Spinal and limbic plasticity in the rat during inflammatory nociception and immobilization stress.

摘要

Clinical observations have identified a significant comorbidity between depression and chronic pain, suggesting the affective or emotional component of pain has an impact on cognition. The present study was designed to test the hypothesis that persistent pain generates depression, in part, by chronic activation of the hippocampus, through cellular and molecular mechanisms resembling those activated during stress. Results demonstrate that pain induces significant neuronal plasticity within the limbic system. At the cellular level, nociception altered hippocampal morphology through a robust diminution of neurogenesis in the dentate gyrus (similar to that in various stress models). Furthermore, the neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF), important activators of nociceptive central sensitization, are intimately associated with depression-related processes in the limbic system. Gene expression analyses revealed that nociception reduced levels of both NK-1 receptor and BDNF mRNAs in the hippocampus, suggesting a role for these neuromediators in pain processing in higher brain centers. Decreased hippocampal levels of phosphorylated cAMP response element binding protein (CREB) further suggest that nociception-regulated transcription of NK-1 or BDNF genes may be partially dependent upon common intracellular mechanisms transduced through activation of CREB.; Treatments with the analgesic drug indomethacin reduced nociception-related peripheral edema, hyperalgesia, and reversed the adverse effects of pain on the up-regulation of NK-1 receptor and BDNF gene expression in the spinal cord. However, indomethacin did not protect against down-regulation of these genes in the hippocampus, suggesting that treatment with anti-inflammatory drugs is sufficient to block nociceptive sensory activation, but not that of affective or emotional centers in the brain. Pretreatments with the antidepressant drug imipramine prevented neither pain-related behaviors nor hyperalgesia, but displayed analgesic-like properties in terms of inhibiting nociception-evoked gene expression in the spinal cord and hippocampus.; Altogether, these studies demonstrate that persistent pain induces stress-like cellular and molecular events in the hippocampus, one of the limbic regions involved in the pathophysiology of depression.{09}Targeting these mechanisms (which are potential contributors to the emotional impact of pain) may provide novel therapeutic approaches for relieving depression-like aspects of chronic pain.