Chronic pain after spinal cord injury (SCI) is a form of central neuropathic pain that is debilitating and often refractory to current pharmacological treatments. Neurostimulation pain therapies, such as epidural spinal cord stimulation, have only moderate success in reducing SCI pain. The pathogenesis of SCI pain may involve a state of central neuronal hyperexcitability, especially in the spinal cord dorsal horn, that develops after injury. We hypothesize that the neuronal structures near the spinal cord injury site may be an important pain generator, and intraspinal microstimulation (ISMS) may normalize dorsal horn neuronal hyperexcitability and hence alleviate SCI pain. Specifically, ISMS may induce frequency-dependent conduction block on axons of afferent sensory neurons, in the spinothalamic tract and Lissauer's tract. ISMS may also facilitate primary afferent depolarization that elicits presynaptic inhibition of incoming afferent inputs. Together, these actions will reduce abnormal afferent inputs and ascending pain signals before they can reach the brain. Furthermore, ISMS may directly induce inhibitory postsynaptic potentials in dorsal horn neurons, and trigger the release of endogenous inhibitory neurotransmitters, opioids and serotonin to inhibit postsynaptic neurons and restore the compromised segmental pain inhibition after SCI. Finally, ISMS may alter the frequency and pattern of discharge such that the rostrally conducted impulses no longer code pain or activate brain areas concerned with pain signaling. Based on recent progress in,understanding spinal learning and plasticity, we also postulate that repetitive or long-term ISMS may help the dorsal horn "reset" neuronal excitability and regain normal pain processing for a prolonged period. By finely tuning the stimulation parameters (e.g., intensity, pulse width, frequency), position, and geometry of ISMS electrode, multiple spinal structures (e.g., dorsal horn, dorsal column, spinothalamic tract) may be modulated to induce synergistic pain inhibition. Our hypothesis can be readily tested in preclinical models of SCI pain by using a combination of in vivo electrophysiological (neuronal activity) and animal behavioral (pain response) approaches. Since ISMS electrodes stimulate the spinal structures directly, we expect that the effective stimulus intensity and energy consumption can be lower than that for epidural spinal cord stimulation. The proposed hypothesis may provide insights and rationales for developing a novel neurostimulation pain therapy by directly inhibiting the pain generators in the spinal cord, and ISMS may be an alternative strategy to treat SCI pain. (C) 2017 Elsevier Ltd. All rights reserved.