Ya-Qun Zhou

Interleukin-6: an emerging regulator of pathological pain.

Interleukin-6 is an inflammatory cytokine with wide-ranging biological effects. It has been widely demonstrated that neuroinflammation plays a critical role in the development of pathological pain. Recently, various pathological pain models have shown elevated expression levels of interleukin-6 and its receptor in the spinal cord and dorsal root ganglia. Additionally, the administration of interleukin-6 could cause mechanical allodynia and thermal hyperalgesia, and an intrathecal injection of anti-interleukin-6 neutralizing antibody alleviated these pain-related behaviors. These studies indicated a pivotal role of interleukin-6 in pathological pain. In this review, we summarize the recent progress in understanding the roles and mechanisms of interleukin-6 in mediating pathological pain associated with bone cancer, peripheral nerve injury, spinal cord injury, chemotherapy-induced peripheral neuropathy, complete Freund’s adjuvant injection, and carrageenan injection. Understanding and regulating interleukin-6 could be an interesting lead to novel therapeutic strategies for pathological pain.

Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes

AIM To investigate the mechanisms underlying the anti-nociceptive effect of minocycline on bone cancer pain (BCP) in rats. METHODS A rat model of BCP was established by inoculating Walker 256 mammary carcinoma cells into tibial medullary canal. Two weeks later, the rats were injected with minocycline (50, 100 μg, intrathecally; or 40, 80 mg/kg, ip) twice daily for 3 consecutive days. Mechanical paw withdrawal threshold (PWT) was used to assess pain behavior. After the rats were euthanized, spinal cords were harvested for immunoblotting analyses. The effects of minocycline on NF-κB activation were also examined in primary rat astrocytes stimulated with IL-1β in vitro. RESULTS BCP rats had marked bone destruction, and showed mechanical tactile allodynia on d 7 and d 14 after the operation. Intrathecal injection of minocycline (100 μg) or intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced mechanical tactile allodynia. Furthermore, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of GFAP (astrocyte marker) and PSD95 in spinal cord. Moreover, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of NF-κB, p-IKKα and IκBα in spinal cord. In IL-1β-stimulated primary rat astrocytes, pretreatment with minocycline (75, 100 μmol/L) significantly inhibited the translocation of NF-κB to nucleus. CONCLUSION Minocycline effectively alleviates BCP by inhibiting the NF-κB signaling pathway in spinal astrocytes.

Chemokines and Their Receptors: Potential Therapeutic Targets for Bone Cancer Pain

Bone cancer pain (BCP) is still an intractable problem currently because the analgesic pharmacological intervention remains insufficient. Thus, the development of novel therapeutic target is critical for the treatment of BCP. Emerging evidence demonstrated that some chemokines and their receptors contribute to the induction and maintenance of BCP. In this article, we reviewed the current evidence for the role of different chemokines and their receptors (e.g. CXCL12/CXCR4, CXCL1/CXCR2, CCL2/CCR2, CCL5/CCR5, CX3CL1/CX3CR1 and CXCL10/CXCR3) in mediating BCP. By extensively understanding the involvement of chemokines and their receptors in BCP, novel therapeutic targets may be revealed for the treatment of BCP.

MHC-I promotes apoptosis of GABAergic interneurons in the spinal dorsal horn and contributes to cancer induced bone pain.

Cancer induced bone pain (CIBP) remains one of the most intractable clinical problems due to poor understanding of its underlying mechanisms. Recent studies demonstrate the decline of inhibitory interneurons, especially GABAergic interneurons in the spinal cord, can evoke generation of chronic pain. It has also been reported that neuronal MHC-I expression renders neurons vulnerable to cytotoxic CD8+ T cells and finally lead to neurons apoptosis in a variety neurological disorders. However, whether MHC-I could induce the apoptosis of GABAergic interneurons in spinal cord and contribute to the development of CIBP remains unknown. In this study, we investigated roles of MHC-I and underlying mechanisms in CIBP on a rat model. Our results showed that increased MHC-I expression on GABAergic interneurons could deplete GABAergic interneurons by inducing their apoptosis in the spinal dorsal horn of tumor-bearing rats. Pretreatment of MHC-I RNAi-lentivirus could prevent the apoptosis of GABAergic interneurons and therefore alleviated mechanical allodynia induced by tumor cells intratibial injection. Additionally, we also found that CD8+ T cells were colocalized with MHC-I and GABAergic neurons and presented a significant and persistent increase in the spinal cord of tumor-bearing rats. Taken together, these findings indicated that MHC-I could evoke CIBP by promoting apoptosis of GABAergic interneurons in the dorsal horn, and this apoptosis was closely related to local CD8+ T cells.

The role of spinal GABAB receptors in cancer-induced bone pain in rats

Cancer-induced bone pain (CIBP) remains a major challenge in advanced cancer patients because of our lack of understanding of its mechanisms. Previous studies have shown the vital role of γ-aminobutyric acid B receptors (GABABRs) in regulating nociception and various neuropathic pain models have shown diminished activity of GABABRs. However, the role of spinal GABABRs in CIBP remains largely unknown. In this study, we investigated the specific cellular mechanisms of GABABRs in the development and maintenance of CIBP in rats. Our behavioral results show that acute as well as chronic intrathecal treatment with baclofen, a GABABR agonist, significantly attenuated CIBP-induced mechanical allodynia and ambulatory pain. The expression levels of GABABRs were significantly decreased in a time-dependent manner and colocalized mostly with neurons and a minority with astrocytes and microglia. Chronic treatment with baclofen restored the expression of GABABRs and markedly inhibited the activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase and the cAMP-response element-binding protein signaling pathway. PERSPECTIVE Our findings provide, to our knowledge, the first evidence that downregulation of GABABRs contribute to the development and maintenance of CIBP and restored diminished GABABRs attenuate CIBP-induced pain behaviors at least partially by inhibiting the protein kinase/cAMP-response element-binding protein signaling pathway. Therefore, spinal GABABR may become a potential therapeutic target for the management of CIBP.

