Activation of the P2X₇receptor in midbrain periaqueductal gray participates in the analgesic effect of tramadol in bone cancer pain rats

Abstract

BackgroundCancer pain is a well-known serious complication in metastatic or terminal cancer patients. Current pain management remains unsatisfactory. The activation of spinal and supraspinal P2X7 receptors plays a crucial role in the induction and maintenance mechanisms of various kinds of acute or chronic pain. The midbrain periaqueductal gray is a vital supraspinal site of the endogenous descending pain-modulating system. Tramadol is a synthetic, centrally acting analgesic agent that exhibits considerable efficacy in clinically relieving pain. The purpose of this study was to determine whether the activation of P2X7 receptor in the ventrolateral region of the periaqueductal gray (vlPAG) participates in the analgesic mechanisms of tramadol on bone cancer pain in rats. The bone cancer pain rat model was established by intratibial cell inoculation of SHZ-88 mammary gland carcinoma cells. The analgesic effects of different doses of tramadol (10, 20, and 40 mg/kg) were assessed by measuring the mechanical withdrawal threshold and thermal withdrawal latency values in rats by using an electronic von Frey anesthesiometer and radiant heat stimulation, respectively. Alterations in the number of P2X7 receptor-positive cells and P2X7 protein levels in vlPAG were separately detected by using immunohistochemistry and Western blot assay. The effect of intra-vlPAG injection of A-740003 (100 nmol), a selective competitive P2X7 receptor antagonist, on the analgesic effect of tramadol was also observed.ResultsThe expression of P2X7 receptor in the vlPAG on bone cancer pain rats was mildly elevated, and the tramadol (10, 20, and 40 mg/kg) dose dependently relieved pain-related behaviors in bone cancer pain rats and further upregulated the expression of P2X7 receptor in the vlPAG. The intra-vlPAG injection of A-740003 pretreatment partly but significantly antagonized the analgesic effect of tramadol on bone cancer pain rats.ConclusionsThe injection of tramadol can dose dependently elicit analgesic effect on bone cancer pain rats by promoting the expression of the P2X7 receptor in vlPAG.

P2RX7 in Dopaminergic Neurons of Ventral Periaqueductal Gray Mediates HTWP Acupuncture-Induced Consciousness in Traumatic Brain Injury

“…We then performed histological analyses to locate the expression of P2RX7, P2RX3, and TRPV1 in the brain, particularly in the awakening-associated nucleus of the ARAS. The vPAG is located at the junction of the dorsal-ventral pathways of the ARAS (Saper et al, 2005 ), and vPAG neural projections express P2RX7 (Li et al, 2018 ), P2RX3 (Xiao et al, 2010 ), and TRPV1 (Li et al, 2006 ). Thus, we analyzed the distribution of P2RX7, P2RX3, and TRPV1 in the vPAG of sham and TBI rats without or with HTWP acupuncture treatment using confocal microscopy ( Figures 3A–C ) to verify that HTWP acupuncture regulates the expression of these receptors in the vPAG to reduce coma duration.…”

“…Subsequently, this information is transmitted to the CNS, which results in the curing of several diseases through neural-immune regulation (Díaz-Ríos et al, 2007 ). ATP is a neurotransmitter widely found throughout the CNS and can bind to P2X receptors to trigger cell morphological changes, the activation of intracellular signal pathways, and the release of glutamate and ATP to regulate neuron excitability (Yu et al, 2008 ; Li et al, 2018 ). TRPV1 also mediates sensory conduction, and the mechanical nociceptive stimulation produced by acupuncture activates the TRPV1 receptor in the local nerve endings of the acupoints; the signal induced by acupuncture transmits to neurons expressing TRPV1 in the CNS.…”

Up-regulation of PKCγ subunits of rACC neurons contributes to the development of pain sensitivity in bone cancer rats

“…The pathogenesis of bone cancer pain (BCP) remains unknown, and no effective treatment has been identified [1,2]. The anterior cingulate cortex (ACC) is an essential part of the cerebral cortex; specifically, the rostral ACC (rACC) is associated with pain perception and regulation [3][4][5].…”

Up-regulation of PKCγ subunits of rACC neurons contributes to the development of pain sensitivity in bone cancer rats

“…The pathogenesis of bone cancer pain remains unknown, and there has been no effective treatment 3 [1,2]. The anterior cingulate cortex (ACC) is an essential part of the cerebral cortex; in particular, the rostral ACC (rACC) is associated with pain perception and regulation [3][4][5].…”