PRG-1 relieves pain and depressive-like behaviors in rats of bone cancer pain by regulation of dendritic spine in hippocampus

Abstract

Rationale: Pain and depression, which tend to occur simultaneously and share some common neural circuits and neurotransmitters, are highly prevalent complication in patients with advanced cancer. Exploring the underlying mechanisms is the cornerstone to prevent the comorbidity of chronic pain and depression in cancer patients. Plasticity-related gene 1 (PRG-1) protein regulates synaptic plasticity and brain functional reorganization during neuronal development or after cerebral lesion. Purinergic P2X7 receptor has been proposed as a therapeutic target for various pain and neurological disorders like depression in rodents. In this study, we investigated the roles of PRG-1 in the hippocampus in the comorbidity of pain and depressive-like behaviors in rats with bone cancer pain (BCP). Methods: The bone cancer pain rat model was established by intra-tibial cell inoculation of SHZ-88 mammary gland carcinoma cells. The animal pain behaviors were assessed by measuring the thermal withdrawal latency values by using radiant heat stimulation and mechanical withdrawal threshold by using electronic von Frey anesthesiometer, and depressive-like behavior was assessed by sucrose preference test and forced swim test. Alterations in the expression levels of PRG-1 and P2X7 receptor in hippocampus were separately detected by using western blot, immunofluorescence and immunohistochemistry analysis. The effects of intra-hippocampal injection of FTY720 (a PRG-1/PP2A interaction activator), PRG-1 overexpression or intra-hippocampal injection of A438079 (a selective competitive P2X7 receptor antagonist) were also observed. Results: Carcinoma intra-tibia injection caused thermal hyperalgesia, mechanical allodynia and depressive-like behaviors in rats, and also induced the deactivation of neurons and dendritic spine structural anomalies in the hippocampus. Western blot, immunofluorescence and immunohistochemistry analysis showed an increased expression of PRG-1 and P2X7 receptor in the hippocampus of BCP rats. Intra-hippocampal injection of FTY720 or A438079 attenuated both pain and depressive-like behaviors. Furthermore, overexpression of PRG-1 in hippocampus has similar analgesic efficacy to FTY720. In addition, they rescued neuron deactivation and dendritic spine anomalies. Conclusion:The results suggest that both PRG-1 and P2X7 receptor in the hippocampus play important roles in the development of pain and depressive-like behaviors in bone cancer condition in rats by dendritic spine regulation via P2X7R/PRG-1/PP2A pathway.

Activation of HCN channels caused by elevated cAMP levels in periaqueductal gray promotes bone cancer pain

“…There was no signi cant difference in TWL between sham and control rats. The development trend of pain sensitivity was similar to previous studies, that is, MWT or TWL decreased signi cantly on days 5 to 21 after SHZ-88 breast cancer cells were implanted into the tibial medulla cavity of rats [2,21].…”

“…The rat tibial carcinoma model was established with reference to the method described by Liu et al [21]. Female SD rats were xed under anesthesia with pentobarbital sodium (40 mg/kg, i.p.…”

MHCII contributes to bone cancer pain via activating the NLRP3 inflammasome in microglia of the medial prefrontal cortex

“…A wealth of evidence has suggested that BCP is a complex clinical syndrome, that shares a number of features with in ammatory and neuropathic pain (Falk and Dickenson 2014), and often comes with concurrent depression, cognitive impairment, and other diseases (Feller et al 2019;Liu et al 2021). It has been reported that the differences between the sexes were minor and did not affect the overall progression of the pain state (Falk et al 2013).…”

PRG-1 prevents neonatal stimuli-induced persistent hyperalgesia and memory dysfunction via NSF/Glu/GluR2 signaling

“…We recently delineated a new physiological role for PRG-1 in chronic pain where we found that hippocampal PRG-1 relieves pain and depressive-like behaviors caused by bone cancer pain via P2X 7 R/PRG-1/PP2A pathway regulation of dendritic spine density in a cell-autonomous fashion (Liu et al, 2021a). We also found that hippocampal PRG-1 expression was upregulated as a compensatory protective effect in response to the bone cancer-induced pain (Liu et al, 2021a).…”

“…To date, studies on PRGs family have mainly focused on neuropsychiatric diseases and nerve injuries such as epilepsy (Ni et al, 2009;Trimbuch et al, 2009;Vogt et al, 2017), schizophrenia (Thalman et al, 2018;Vogt et al, 2016), memory disorders (Liu et al, 2016), nerve trauma (Hashimoto et al, 2013;Peeva et al, 2006), and sensory discrimination deficit (Cheng et al, 2016;Unichenko et al, 2016). We recently delineated a new physiological role for PRG-1 in chronic pain where we found that hippocampal PRG-1 relieves pain and depressive-like behaviors caused by bone cancer pain via P2X 7 R/PRG-1/PP2A pathway regulation of dendritic spine density in a cell-autonomous fashion (Liu et al, 2021a). We also found that hippocampal PRG-1 expression was upregulated as a compensatory protective effect in response to the bone cancer-induced pain (Liu et al, 2021a).…”