Involvement of chemokine CXCL11 in the development of morphine tolerance in rats with cancer‐induced bone pain

Abstract

Morphine is viewed as one of the classical treatments for intractable pain, but its role is limited by side effects, including analgesic tolerance. A few chemokines have been reported to be engaged in the mechanisms of morphine tolerance. However, the exact roles of CXC chemokine 11 (CXCL11) in chronic morphine tolerance remain unknown. In this study, Walker 256 mammary gland carcinoma cells were inoculated into the tibia of rats to provoke cancer-induced bone pain. Then, morphine was intrathecally administered twice daily for seven consecutive days to induce drug tolerance. We found that the level of CXCL11 in lumbar spinal cord was increased during the development of morphine tolerance in cancer-induced bone pain rats. Meanwhile, CXCL11 was co-localized with markers of astrocytes and neurons in the spinal cord. Inhibition of CXCL11 by neutralizing antibodies could remarkably attenuate the degree of morphine tolerance and decrease the activation of astrocytes. Moreover, blocking astrocyte activation by d, l-Fluorocitric acid could distinctly alleviate morphine tolerance and reduce the expression of CXCL11. Finally, morphine stimulation could induce the release of CXCL11 by cultured astrocytes and neurons in vitro. In summary, our results provide evidence that spinal CXCL11 plays a powerful modulatory role in the development of morphine tolerance through cross-talking between astrocytes and neurons. Read the Review series "Pain".

Optimization and In Vivo Profiling of a Refined Rat Model of Walker 256 Breast Cancer Cell-Induced Bone Pain Using Behavioral, Radiological, Histological, Immunohistochemical and Pharmacological Methods

“…The ED 50-Ipsilateral of morphine in this model (1.3 mg/kg) was found to be higher than that in a cisplatin induced peripheral neuropathy model (0.8 mg/kg; s.c.) (Han et al, 2014), similar to that in a neuropathic pain model of spared nerve injury (1.2 mg/kg; s.c.) (Zhao et al, 2004), but lower than that in nociceptive paw pressure test (2.8 mg/kg; s.c.) (Morgan et al, 2006) in rats. Our findings are aligned with others who showed that morphine is effective in alleviating pain hypersensitivities in this model (Guo et al, 2017; Liu et al, 2017). In other work, spinal levels of endomorphin-2, an endogenous ligand at μ-opioid receptors, were reduced following ITI of W256 cells, and this was correlated with development of mechanical allodynia in these rats (Chen et al, 2015).…”

PI3K/Akt Pathway: A Potential Therapeutic Target for Chronic Pain

“…Despite a plethora of available potential treatment options for chronic pain, opioids are still the gold standard for its pharmacological management in the clinical setting. However, long-term use of these drugs is often limited due to the development of opioid tolerance or opioid-induced hyperalgesia(OIH), characterized as progressive loss of analgesic potency after continuous morphine exposure that necessitates dose escalation to achieve equal pain relief [119][120][121][122][123]. μ-opioid receptors (MOR) is a GPCR existing in the superficial dorsal horn of the spinal cord.…”

Establishment, optimization and characterization of a rat model of breast cancer induced bone pain

“…The ED50-Ipsilateral of morphine in this model (1.3 mg/kg) was found to be higher than that in a cisplatin induced peripheral neuropathy model (0.8 mg/kg; s.c.) (Han et al, 2014a), similar to that in a neuropathic pain model of spared nerve injury (1.2 mg/kg; s.c.) (Zhao et al, 2004), but lower than that in nociceptive paw pressure test (2.8 mg/kg; s.c.) (Morgan et al, 2006) in rats. Our findings are aligned with others who showed that morphine is effective in alleviating pain hypersensitivities in this model (Guo et al, 2017, Liu et al, 2017a. In other studies, mRNA and protein levels of μ-opioid receptors in the spinal dorsal horn and dorsal root ganglia of rats were reduced following unilateral ITI of W256 cells in this model (Yao et al, 2016, Hou et al, 2017.…”