Propofol attenuates postoperative hyperalgesia via regulating spinal GluN2B‐p38MAPK/EPAC1 pathway in an animal model of postoperative pain

Abstract

Background Total intravenous anesthesia with propofol has been shown to reduce postoperative pain in some clinical studies, but knowledge of its underlying analgesic mechanism remains limited. In this study, we compared the analgesic effects of propofol versus isoflurane in an animal model of postoperative pain and evaluated its underlying molecular mechanisms. Methods Plantar incision was made in the hind paws of rats under general anesthesia with 2.5% of inhalational isoflurane (isoflurane group) or intravenous infusion of propofol (1.5 mg kg−1 min−1, propofol group). Mechanical allodynia was assessed by paw withdrawal threshold before and after incision. Spinal dorsal horns (L3–L5) were harvested 1 hr after incision to assess the level of phosphorylated GluN2B, p38MAPK, ERK, JNK, and EPAC using Western blot and immunofluorescence. Results Mechanical allodynia induced by plantar incision peaked at 1 hr and lasted for 3 days after incision. It was significantly less in the propofol group compared with the isoflurane group in the first 2 hr following incision. The incision‐induced increases in phosphorylated GluN2B, p38MAPK, and EPAC1 were significantly reduced in the propofol group. The number of spinal dorsal neurons co‐expressed with EPAC1 and c‐Fos after the incision was significantly lower in the propofol group. Conclusion Propofol reduced pain responses in an animal model of postoperative pain and suppressed the spinal GluN2B‐p38MAPK/EPAC1 signaling pathway. Since the p38MAPK/EPAC pathway plays a critical role in the development of postoperative hyperalgesia, our results provide evidence‐based behavioral, molecular, and cellular mechanisms for the analgesic effects of propofol when used for general anesthesia. Significance These findings may provide a new mechanism for the postsurgical analgesic effect of propofol, which is particularly interesting during the subacute period after surgery as it is the critical period for the development of persistent postsurgical pain.

Pharmacologic Modulation of Noxious Stimulus-evoked Brain Activation in Cynomolgus Macaques Observed with Functional Neuroimaging

“…21,30 Defined spinal cord mechanisms of propofol and pentobarbital antinociception have been suggested for both drugs, and limited clinical data suggests reduced postoperative pain following intraoperative propofol treatment, compared with sevoflurane. 11,62,70,74,86,94 Preclinical rodent findings suggest that both propofol and pentobarbital possess significant, intrinsic antinociceptive efficacy. However, the current findings in NHP demonstrated that sedating doses of either propofol or pentobarbital did not suppress noxious pressure activation of SII/Ins.…”

“…4,26,27,34,64 Data from rodent studies suggest that sedative doses of propofol, both 36 and 90 mg/kg/hr., are antinociceptive. 74,94 It is possible that propofol's analgesic effect in NHP could be observed at doses that are higher than that needed for stable sedation, which would be, in macaques, between 12 to 36 mg/ kg/hr. 34 The current study tested the effects of 20 and 30 mg/ kg/hr propofol on noxious stimulus-evoked brain activation.…”

Unraveling the role of Epac1‐SOCS3 signaling in the development of neonatal‐CRD‐induced visceral hypersensitivity in rats

“…A paucity of studies has demonstrated that Epac1 is involved in the inflammation‐induced nociception. With pre‐clinical neuropathic or chronic pain model, Epac1 facilitated the hyperalgesia via multiple signaling pathways, for example, Rap1, PLC, PLD, MEK/ERK, GRK2, PKCα, and PKCε 19,20,44–47 . However, most of these studies only explore the Epac mechanism in pain on peripheral tissues or organs, especially dorsal root ganglion.…”

Propofol total intravenous anaesthesia versus inhalational anaesthesia for acute postoperative pain in patients with morphine patient-controlled analgesia: a large-scale retrospective study with covariate adjustment

“…Another potential mechanism may be via propofol’s effect on the exchange protein directly activated by cAMP (EPAC). EPAC is involved in the transition from acute to persistent pain, and propofol has been shown to reduce spinal dorsal horn EPAC1 expression in an animal model for postoperative pain [ 31 , 32 ].…”