Abstract
Perioperative sleep disturbance is a risk factor for persistent pain after surgery. Clinical studies have shown that patients with insufficient sleep before and after surgery experience more intense and long-lasting postoperative pain. We hypothesize that sleep deprivation alters L-type calcium channels in the dorsal root ganglia (DRG), thus delaying the recovery from post-surgical pain. To verify this hypothesis, and to identify new predictors and therapeutic targets for persistent postoperative pain, we first established a model of postsurgical pain with perioperative sleep deprivation (SD) by administering hind paw plantar incision to sleep deprivation rats. Then we conducted behavioral tests, including tests with von Frey filaments and a laser heat test, to verify sensory pain, measured the expression of L-type calcium channels using western blotting and immunofluorescence of dorsal root ganglia (an important neural target for peripheral nociception), and examined the activity of L-type calcium channels and neuron excitability using electrophysiological measurements. We validated the findings by performing intraperitoneal injections of calcium channel blockers and microinjections of dorsal root ganglion cells with adeno-associated virus. We found that short-term sleep deprivation before and after surgery increased expression and activity of L-type calcium channels in the lumbar dorsal root ganglia, and delayed recovery from postsurgical pain. Blocking these channels reduced impact of sleep deprivation. We conclude that the increased expression and activity of L-type calcium channels is associated with the sleep deprivation-mediated prolongation of postoperative pain. L-type calcium channels are thus a potential target for management of postoperative pain.
Highlights
Surgical patients often report pre- and post-surgical sleep disorders, and this is mainly due to anxiety, depression, stress, and the use of opioids [12]
dorsal root ganglia (DRG) microinjection To knock-down the expression of L-type calcium channels in the L4/5 DRG, which are responsible for the transmission of nociceptive information and conduct pain perception in the plantar incision model, we performed direct DRG microinjection with the recombinant adeno-associated virus 2/5 (AAV2/5) with Cav1.2 (Cacna1c) shRNA
We focused on L-type channels, because they play an important role in pain, especially Cav1.2, and almost 90% of the these channels are encoded by Cav1.2 in nervous system [28]
Summary
Surgical patients often report pre- and post-surgical sleep disorders, and this is mainly due to anxiety, depression, stress, and the use of opioids [12]. More than 320 million people worldwide undergo surgery every year, and persistent postsurgical pain is a significant public health issue [17]. This pain can be severe enough to cause serious functional impairment or even disability resulting in decreased quality of life [33]. As the population ages and the number of surgeries continue to increase, persistent postsurgical pain will become an increasingly serious problem. Longterm pain after surgery can increase use of health resources, and thereby greater disability and suffering [26]. There is an urgent need to understand the mechanism of persistent postsurgical pain and to find new predictors and therapeutic targets to prevent and control persistent postsurgical pain
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