**5. Translational equivalence of animal models**

Besides rodent (mostly rat) models, there have been reports of SCS effects on ovine models of neuropathic pain. As presented in section 2.1 above, Reddy et al. [17] reported on the utilization of female sheep to develop a CCI model to study the effect of tonic SCS. The advantage of using a large animal model is that it provides a way to bridge the translation of SCS parameters toward clinical application for longer exposures in anatomical environments that are more similar to that of humans. These authors found that the model provided a significant reduction of mechanical hypersensitivity upon continuous SCS for one week. A closer examination of the

#### **Figure 10.**

*Top row: Mechanical hypersensitivity of rats subjected to SCS with a DTMP approach in comparison with untreated animals (No SCS) and corresponding areas under the curve (AUC). Bottom row: equivalent measurement obtained from sheep. \* denotes significant differences (p < 0.05) between treated and untreated animals.*

reported data for 5 animals, reveals that one of them was a non-responder to the pain model since there was not a decrease of the limb withdrawal threshold (WT). If data from this animal is discarded, the CCI model reduced the WT to a mean 51% (± 6%) relative to the mean WT of the control measurements in the contralateral limb. The mean WT of the responders after SCS corresponded to 85% (± 13%) of the mean WT of the control. This is consistent with the findings in rodents, although a direct comparison is not possible because there are not reports on rodent CCI models with continuous SCS.

Vallejo et al. [74] reported on a comparison of the effect of SCS based on the DTMP approach on a rat and sheep models after 24 and 48 h of continuous treatment. The pain model in the rats was the SNI as previously described [42, 43], while the sheep model is the equivalent peroneal nerve injury (PNI) developed by Wilkes et al. [75] and adapted for SCS by implanting a cylindrical octapolar human-grade lead (1.3 mm diameter) in the L1-L3 epidural space. DTMP consisted of multiplexing 4 pulsed signals with frequencies in the 50 Hz to 1.2 kHz and PW of 200 μs at an intensity of 50% of the MT. Mechanical hypersensitivity was obtained before starting SCS, as well as at 24 h and 48 h of continuous SCS, using an electronic von Frey anesthesiometer. In order to compare rodent and ovine results, the WT were normalized to the pre-SCS values (**Figure 10**). Rodent data is for individual subjects (N = 13). Ovine data is from two sheep that were evaluated in a crossover experiment, in which one sheep was stimulated while the other one served as a No-SCS control. After a one-week break for washing out the effects of SCS, the animal that had not been treated was subjected to SCS while the other one was the No-SCS control. This process was repeated until obtaining a set of six measurements.

DTMP significantly relieved mechanical hypersensitivity in the rat model equivalent to 78.6% at 24h and 77.3% at 48 h in the rat model relative to the pre-SCS and No-SCS measurements. Similar effects were seen in the sheep model where the decrease in mechanical hypersensitivity was 84.8% at 24h and 73.7% at 48 h. These results demonstrate translational equivalence between two animal models of neuropathic pain for the first time.
