**4. Animal models of SCS for ischemic pain**

It has been established that SCS modulates vasodilation in the lower limbs and feet dermatomes associated with vertebral segments being stimulated [70]. This has justified SCS as an alternative treatment for nociceptive pain and associated symptoms related to advanced cases of peripheral arterial occlusion disease (PAOD), which leads to ischemia and the subsequent neuropathy due to the lack of blood supply to nerve terminals. Other clinical uses of SCS related to vasodilation modulation include Rynaud's syndrome and angina pectoris. In the absence of a pain model related to PAOD, animal models that measure the modulation of blood flow and vasodilation have been used to demonstrate the mechanism of action of SCS treatment of peripheral vascular diseases. Although there is no evidence that SCS is effective on acute nociceptive pain, the modulation of vasodilation is hypothesized as the mechanism of action for relieving ischemic conditions and recover the flow of nutrients into the affected nerve terminals. Linderoth and Foreman's groups have collaborated to measure the effect of low rate SCS on blood flow changes in the skin dermatomes of the hind paws of anesthetized rats. In one experiment [71], a springloaded monopolar ball cathode was placed in the subdural surface of the L1-L3 dorsal columns (left or right) of anesthetized rats to assess the role of SCS in modulating the sympathetic autonomous system. SCS monophasic pulses (50 Hz, 200 μs PW, 66% of the MT) were applied for 2 minutes. Blood flow was monitored using laserbased doppler probes placed in the glabrous surfaces of the hind paws ipsilateral and contralateral to the stimulation. Another group of animals was subjected to total sympathectomy, while the other was subjected to the ganglionic transmission blocker hexamethonium. In a separate experiment [72], the effect of SCS on the sympathetic nervous system was determined by evaluating the role of ganglionic transmission (with hexamethonium blockade), alpha-adrenergic receptors (phentolamine or prazosin blockade), beta-adrenergic receptors (propanolol blockade), and adrenal catecholamine secretion (adrenal demedullation) in paralyzed anesthetized animals. The left L1-L2 vertebral region was stimulated epidurally with a monopolar ball cathode (0.9 mm diameter) that delivered pulses at 50 Hz, 200 μs PW, and 0.6 mA of intensity. Blood flow was monitored using laser Doppler probes in each hind paw. Although both studies concurred that SCS increases peripheral blood flow in the ipsilateral limb by about 200% concomitant to a reduction of flow resistance of ~50%, there were disagreements in the role of sympathetic contributions, which prompted the formulation of a second hypothesis involving the antidromic activation of the release of vasodilators, such as calcitonin gene-related peptide (CGRP) and nitric oxide. A further report [73] explored the effect of SCS pulse rate on blood flow, finding that pulsing at 500 Hz provided a significant increase of vasodilation relative to pulsing at 200 Hz and 50 Hz at similar pulse widths and intensities. The frequency effect seems to be related to increased release of CGRP, induced by activation of fibers containing the capsaicin receptor (TRPV-1). In conclusion, the reduction of nociceptive lower limb pain due to ischemia has been indirectly associated with SCS-induced vasodilation that provides an increase in blood flow and

the concomitant decrease of flow resistance in the affected limb. It is plausible that vasodilation is due to the release of agents CGRP and nitric oxide from the stimulated fiber afferents and at some extent by modulation of the sympathetic nervous system.
