Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation.
Nerve injury may result in neuropathic pain, characterized by allodynia and hyperalgesia. Accumulating evidence suggests the existence of a molecular substrate for neuropathic pain produced by neurons, glia, and immune cells. Here, we show that leptin, an adipokine exclusively produced by adipocytes, is critical for the development of tactile allodynia through macrophage activation in mice with partial sciatic nerve ligation (PSL). PSL increased leptin expression in adipocytes distributed at the epineurium of the injured sciatic nerve (SCN). Leptin-deficient animals, ob/ob mice, showed an absence of PSL-induced tactile allodynia, which was reversed by the administration of leptin to the injured SCN. Perineural injection of a neutralizing antibody against leptin reproduced this attenuation. Macrophages recruited to the perineurium of the SCN expressed the leptin receptor and phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a transcription factor downstream of leptin. PSL also up-regulated the accepted mediators of neuropathic pain--namely, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloprotease-9--in the injured SCN, with transcriptional activation of their gene promoters by pSTAT3. This up-regulation was partly reproduced in a macrophage cell line treated with leptin. Administration of peritoneal macrophages treated with leptin to the injured SCN reversed the failure of ob/ob mice to develop PSL-induced tactile allodynia. We suggest that leptin induces recruited macrophages to produce pronociceptive mediators for the development of tactile allodynia. This report shows that adipocytes associated with primary afferent neurons may be involved in the development of neuropathic pain through adipokine secretion.
Maeda
Takehiko
T
Department of Pharmacology, Wakayama Medical University, Wakayama 641-0012, Japan. tmaeda@wakayama-med.ac.jp
Kiguchi
Norikazu
N
Kobayashi
Yuka
Y
Ikuta
Toshihiko
T
Ozaki
Masanobu
M
Kishioka
Shiroh
S
D017667:Adipocytes / Q000502:physiology*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000502:physiology; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000502:physiology; D006930:Hyperalgesia / Q000209:etiology*; D020738:Leptin / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D050796:STAT3 Transcription Factor / Q000502:physiology; D020426:Sciatic Neuropathy / Q000503:physiopathology*; D015533:Transcriptional Activation
D022763:CCAAT-Enhancer-Binding Protein-alpha; D020738:Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2