Upregulation of P2X3 receptors by neuronal calcium sensor protein VILIP-1 in dorsal root ganglions contributes to the bone cancer pain in rats

Abstract

Primary and metastatic cancers that affect bone are frequently associated with severe and intractable pain. The mechanisms underlying the development of bone cancer pain are largely unknown. In this study, we first demonstrated that a functional upregulation of P2X3 receptors in dorsal root ganglion (DRG) neurons is closely associated with the neuronal hyperexcitability and the cancer-induced bone pain in MRMT-1 tumor cell-inoculated rats. Second, we revealed that visinin-like protein 1 (VILIP-1), a member of visinin-like proteins that belong to the family of neuronal calcium sensor proteins is responsible for the observed upregulation of P2X3 receptors in DRG neurons. The interaction between the amino terminus of VLIP-1 and the carboxyl terminus of the P2X3 receptor is critical for the surface expression and functional enhancement of the receptor. Finally, overexpression of VILIP-1 increases the expression of functional P2X3 receptors and enhances the neuronal excitability in naive rat DRG neurons. In contrast, knockdown of VILIP-1 inhibits the development of bone cancer pain via downregulation of P2X3 receptors and repression of DRG excitability in MRMT-1 rats. Taken together, these results suggest that functional upregulation of P2X3 receptors by VILIP-1 in DRG neurons contributes to the development of cancer-induced bone pain in MRMT-1 rats. Hence, P2X3 receptors and VILIP-1 could serve as potential targets for therapeutic interventions in cancer patients for pain management. Pharmacological blockade of P2X3 receptors or knockdown of VILIP-1 in DRGs would be used as innovative strategies for the treatment of bone cancer pain.

The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors

“…Purinergic receptors are important pain processing molecules known to be expressed on nociceptive small diameter neurons in the DRG (46), with important roles having been demonstrated for P2X2/3 (23, 24, 47), P2X4 (48), and P2X7 (49). P2X2/3 receptors have been shown to contribute to multiple pain modalities, including inflammatory pain (23, 24, 47, 50), neuropathic pain (51), visceral pain (52), musculoskeletal pain (53), cancer pain (54), and migraine (55). Presumably the α6* nicotinic receptors interacting in the periphery with P2X2/3 receptors are activated endogenously by acetylcholine, which exists abundantly in mammals both neuronally and non-neuronally, for example in keratinocytes (56).…”

BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation

“…Mechanical allodynia, as a behavioral sign of neuropathic pain, was assessed by measuring 50% paw withdrawal threshold (PWT) as described in our previous reports (Liu et al, 2013;Zheng et al, 2012). The 50% PWT in response to a series of von Frey filaments (Stoelting, Wood Dale, IL) was determined by the Up and Down method (Chaplan et al, 1994).…”

Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats

“…The sequence coding Shp-1 was amplified from pMig plasmid with polymerase chain reaction (PCR) and cloned into a lentivirus (LV) packaging vector GV287 (GeneChem, Shanghai, China) with an ubiquitin promoter. The lentiviral vectors were constructed, and the lentiviruses (LVShp-1 and LV-GFP) were packaged by Shanghai Jikai Gene Chemistry Technology Inc. 16 LV-GFP without Shp-1 insertion was used as a control.…”