neuropeptide-y and Hypesthesia

Dorsal root injuries (DRIs), resulting in the permanent disconnection of nerve roots from the spinal cord, lead to sensory impairments, including both the loss of sensation and the development of neuropathic pain in the affected limb. DRI results in axonal sprouting of intraspinal serotonergic fibers, but the functional consequences of this response to spinal deafferentation remains unclear. Here we aimed to clarify the role of descending serotonergic projections in both mechanosensation and pain following DRI. By ablating serotonergic input to the spinal cord via 5,7-dihydroxytryptamine (5,7-DHT) prior to DRI in rats, we found that serotonergic input to the dorsal horn normally inhibits the recovery of mechanosensation but has no effect on the development or resolution of cold pain. Endogenous brain-derived neurotrophic factor (BDNF) is upregulated by activated microglia, is required for sprouting of serotonergic axons and neuropeptide tyrosine (NPY)-positive interneurons, and suppresses mechanosensory recovery following DRI. Intriguingly, we found that the density of activated microglia, the amount of BDNF protein, and density of NPY-positive processes were all significantly reduced in 5,7-DHT-treated rats, suggesting that serotonergic input to the deafferented dorsal horn is required for all of these consequences of spinal deafferentation. These results indicate that BDNF-dependent serotonergic and/or increases in NPY-positive fiber density slows, and ultimately halts, mechanosensory recovery following DRI.

Topics: 5,7-Dihydroxytryptamine; Animals; Brain; Brain-Derived Neurotrophic Factor; Calcitonin Gene-Related Peptide; Disease Models, Animal; Hyperalgesia; Hypesthesia; Lectins; Male; Microglia; Neuropeptide Y; Pain Threshold; Peripheral Nervous System Diseases; Physical Stimulation; Rats; Rats, Sprague-Dawley; Recovery of Function; Rhizotomy; Serotonin; Serotonin Agents; Serotonin Plasma Membrane Transport Proteins; Spinal Cord; Spinal Nerve Roots; Tyrosine 3-Monooxygenase; Up-Regulation; Vesicular Glutamate Transport Protein 1

Vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) in dorsal root ganglia (DRGs) are known to be upregulated and to contribute to the mechanisms of neuropathic pain following peripheral nerve injury. Moreover, transcription factor c-Jun regulates the expressions of both VIP and NPY in cultured DRG neurons. To elucidate the role of c-Jun in the induction of neuropathic pain hypersensitivity, we examined whether activated c-Jun affects pain behavior and the expressions of VIP and NPY following chronic constriction injury (CCI) of rat sciatic nerve. Intrathecal treatment with c-jun antisense oligodeoxynucleotides (AS-ODN) significantly reduced mechanical allodynia, but not thermal hyperalgesia following CCI. In addition, c-jun AS-ODN also suppressed the remarkable elevations of VIP and NPY mRNAs and the percentages of phosphorylated c-Jun-, VIP-, and NPY-immunoreactive neurons observed in DRGs following CCI. These results show that the activation of c-Jun in DRGs induces VIP and NPY upregulation and contributes to the pathogenesis of neuropathic pain following CCI.

Topics: Animals; Constriction, Pathologic; Ganglia, Spinal; Hot Temperature; Hypesthesia; Immunohistochemistry; Male; Neuralgia; Neurons; Neuropeptide Y; Oligonucleotides, Antisense; Phosphorylation; Physical Stimulation; Proto-Oncogene Proteins c-jun; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sciatic Nerve; Time Factors; Up-Regulation; Vasoactive Intestinal Peptide