**1. Introduction**

The field of electrical neuromodulation was developed under the hypothesis that the activation of large, myelinated nerve fibers could modulate sensory nociceptive signals carried by A-delta and C nerve fibers into the dorsal horn in the spinal cord. The gate control theory (GCT) formulated by Melzack and Wall [1], served as inspiration for the use of peripheral nerve stimulation and spinal cord stimulation (SCS) to treat pain. The simplicity of the proposed mechanism, based on the understanding of pain in 1965, granted researchers with the ability to formulate finite mathematical and complex computational models to assess the effects of different variables of the electrical signal on the neuronal conduction. The GCT's enduring value in neuromodulation for more than 50 years is due to its simplicity and utility as a working tool to postulate therapies to patients in pain. Unfortunately, as the German psychologist Wolfgang Köhler explains: "premature simplifications and systematization in science, could ossify science and prevent vital growth" [2].

The early 1990s marked the beginning of a revolution in the field of neuroscience in understanding the mechanism of pathological pain from a molecular perspective. The use of animal models has helped unravel the role of neuroinflammatory

processes driven by glial cells in the development and maintenance of chronic neuropathic pain. Those advances though, were largely neglected in the field of electrical neuromodulation, which remained focused on the effects of electrical signals on neuronal conduction, ignoring the benefit of understanding how these signals could affect biological processes at the neuron-glia interaction. The differential electrophysiological characteristics of neurons and glial cells is now at the core of our quest to understand how electrical signals affect such biological processes. To begin with, the resting membrane potential of these cell populations is different, driven by the fact that the main neuronal intracellular cation is potassium, while sodium is the predominant one in glial cells [3]. Considering the critical roles that various specialized glial cell populations play in the intimate communication between neurons and glial cells, it is pertinent to briefly describe these roles. Following peripheral injury, persistent release of neurotransmitters at the synaptic cleft activates microglial and astrocyte membrane receptors generating transcriptional changes that generate the synthesis and release of pro-inflammatory and anti-inflammatory cytokines. Astrocytes are critical to maintain homeostasis at the synapse. The synaptic cleft is surrounded by astroglial perisynaptic processes in what is now known as the tripartite synapse. Perisynaptic glial processes are densely packed with numerous transporters, which provide proper homeostasis of ions and neurotransmitters in the synaptic cleft, for local metabolism support, and for release of astrogliaderived scavengers of oxygen species [4]. For example, membrane ionotropic and metabotropic glutamate receptors in the astrocyte regulate glutamate concentration. Interestingly, a single astrocyte provides processes that extend over distance to surround over 100,000 synapses. During intense neuronal firing, the release of neurotransmitters, such as glutamate and GABA, induces the elevation of calcium ion concentrations in glial cells, causing Ca2+-dependent release of molecules that affects neural excitability and synaptic transmission and plasticity. Even more thoughtprovoking is that although astrocytes are unable to generate action potentials, they can raise intracellular calcium concentrations that spread from astrocyte to astrocyte through gap channels that allow propagation of so-called calcium waves as a way of cell-to-cell communication. The presence of Ca2+mobilizations mediated by astrocytes implies that glial cells have some excitability and neuromodulator activities [5]. Finally, oligodendrocytes provide myelin to hundreds of surrounding axons and are known to affect the conduction velocity of action potentials propagating along the axons they surround when electrically stimulated [6].

An important distinction between glial cells and neurons is that glial cells depolarize following electrical stimulation, but do not generate action potentials. In 1981, Roitbak and Fanardjian [7] demonstrated in a live feline model that changes in the frequency and intensity of the applied pulsed electrical signals could lead to differential degrees of astrocytic depolarization. Another interesting clue on how electrical signals could affect glial cells was provided by Agnesi et al. [8], in an experiment with anesthetized rats that showed that changing the repolarization of an electrical stimulation signal from monophasic to a biphasic led to different degrees of glutamate release by the stimulated astrocytes.

The complexity of changes in neuron-glial biological processes triggered by pain and further modulation by electrical stimulation demands the use of experimental animal models. Testing such hypotheses in humans would require large-scale, wellcontrolled clinical trials because of the heterogeneity of genetics and pain etiology in the general population [9].

The notable anatomical, biological, and physiological resemblances between humans and animals, predominantly mammals, have encouraged researchers to investigate a large range of mechanisms and assess novel therapies in animal models before applying their discoveries to humans.

*Animal Pain Models for Spinal Cord Stimulation DOI: http://dx.doi.org/10.5772/intechopen.96403*

Scientists cross-examine organisms at multiple levels: molecules, cells, organs, and physiological functions in healthy or diseased conditions. Advance molecular technologies are required to get a complete portrayal and understanding of the mechanisms. Certain aspects of the responses can be evaluated using in vitro approaches (e.g., cell culture). On the other hand, the exploration of physiological functions and systemic interactions between organs requires a whole organism.

This chapter explores the efforts of diverse research groups to understand from a behavioral and molecular perspective, how spinal cord stimulation affects pathological pain by utilizing animal models. This research may provide strong hypotheses on what may be happening in humans and ways to continue improving therapeutic efficacy.

The following sections provide a description of existing, well-validated models for pain caused by neuropathies, inflammation, and ischemic conditions. Due to technical limitations, most of these are based on *Rattus norvegicus*, although recently models in a larger animal (*Ovis aries*) have been developed.
