Malignant bone tumors, including primary bone cancer and metastatic bone tumors, are a significant clinical challenge due to their high frequency of presentation, poor prognosis and lack of effective treatments and therapies. Bone tumors are often accompanied by skeletal complications such as bone destruction and cancer-induced bone pain. However, the mechanisms involved in bone cancer progression, bone metastasis and skeletal complications remain unclear. Lysophosphatidic acid (LPA), an intercellular lipid signaling molecule that exerts a wide range of biological effects mainly through specifically binding to LPA receptors (LPARs), has been found to be present at high levels in the ascites of bone tumor patients. Numerous studies have suggested that LPA plays a role in primary malignant bone tumors, bone metastasis, and skeletal complications. In this review, we summarize the role of LPA signaling in primary bone cancer, bone metastasis and skeletal complications. Modulating LPA signaling may represent a novel avenue for future therapeutic treatments for bone cancer, potentially improving patient prognosis and quality of life.

Cancer-induced bone pain (CIBP) significantly impacts the quality of life and survival of patients with advanced cancer. Despite the established role of neurexins in synaptic structure and function, their involvement in sensory processing during injury has not been extensively studied. In this study using a rat model of CIBP, we observed increased neurexin 2 expression in spinal cord neurons. Knockdown of neurexin 2 in the spinal cord reversed CIBP-related behaviors, sensitization of spinal c-Fos neurons, and pain-related negative emotional behaviors. Additionally, increased acetylation of neurexin 2 mRNA was identified in the spinal dorsal horn of CIBP rats. Decreasing the expression of N-acetyltransferase 10 (NAT10) reduced neurexin 2 mRNA acetylation and neurexin 2 expression. In PC12 cells, we confirmed that neurexin 2 mRNA acetylation enhanced its stability, and neurexin 2 expression was regulated by NAT10. Finally, we discovered that the NAT10/ac4C-neurexin 2 axis modulated neuronal synaptogenesis. This study demonstrated that the NAT10/ac4C-mediated posttranscriptional modulation of neurexin 2 expression led to the remodeling of spinal synapses and the development of conscious hypersensitivity in CIBP rats. Therefore, targeting the epigenetic modification of neurexin 2 mRNA ac4C may offer a new therapeutic approach for the treatment of nociceptive hypersensitivity in CIBP.

OBJECTIVE: Cancer-induced bone pain (CIBP) is one of the most common symptoms of bone metastasis of tumor cells. The hypothalamus may play a pivotal role in the regulation of CIBP. However, little is known about the exact mechanisms.
METHODS: First, we established a CIBP model to explore the relationship among hypothalamic ghrelin, NPY and CIBP. Then, we exogenously administered NPY and NPY receptor antagonists to investigate whether hypothalamic NPY exerted an antinociceptive effect through binding to NPY receptors. Finally, we exogenously administered ghrelin to investigate whether ghrelin alleviated CIBP by inducing the production of hypothalamic NPY through the AMPK-mTOR pathway. Body weight, food intake and behavioral indicators of CIBP were measured every 3 days. Hypothalamic ghrelin, NPY and the AMPK-mTOR pathway were also measured.
RESULTS: The expression of hypothalamic ghrelin and NPY was simultaneously decreased in cancer-bearing rats, which was accompanied by CIBP. Intracerebroventricular (i.c.v.) administration of NPY significantly alleviated CIBP in the short term. The antinociceptive effect of NPY was reversed with the i.c.v. administration of the Y1R and Y2R antagonists. The administration of ghrelin activated the AMPK-mTOR pathway and induced hypothalamic NPY production to alleviate CIBP. This effect of ghrelin on NPY and antinociception was reversed with the administration of a GHS-R1α antagonist.
CONCLUSIONS: Ghrelin could induce the production of hypothalamic NPY through the AMPK-mTOR pathway to alleviate CIBP, which can provide a novel therapeutic mechanism for CIBP.

