β2-and β3-Adrenergic Receptors Contribute to Cancer-Evoked Pain in a Mouse Model of Osteosarcoma via Modulation of Neural Macrophages

Abstract

The mechanisms involved in the development and maintenance of cancer pain remain largely unidentified. Recently, it has been reported that β-adrenergic receptors (β-ARs), mainly β2-and β3-ARs, contribute to tumor proliferation and progression and may favor cancer-associated pain and neuroinflammation. However, the mechanism underlying β-ARs in cancer pain is still unknown. Here, we investigated the role of β1-, β2-and β3-ARs in a mouse model of cancer pain generated by the para-tibial injection of K7M2 osteosarcoma cells. Results showed a rapid tumor growth in the soft tissue associated with the development of mechanical allodynia in the hind paw ipsilateral to the injected site. In addition to reduce tumor growth, both propranolol and SR59230A, β1-/β2-and β3-AR antagonists, respectively, attenuated mechanical allodynia, the number of macrophages and an oxidative stress by-product accumulated in the ipsilateral tibial nerve. The selective β1-AR antagonist atenolol was able to slightly reduce the tumor growth but showed no effect in reducing the development of mechanical allodynia. Results suggest that the development of the mechanical allodynia in K7M2 osteosarcoma-bearing mice is mediated by oxidative stress associated with the recruitment of neural macrophages, and that antagonism of β2-and β3-ARs contribute not solely to the reduction of tumor growth, but also in cancer pain. Thus, the targeting of the β2-and β3-ARs signaling may be a promising therapeutic strategy against both tumor progression and the development of cancer-evoke pain in osteosarcoma.

Sustainable Release of Propranolol Hydrochloride Laden with Biconjugated-Ufasomes Chitosan Hydrogel Attenuates Cisplatin-Induced Sciatic Nerve Damage in In Vitro/In Vivo Evaluation

“…Additionally, a cisplatin-induced neuropathy model affected catalase levels protected by co-administration of melatonin, revealing its potent antioxidant activity [ 144 ]. Recently, the role of propranolol in tumor suppression oxidative stress in neural macrophages has been reported by targeting β adrenergic receptors [ 145 ]. Its neuroprotective effect in several models of transient focal stroke was attributed to its antioxidant and free radical scavenger properties [ 146 , 147 ].…”

Inside the Biology of the β3-Adrenoceptor

“…The literature data reported the β3-ARs' ability to reduce tumor growth and metastases. Bruno et al showed that β-ARs, principally through β2and β3-ARs, supported tumor growth and cancer pain in a murine model of syngeneic osteosarcoma (OS) [184].…”

“…Zheng et al showed that β3-AR expression was significantly increased in NB tissues and that β3-AR-pathway blockade inhibited cell growth via mTOR signaling suppression that enlightened a novel regulatory axis of β3-AR and mTOR in NB cells [260]. Moreover, data have shown the pro-tumoral role of β3-AR in NB and its involvement in tumor growth in a syngeneic murine model [184]. In the murine Neuro2A cell line, both the antagonism of β3-AR and β3-AR silencing inhibited cell growth and progression, in particular, the antagonism reduced the stemness markers' expression but enhanced the markers of differentiation [258].…”

Contribution of immune cells to cancer-related neuropathic pain: An updated review

“…Recent findings from Bruno et al have revealed that β2-and β3-adrenergic receptor (AR)-expressed neural macrophages contribute to cancer-evoked pain through utilizing the K7M2 osteosarcoma-bearing mouse model. 53 In their study, the progression of mechanical allodynia elicited by oxidative stress is closely associated with the recruitment of neural macrophages. Importantly, the antagonism of β2-and β3-ARs is found to not only result in the supression of tumor growth, but also in cancer pain, together highlighting the therapeutic potential of the β2-and β3-ARs signaling against osteosarcoma-evoked pain.…”

“…Importantly, the antagonism of β2-and β3-ARs is found to not only result in the supression of tumor growth, but also in cancer pain, together highlighting the therapeutic potential of the β2-and β3-ARs signaling against osteosarcoma-evoked pain. 53 Through using human monocyte-derived macrophages, Fei et al have demonstrated that α7 nicotinic acetylcholine receptor (α7nAChR) in tumor-associated macrophages suppresses colorectal cancer (CRC) metastasis and relavant pain signaling. 47 When co-culturing with LoVo cells, a commonly-used CRC cell line, the knockdown of α7nAChR in macrophages dramatically attenuated the phosphorylation of STAT3, p85 as well as p65.…”