Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation
Edited by David Julius, University of California, San Francisco, CA, and approved June 12, 2009
Abstract
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.
Acknowledgments.
This research was supported by Grant-in-Aid for Scientific Research 18613014 and Grant-in-Aid for Exploratory Research 19659404 from the Japan Society for the Promotion of Science.
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Cover image: Pictured is a microbial mat growing near White Creek in Yellowstone National Park. These microbial communities produce lipids with unusually large variations in their deuterium content. Zhang et al. show that such variations likely relate to the different metabolic pathways employed by the microbes and suggest that deuterium variations in ancient lipids could be used to identify pathways of energy metabolism active in the past. See the Feature Article by Xinning Zhang et al. on pages 12580–12586. Image by Alex Sessions.
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© 2009.
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Received: April 1, 2009
Published online: August 4, 2009
Published in issue: August 4, 2009
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Acknowledgments
This research was supported by Grant-in-Aid for Scientific Research 18613014 and Grant-in-Aid for Exploratory Research 19659404 from the Japan Society for the Promotion of Science.
Notes
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0903524106/DCSupplemental.
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The authors declare no conflict of interest.
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