Targeting glia for bone cancer pain

ABSTRACT Introduction: Bone cancer pain (BCP) remains to be a clinical challenge with limited pharmaceutical interventions. Therefore, novel therapeutic targets for the management of BCP are in desperate need. Recently, a growing body of evidence has suggested that glial cells may play a pivotal role in the pathogenesis of BCP. Areas covered: This review summarizes the recent progress in the understanding of glia in BCP and reveals the potential therapeutic targets in glia for BCP treatment. Expert opinion: Pharmacological interventions inhibiting the activation of glial cells, suppressing glia-derived proinflammatory cytokines, cell surface receptors, and the intracellular signaling pathways may be beneficial for the pain management of advanced cancer patients. However, these pharmacological interventions should not disrupt the normal function of glia cells since they play a vital supportive and protective role in the central nervous system.

STAT1 as a downstream mediator of ERK signaling contributes to bone cancer pain by regulating MHC II expression in spinal microglia

Major histocompatibility class II (MHC II)-specific activation of CD4+ T helper cells generates specific and persistent adaptive immunity against tumors. Emerging evidence demonstrates that MHC II is also involved in basic pain perception; however, little is known regarding its role in the development of cancer-induced bone pain (CIBP). In this study, we demonstrate that MHC II expression was markedly induced on the spinal microglia of CIBP rats in response to STAT1 phosphorylation. Mechanical allodynia was ameliorated by either pharmacological or genetic inhibition of MHC II upregulation, which was also attenuated by the inhibition of pSTAT1 and pERK but was deteriorated by intrathecal injection of IFNγ. Furthermore, inhibition of ERK signaling decreased the phosphorylation of STAT1, as well as the production of MHC II in vivo and in vitro. These findings suggest that STAT1 contributes to bone cancer pain as a downstream mediator of ERK signaling by regulating MHC II expression in spinal microglia.

Reactive oxygen species scavengers ameliorate mechanical allodynia in a rat model of cancer-induced bone pain.

Cancer-induced bone pain (CIBP) is a frequent complication in patients suffering from bone metastases. Previous studies have demonstrated a pivotal role of reactive oxygen species (ROS) in inflammatory and neuropathic pain, and ROS scavengers exhibited potent antinociceptive effect. However, the role of spinal ROS remains unclear. In this study, we investigated the analgesic effect of two ROS scavengers in a well-established CIBP model. Our results found that intraperitoneal injection of N-tert-Butyl-α-phenylnitrone (PBN, 50 and 100 mg/kg) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol, 100 and 200 mg/kg) significantly suppressed the established mechanical allodynia in CIBP rats. Moreover, repeated injection of PBN and Tempol showed cumulative analgesic effect without tolerance. However, early treatment with PBN and Tempol failed to prevent the development of CIBP. Naive rats received repetitive injection of PBN and Tempol showed no significant change regarding the nociceptive responses. Finally, PBN and Tempol treatment notably suppressed the activation of spinal microglia in CIBP rats. In conclusion, ROS scavengers attenuated established CIBP by suppressing the activation of microglia in the spinal cord.

Cellular and molecular mechanisms of calcium/calmodulin-dependent protein kinase II in chronic pain

Chronic pain, often defined as any pain lasting more than 3 months, is poorly managed because of its multifaceted and complex mechanisms. Calcium/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinase that plays a fundamental role in synaptic plasticity, learning, and memory. Recent emerging evidence demonstrates increased expression and activity of CaMKII in the spinal cord and dorsal root ganglia of various chronic pain models. Moreover, our previous studies also find that inhibiting CaMKII could attenuate inflammatory pain and neuropathic pain. In this review, we provide evidence for the involvement of CaMKII in the initiation and development of chronic pain, including neuropathic pain, bone cancer pain, and inflammatory pain. Novel CaMKII inhibitors with potent inhibitory effect and high specificity may be alternative therapeutic strategies for the management of chronic pain in the future.

Endoplasmic Reticulum Stress in Spinal Cord Contributes to the Development of Morphine Tolerance

Morphine tolerance remains an intractable problem, which hinders its prolonged use in clinical practice. Endoplasmic reticulum (ER) stress has been proved to play a fundamental role in the pathogenesis of Alzheimer’s disease, diabetes, atherosclerosis, cancer, etc. In this study, we provide the first direct evidence that ER stress may be a significant driver of morphine tolerance. Binding immunoglobulin protein (BiP), the ER stress marker, was significantly upregulated in neurons in spinal dorsal horn in rats being treated with morphine for 7 days. Additionally, chronic morphine treatment resulted in the activation of three arms of unfolded protein response (UPR): inositol-requiring enzyme 1/X-box binding protein 1 (IRE1/XBP1), protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 subunit alpha (PERK/eIF2α), and activating transcription factor 6 (ATF6). More importantly, inhibiting either one of the three cascades could attenuate the development of morphine tolerance. Taken together, our results suggest that ER stress in spinal cord might contribute to the development of morphine tolerance. These findings implicate a potential clinical strategy for preventing morphine tolerance and may contribute to expanding the morphine usage in clinic.