Alleviation of inflammation in paraventricular nucleus and sympathetic outflow by melatonin efficiently repairs endplate porosities and attenuates spinal hyperalgesia.

Low back pain, largely attributed to intervertebral disc (IVD) degeneration, is correlated with increased sympathetic nerve activity. Toll-like receptor 4 (TLR4)-mediated inflammation in the paraventricular nucleus (PVN) triggers sympathetic nerve activation, which remains uncharted in IVD degeneration. We hypothesized that lumbar spine instability (LSI) surgery in mice elevated sympathetic outflow by activating TLR4/NF-κB axis in PVN, and exacerbated endplate porosities and spinal hyperalgesia following 4 or 8 weeks LSI surgery. Treatment of melatonin for 8 weeks notably alleviated the inflammation and sympathetic outflow in the PVN, and attenuated sympathetic nerve activity, oxidative stress, endplate porosities and spinal hyperalgesia in the peripheral. These effects were abolished by melatonin receptor antagonist luzindole. Immunofluorescent staining of melatonin receptor 1A (MT1) and 1B (MT2) confirmed that MT2 expression exceeded that of MT1 in PVN. Knockdown of MT2 in PVN blocked the inhibitory effect of melatonin on inflammation and sympathetic activation both in PVN and endplate, as well as spinal hyperalgesia, oxidative stress, and porosities of endplate. Additionally, norepinephrine induces inflammation and oxidative stress, disrupts metabolic homeostasis of endplate cells via α2-adrenergic receptor in vitro. This study suggests that melatonin, via activation of MT2, inhibits inflammation and sympathetic activities both in PVN and endplate, therefore, efficiently repairing endplate porosities and alleviating spinal hyperalgesia induced by LSI.