ERK1/2: Function, signaling and implication in pain and pain-related anxio-depressive disorders

• Spinal ERK1/2 activation occurs in pain and its blockade is related with analgesia.
• Supraspinal ERK1/2 activation is implicated in pain and anxio-depressive disorders.
• Blockade of ERK1/2 cascade differentially affects pain and pain-related features.
• ERK1/2 activation is a good marker to study the anxio-depressive phenotype in pain.
• ERK1/2 manipulation therapy for pain-related anxio-depression is a possibility.

Despite the increasing knowledge regarding pain modulation, the understanding of the mechanisms behind a complex and pathologic chronic pain condition is still insufficient. These knowledge gaps might result in ineffective therapeutic approaches to relieve painful sensations. As a result, severe untreated chronic pain frequently triggers the onset of new disorders such as depression and/or anxiety, and therefore, both the diagnosis and treatment of patients suffering from chronic pain become seriously compromised, prompting a self-perpetuating cycle of symptomatology. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are molecules strongly implicated in the somatic component of pain at the spinal cord level and have been emerging as mediators of the emotional-affective component as well. Although these molecules might represent good biomarkers, their use as pharmacological targets is still open to discussion as paradoxical information has been obtained. Here we review the current scientific literature regarding ERK1/2 signaling in the modulation of pain, depression and anxiety, including the emotional-affective spheres of the pain experience.