Cancer-induced bone pain (CIBP) is one of the most common and feared symptoms in patients with advanced tumors. The X-C motif chemokine ligand 12 (CXCL12) and the CXCR4 receptor have been associated with glial cell activation in bone cancer pain. Moreover, mitogen-activated protein kinases (MAPKs), as downstream CXCL12/CXCR4 signals, and c-Jun, as activator protein AP-1 components, contribute to the development of various types of pain. However, the specific CIBP mechanisms remain unknown. Esketamine is a non-selective N-methyl-d-aspartic acid receptor (NMDA) inhibitor commonly used as an analgesic in the clinic, but its analgesic mechanism in bone cancer pain remains unclear. We used a tumor cell implantation (TCI) model and explored that CXCL12/CXCR4, p-MAPKs, and p-c-Jun were stably up-regulated in the spinal cord. Immunofluorescence images showed activated microglia in the spinal cord on day 14 after TCI and co-expression of CXCL12/CXCR4, p-MAPKs (p-JNK, p-ERK, p-p38 MAPK), and p-c-Jun in microglia. Intrathecal injection of the CXCR4 inhibitor AMD3100 reduced JNK and c-Jun phosphorylations, and intrathecal injection of the JNK inhibitor SP600125 and esketamine also alleviated TCI-induced pain and reduced the expression of p-JNK and p-c-Jun in microglia. Overall, our data suggest that the CXCL12/CXCR4-JNK-c-Jun signaling pathway of microglia in the spinal cord mediates neuronal sensitization and pain hypersensitivity in cancer-induced bone pain and that esketamine exerts its analgesic effect by inhibiting the JNK-c-Jun pathway.

Cancer-induced bone pain (CIBP) stands out as one of the most challenging issues in clinical practice due to its intricate and not fully elucidated pathophysiological mechanisms. Existing evidence has pointed toward the significance of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) down-regulation in contributing to pain behaviors in various rodent models of neuropathic pain. In our current study, we aimed to investigate the role of PGC-1α in CIBP. Our results unveiled a reduction in PGC-1α expression within the spinal cord of CIBP rats, particularly in GABAergic interneurons. Notably, intrathecal administration of the PGC-1α activator ZLN005 suppressed the loss of spinal GABAergic interneurons. This suppression was achieved by inhibiting caspase-3-mediated apoptosis, ultimately leading to the alleviation of mechanical allodynia in CIBP rats. Further exploration into the mechanism revealed that PGC-1α activation played a pivotal role in mitigating ATP depletion and reactive oxygen species accumulation linked to mitochondrial dysfunction. This was achieved through the restoration of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. Impressively, the observed effects were prominently reversed upon the application of SR18292, a specific PGC-1α inhibitor. In conclusion, our findings strongly suggest that PGC-1α activation acts as a potent inhibitor of apoptosis in spinal GABAergic interneurons. This inhibition is mediated by the improvement of mitochondrial function, facilitated in part through the enhancement of mitochondrial biogenesis and the activation of the SIRT3-SOD2 pathway. The results of our study shed light on potential therapeutic avenues for addressing CIBP.

Long noncoding RNA (lncRNA) is implicated in both cancer development and pain process. However, the role of lncRNA in the development of cancer-induced bone pain (CIBP) is unclear. LncRNA NONRATT014888.2 is highly expressed in tibia related dorsal root ganglions (DRGs) in CIBP rats which function is unknown. CIBP was induced by injection of Walker 256 mammary gland tumor cells into the tibia canal of female SD rats. Paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) of rats were measured. Down-regulation of NONRATT014888.2 by siRNA in CIBP rats markedly attenuated hind-paw mechanical pain hypersensitivity. LncRNA-predicted target mRNAs analysis and mRNA sequencing results cued Socs3, Npr3 were related with NONRATT014888.2. Intrathecal injection of NONRATT014888.2-siR206 upregulated Npr3 both in mRNA and protein level. Npr3 was co-expressed in NONRATT014888.2-positive DRGs neurons and mainly located in cytoplasm, but not in Glial fibrillary acidic protein (GFAP)-positive cells. Intrathecal injection of ADV-Npr3 upregulated Npr3 expression and enhanced the PWT of CIBP rats. Our results suggest that upregulated lncRNA NONRATT014888.2 contributed to hyperalgesia in CIBP rats, and the mechanism may through downregulation of Npr3.

