Alpha-Adrenoceptor Modulation in Central Nervous System Trauma: Pain, Spasms, and Paralysis - An Unlucky Triad

Abstract

Many researchers have attempted to pharmacologically modulate the adrenergic system to control locomotion, pain, and spasms after central nervous system (CNS) trauma, although such efforts have led to conflicting results. Despite this, multiple studies highlight that α-adrenoceptors (α-ARs) are promising therapeutic targets because in the CNS, they are involved in reactivity to stressors and regulation of locomotion, pain, and spasms. These functions can be activated by direct modulation of these receptors on neuronal networks in the brain and the spinal cord. In addition, these multifunctional receptors are also broadly expressed on immune cells. This suggests that they might play a key role in modulating immunological responses, which may be crucial in treating spinal cord injury and traumatic brain injury as both diseases are characterized by a strong inflammatory component. Reducing the proinflammatory response will create a more permissive environment for axon regeneration and may support neuromodulation in combination therapies. However, pharmacological interventions are hindered by adrenergic system complexity and the even more complicated anatomical and physiological changes in the CNS after trauma. This review is the first concise overview of the pros and cons of α-AR modulation in the context of CNS trauma.

Breaking barriers to novel analgesic drug development

“…From pharmacological studies and null mice, α2 receptors seem to play a role in diverse painful syndromes due to an inhibition of presynaptic release of neuropeptides in the spinal cord and action on microglia 102–106 . However, pontine α2 adrenergic activation increases pain by attenuating descending inhibition 107 .…”