of the study. We also determined the relative frequency of paw withdrawal for each of a series of 11 von Frey hairs. Analysis of response frequency using a mixed-effects model that integrates all variables (nerve injury, paw, gender, and time) shows a very stable effect of SNI over time and also reveals subtle divergences between variables, including gender-based differences in mechanical sensitivity. We tested two variants of the SNI model and found that injuring the tibial nerve alone induces mechanical hypersensitivity, while injuring the common peroneal and sural nerves together does not induce any significant increase in mechanical sensitivity in the territory of the spared tibial nerve. SNI induces a mechanical allodynia-like response in mice and we believe that our improved method of assessment and data analysis will reveal additional internal and external variability factors in models of persistent pain. Use of this model in genetically altered mice should be very effective for determining the mechanisms involved in neuropathic pain.

Summary

Ease of genetic manipulation makes the mouse a desirable system for investigating the mechanisms underlying neuropathic pain. While there are few models for neuropathic pain in the mouse, several experimental models of peripheral nerve injury have been developed in the rat. Among these, the spared nerve injury model (SNI)(Decosterd and Woolf, 2000) offers several advantages, including the fact that there is no co-mingling of injured and non-injured nerve fibers distal to the lesion, thus injured and non-injured nerves and territories can be readily identified and manipulated for further analysis, including behavioral assessment, retrograde tracing, and specific nerve treatment or recording (Decosterd et al., 2002). In SNI model, two branches of the sciatic nerve–the common peroneal and tibial nerves–are selectively transected, leaving the sural nerve intact. The injury leads to the development of pain hypersensitivity and cold allodynia in the territory of the spared sural nerve, mimicking the mechanical allodynia/hyperalgesia seen in humans with neuropathic pain. In this study, we investigated whether SNI also induces mechanical allodynia-like behaviors in mice. We also compared the reliability and sensitivity of two different methods for assessing mechanical hypersensitivity in mice: paw withdrawal threshold and relative frequency of paw withdrawal. Finally, we used a mixed effects model for statistical analysis that accounts for multiple variables. The material provided online emphasizes methods used for surgical procedures (photographs) and behavioral assessment (movies) in the SNI model.