Accepted

Spinal cord injury (SCI) is a tragic event causing irreversible losses of sensory, motor, and autonomic functions, that may also be associated with chronic neuropathic pain. Serotonin (5-HT) neurotransmission in the spinal cord is critical for modulating sensory, motor, and autonomic functions. Following SCI, 5-HT axons caudal to the lesion site degenerate, and the degree of axonal degeneration positively correlates with lesion severity. Rostral to the lesion, 5-HT axons sprout, irrespective of the severity of the injury. Unlike callosal fibers and cholinergic projections, 5-HT axons are more resistant to an inhibitory milieu and undergo active sprouting and regeneration after central nervous system (CNS) traumatism. Numerous studies suggest that a chronic increase in serotonergic neurotransmission promotes 5-HT axon sprouting in the intact CNS. Moreover, recent studies in invertebrates suggest that 5-HT has a pro-regenerative role in injured axons. Here we present a brief description of 5-HT discovery, 5-HT innervation of the CNS, and physiological functions of 5-HT in the spinal cord, including its role in controlling bladder function. We then present a comprehensive overview of changes in serotonergic axons after CNS damage, and discuss their plasticity upon altered 5-HT neurotransmitter levels. Subsequently, we provide an in-depth review of therapeutic approaches targeting 5-HT neurotransmission, as well as other pre-clinical strategies to promote an increase in re-growth of 5-HT axons, and their functional consequences in SCI animal models. Finally, we highlight recent findings signifying the direct role of 5-HT in axon regeneration and suggest strategies to further promote robust long-distance re-growth of 5-HT axons across the lesion site and eventually achieve functional recovery following SCI.

Today's treatment for chronic pain is inadequate, and novel targets need to be identified. This requires a better understanding of the mechanisms involved in pain sensitization and chronification. In this review, we discuss how peripheral inflammation, as occurs during an infection, modulates the central pain system. In rodents, neonatal inflammation leads to increased pain sensitivity in adulthood by priming immune components both peripherally and centrally. The excitability of neurons in the spinal cord is also altered by neonatal inflammation and may add to pain sensitization later in life. In adult humans, inflammation modulates pain sensitivity as well, partly by affecting the activity in brain areas that process and regulate pain signals. Low-grade inflammation is common in clinical populations both peripherally and centrally, and priming of the immune system has also been suggested in some pain populations. The nociceptive and immune systems are primed by infections and inflammation. The early life programming of nociceptive responses following exposure to infections or inflammation will define individual differences in adult pain perception. Immune-to-brain mechanisms and neuroimmune pathway need further investigation as they may serve both as predictors and therapeutic targets in chronic pain.