Leptin enhances NMDA-induced spinal excitation in rats: A functional link between adipocytokine and neuropathic pain

Abstract

Recent studies have shown that leptin (an adipocytokine) played an important role in nociceptive behavior induced by nerve injury, but the cellular mechanism of this action remains unclear. Using the whole cell patch-clamp recording from rat’s spinal cord slices, we showed that superfusion of leptin onto spinal cord slices dose-dependently enhanced NMDA receptor-mediated currents in spinal cord lamina II neurons. At the cellular level, the effect of leptin on spinal NMDA-induced currents was mediated through the leptin receptor and the JAK2/STAT3 (but not PI3K or MAPK) pathway, as the leptin effect was abolished in leptin receptor deficient (db/db) mice and inhibited by a JAK/STAT inhibitor. Moreover, we demonstrated in naïve rats that a single intrathecal administration of leptin enhanced spontaneous biting, scratching and licking behavior induced by intrathecal NMDA and that repeated intrathecal administration of leptin elicited thermal hyperalgesia and mechanical allodynia, which was attenuated by the non-competitive NMDA receptor antagonist MK-801. Intrathecal leptin also upregulated the expression of NMDA receptors and pSTAT3 within the rat’s spinal cord dorsal horn and intrathecal MK-801 attenuated this leptin effect as well. Our data demonstrate a relationship between leptin and NMDA receptor-mediated spinal neuronal excitation and its functional role in nociceptive behavior. Since leptin contributes to nociceptive behavior induced by nerve injury, the present findings suggest an important cellular link between the leptin’s spinal effect and the NMDA receptor-mediated cellular mechanism of neuropathic pain.

Do synovial leptin levels correlate with pain in end stage arthritis?

“…The proinflammatory cytokine-like functions of leptin in OA [10,[44][45][46][47] could explain its role in peripheral sensitization. Second, animal models suggest an involvement of leptin in the pathogenesis of pain at the spinal level and a possible role in the development of neuropathic pain [28][29][30]. Our clinical results support these experimental findings in patients with lower limb OA.…”

“…Leptin levels in peritoneal fluid correlated positively with pain severity in endometriosis patients [27]. Furthermore, recent studies in rodents [28][29][30] suggested that spinal leptin might be involved in the pathogenesis of neuropathic pain.…”

Ictal adipokines are associated with pain severity and treatment response in episodic migraine

“…[1][2][3][4] Adiponectin (ADP), leptin (LEP), and resistin are 3 such adipokines. These adipokines modulate inflammation and endothelial function-processes that overlap with the proposed mechanisms of migraine pathophysiology.…”

“…In addition, receptors for these adipokines are expressed in key structures implicated in migraine, including the hypothalamus and the cerebral microvasculature. [1][2][3][4] Previous studies have reported that interictal ADP levels are increased in those with migraine, and that ictal ADP levels decline with successful abortive treatment in women episodic migraineurs. [5][6][7] Studies evaluating interictal LEP levels in migraineurs have been inconclusive.…”

“…This finding may at first appear to be less consistent with the existing data supporting a proinflammatory role for LEP in some painful conditions. 3,16,28,29 However, there is also a growing volume of data to suggest anti-inflammatory properties of LEP, especially in settings of neural injury. In animal models of spinal cord injury or stroke, LEP has been found to induce neuron growth and differentiation and to reduce microglial reactivity.…”