Abstract
Chronic neuropathic pain is a highly disabling syndrome that is poorly controlled by currently available analgesics. Here, we show that painful symptoms and associated cognitive deficits induced by spinal nerve ligation in the rat are prevented by the administration of serotonin 5-HT6 receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT6 receptor neutral antagonists. Likewise, activation of mTOR by constitutively active 5-HT6 receptors mediates allodynia in oxaliplatin-induced peripheral neuropathy in rats but not mechanical nociception in healthy rats. Furthermore, both painful and co-morbid cognitive symptoms in neuropathic rats are strongly reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT6 receptor/mTOR physical interaction. Collectively, these findings demonstrate a deleterious influence of non-physiological mTOR activation by constitutively active spinal 5-HT6 receptors upon painful and cognitive symptoms in neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT6 receptors with inverse agonists or disrupting the 5-HT6 receptor/mTOR interaction might be valuable strategies for the alleviation of neuropathic pain and cognitive co-morbidities.
Highlights
Neuropathic pains refer to an heterogeneous group of pains arising as a direct consequence of a lesion or disease affecting the somatosensory system (Treede et al, 2008)
Rapamycin administration attenuates mechanical allodynia induced by chronic nerve constriction injury in mice (Zhang et al, 2013), reduces mechanical allodynia and cold hypersensitivity in bortezomib-induced peripheral neuropathy in rats (Duan et al, 2018) and mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic neuropathy (He et al, 2019). In light of these observations, we investigated, in the present study, the role of 5-HT6 receptor constitutive activity and mechanistic Target Of Rapamycin (mTOR) signaling under the control of constitutively active 5-HT6 receptors in neuropathic pain and co-morbid cognitive symptoms induced by spinal nerve ligation (SNL) or oxaliplatin (OXA) administration in the rat
We explored whether the anti-allodynic effects of SB258585 and PZ1388 observed in SNL-induced traumatic neuropathic pain could be extended to chemotherapy-induced peripheral neuropathy (CIPN), a major cause of chemotherapy dose reduction or cessation in patients with cancer (Balayssac et al, 2011; Seretny et al, 2014)
Summary
Neuropathic pains refer to an heterogeneous group of pains arising as a direct consequence of a lesion or disease affecting the somatosensory system (Treede et al, 2008). Reference treatments induce frequent adverse effects, with a safety profile, evaluated by the number needed to harm (number of patients who need to be treated for one patient to drop out because of adverse effects), in the range of 11.8–13.9 (Finnerup et al, 2015). These observations underscore the need for new therapeutic strategies for the treatment of neuropathic pain
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