Cancer-induced bone pain (CIBP) is a type of ongoing or breakthrough pain caused by a primary bone tumor or bone metastasis. CIBP constitutes a specific pain state with distinct characteristics; however, it shares similarities with inflammatory and neuropathic pain. At present, although various therapies have been developed for this condition, complete relief from CIBP in patients with cancer is yet to be achieved. Hence, it is urgent to study the mechanism underlying CIBP to develop efficient analgesic drugs. Herein, we focused on the peripheral mechanism associated with the initiation of CIBP, which involves tissue injury in the bone and changes in the tumor microenvironment (TME) and dorsal root ganglion. The nerve-cancer and cancer-immunocyte cross-talk in the TME creates circumstances that promote tumor growth and metastasis, ultimately leading to CIBP. The peripheral mechanism of CIBP and current treatments as well as potential therapeutic targets are discussed in this review.

Pericapsular nerve group block (PENG) is an ultrasound-guided regional block technique that blocks the articular branches of the femoral nerve, accessory obturator nerve and obturator nerve. These nerves richly innervate the anterior capsule of the hip joint and blocking these nerves helps in hip analgesia. PENG block is commonly used in hip fracture pain perioperatively. In this case series, we have used PENG block in cancer patients with hip pain. PENG block was given to six patients with bupivacaine and triamcinolone, out of which five patients had good pain relief and their functional mobility to activities of daily living improved.

Drive from peripheral neurons is essential in almost all pain states, but pharmacological silencing of these neurons to effect analgesia has proved problematic. Reversible gene therapy using long-lived chemogenetic approaches is an appealing option. We used the genetically activated chloride channel PSAM4-GlyR to examine pain pathways in mice. Using recombinant AAV9-based delivery to sensory neurons, we found a reversal of acute pain behavior and diminished neuronal activity using in vitro and in vivo GCaMP imaging on activation of PSAM4-GlyR with varenicline. A significant reduction in inflammatory heat hyperalgesia and oxaliplatin-induced cold allodynia was also observed. Importantly, there was no impairment of motor coordination, but innocuous von Frey sensation was inhibited. We generated a transgenic mouse that expresses a CAG-driven FLExed PSAM4-GlyR downstream of the Rosa26 locus that requires Cre recombinase to enable the expression of PSAM4-GlyR and tdTomato. We used NaV1.8 Cre to examine the role of predominantly nociceptive NaV1.8+ neurons in cancer-induced bone pain (CIBP) and neuropathic pain caused by chronic constriction injury (CCI). Varenicline activation of PSAM4-GlyR in NaV1.8-positive neurons reversed CCI-driven mechanical, thermal, and cold sensitivity. Additionally, varenicline treatment of mice with CIBP expressing PSAM4-GlyR in NaV1.8+ sensory neurons reversed cancer pain as assessed by weight-bearing. Moreover, when these mice were subjected to acute pain assays, an elevation in withdrawal thresholds to noxious mechanical and thermal stimuli was detected, but innocuous mechanical sensations remained unaffected. These studies confirm the utility of PSAM4-GlyR chemogenetic silencing in chronic pain states for mechanistic analysis and potential future therapeutic use.

Cancer-induced bone pain (CIBP) caused by bone metastasis is one of the most prevalent diseases, and current treatments rely primarily on opioids, which have significant side effects. However, recent developments in pharmaceutical science have identified several new mechanisms for CIBP, including the targeted modification of certain ion channels and receptors. Ion channels are transmembrane proteins, which are situated on biological cell membranes, which facilitate passive transport of inorganic ions across membranes. They are involved in various physiological processes, including transmission of pain signals in the nervous system. In recent years, there has been an increasing interest in the role of ion channels in chronic pain, including CIBP. Therefore, in this review, we summarize the current literature on ion channels, related receptors, and drugs and explore the mechanism of CIBP. Targeting ion channels and regulating their activity might be key to treating pain associated with bone cancer and offer new treatment avenues.