Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents
Grewo Lim, … , Yinghong Tian, Jianren Mao
Grewo Lim, … , Yinghong Tian, Jianren Mao
Published January 12, 2009
Citation Information: J Clin Invest. 2009;119(2):295-304. https://doi.org/10.1172/JCI36785.
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Research Article Neuroscience

Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents

Abstract

Pain after nerve injury, a phenomenon referred to as neuropathic pain, is a debilitating clinical condition, but the underlying mechanisms remain unclear. As leptin, an adipocytokine produced mainly by nonneuronal tissue, has been implicated in the regulation of neuronal functions, we examined the role of leptin in neuropathic pain using a rat model of the condition chronic constriction sciatic nerve injury (CCI). We report that leptin critically contributed to pain behaviors following CCI. Specifically, spinal administration of a leptin antagonist prevented and reversed neuropathic pain behaviors in rats. Further examination revealed that levels of both leptin and the long form of the leptin receptor (Ob-Rb) were substantially increased within the ipsilateral spinal cord dorsal horn after peripheral nerve injury. Mechanistic studies showed that leptin upregulated the expression of both the spinal NMDA receptor and IL-1β through the JAK/STAT pathway. Furthermore, these CCI-induced behavioral and cellular responses were diminished in leptin-deficient mice and mimicked by spinal administration of exogenous leptin in naive rats. Our findings reveal a critical role for spinal leptin in the pathogenesis of neuropathic pain and suggest what we believe to be a novel form of nonneuronal and neuronal interactions in the mechanisms of pathological pain.

Authors

Grewo Lim, Shuxing Wang, Yi Zhang, Yinghong Tian, Jianren Mao

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Figure 4

Role of JAK2 and STAT3 in the spinal leptin effect.

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Effect of leptin gene mutation on behavioral and cellular changes. Therm...
(A–D) The expression (Western blot) of JAK2, p-STAT3, NR1, and IL-1β was increased, whereas STAT3 was decreased on day 7 in CCI rats. The altered expression of JAK2, STAT3, p-STAT3, NR1, and IL-1β was prevented by once daily intrathecal administration of leptin antagonist (LA, 3 μg) for 7 days. S, sham; C, CCI; LA, leptin antagonist. (E and F) Exposure to leptin (100 ng/ml) for 5 or 72 hours upregulated NR1 and IL-1β expression in an organotypic spinal tissue culture (Western blot) and increased IL-1β in the culture medium (ELISA) (G). T5h, leptin exposure for 5 hours; T72h, leptin exposure for 72 hours; C5h, vehicle exposure for 5 hours; C72h, vehicle exposure for 72 hours. (H and I) Adding AG 490 (6 ng/ml) into leptin (100 ng/ml) culture medium for 72 hours significantly reduced leptin-dependent NR1 and IL-1β upregulation. V, vehicle; A, AG 490; L, leptin. (J) Exposure to leptin increased the expression of microglia (OX-42) in the spinal tissue culture. Scale bars: 120 μm (GFAP); 60 μm (OX-42). Histogram shows density measurement of immunofluorescent images (n = 5). (K) NMDA-induced current was enhanced in the presence of leptin. Arrow indicates recovery of NMDA current at 30 minutes after leptin washout. Data are shown as mean ± SD. *P < 0.05 versus sham; #P < 0.05 versus control.