Intrathecal delivery of PDGF produces tactile allodynia through its receptors in spinal microglia.
Neuropathic pain is a debilitating pain condition that occurs after nerve damage. Such pain is considered to be a reflection of the aberrant excitability of dorsal horn neurons. Emerging lines of evidence indicate that spinal microglia play a crucial role in neuronal excitability and the pathogenesis of neuropathic pain, but the mechanisms underlying neuron-microglia communications in the dorsal horn remain to be fully elucidated. A recent study has demonstrated that platelet-derived growth factor (PDGF) expressed in dorsal horn neurons contributes to neuropathic pain after nerve injury, yet how PDGF produces pain hypersensitivity remains unknown. Here we report an involvement of spinal microglia in PDGF-induced tactile allodynia. A single intrathecal delivery of PDGF B-chain homodimer (PDGF-BB) to naive rats produced a robust and long-lasting decrease in paw withdrawal threshold in a dose-dependent manner. Following PDGF administration, the immunofluorescence for phosphorylated PDGF beta-receptor (p-PDGFR beta), an activated form, was markedly increased in the spinal dorsal horn. Interestingly, almost all p-PDGFR beta-positive cells were double-labeled with an antibody for the microglia marker OX-42, but not with antibodies for other markers of neurons, astrocytes and oligodendrocytes. PDGF-stimulated microglia in vivo transformed into a modest activated state in terms of their cell number and morphology. Furthermore, PDGF-BB-induced tactile allodynia was prevented by a daily intrathecal administration of minocycline, which is known to inhibit microglia activation. Moreover, in rats with an injury to the fifth lumbar spinal nerve (an animal model of neuropathic pain), the immunofluorescence for p-PDGFR beta was markedly enhanced exclusively in microglia in the ipsilateral dorsal horn. Together, our findings suggest that spinal microglia critically contribute to PDGF-induced tactile allodynia, and it is also assumed that microglial PDGF signaling may have a role in the pathogenesis of neuropathic pain.
Masuda
Junya
J
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. junyamsd@kyudai.jp
Tsuda
Makoto
M
Tozaki-Saitoh
Hidetoshi
H
Inoue
Kazuhide
K
D000818:Animals; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D006930:Hyperalgesia / Q000473:pathology; D008297:Male; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D010146:Pain / Q000209:etiology / Q000378:metabolism*; D010147:Pain Measurement; D010982:Platelet-Derived Growth Factor / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013127:Spinal Nerves / Q000166:cytology / Q000293:injuries* / Q000473:pathology; D014110:Touch / Q000502:physiology*
D010982:Platelet-Derived Growth Factor