Deletion of the neuropeptide Y Y1 receptor affects pain sensitivity, neuropeptide transport and expression, and dorsal root ganglion neuron numbers.
Neuropeptide Y has been implicated in pain modulation and is substantially up-regulated in dorsal root ganglia after peripheral nerve injury. To identify the role of neuropeptide Y after axotomy, we investigated the behavioral and neurochemical phenotype of neuropeptide Y Y1 receptor knockout mice with focus on dorsal root ganglion neurons and spinal cord. Using a specific antibody Y1 receptor immunoreactivity was found in dorsal root ganglia and in dorsal horn neurons of wild-type, but not knockout mice. The Y1 receptor knockout mice exhibited a pronounced mechanical hypersensitivity. After sciatic nerve axotomy, the deletion of Y1 receptor protected knockout mice from the axotomy-induced loss of dorsal root ganglion neurons seen in wild-type mice. Lower levels of calcitonin gene-related peptide and substance P were identified by immunohistochemistry in dorsal root ganglia and dorsal horn of knockout mice, and the axotomy-induced down-regulation of both calcitonin gene-related peptide and substance P was accentuated in Y1 receptor knockout. However, the transcript levels for calcitonin gene-related peptide and substance P were significantly higher in knockout than in wild-type dorsal root ganglia ipsilateral to the axotomy, while more calcitonin gene-related peptide- and substance P-like immunoreactivity accumulated proximal and distal to a crush of the sciatic nerve. These results indicate that the deletion of the Y1 receptor causes increased release and compensatory increased synthesis of calcitonin gene-related peptide and substance P in dorsal root ganglion neurons. Together, these findings suggest that, after peripheral nerve injury, neuropeptide Y, via its Y1 receptor receptor, plays a key role in cell survival as well as in transport and synthesis of the excitatory dorsal horn messengers calcitonin gene-related peptide and substance P and thus may contribute to pain hypersensitivity.
Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Tiejun.Shi@ki.se
T-J S
TJ
Shi
J
J
Li
A
A
Dahlström
E
E
Theodorsson
S
S
Ceccatelli
I
I
Decosterd
T
T
Pedrazzini
T
T
Hökfelt
D000818:Animals; D019771:Axotomy / Q000379:methods; D001522:Behavior, Animal; D001692:Biological Transport / Q000235:genetics; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000166:cytology*; D015870:Gene Expression / Q000235:genetics*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D020671:Posterior Horn Cells / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000172:deficiency*; D013373:Substance P / Q000235:genetics / Q000378:metabolism
D009479:Neuropeptides; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide