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-HT receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT receptor neutral antagonists. Likewise, activation of mTOR by constitutively active 5-HT 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-HT receptor/mTOR physical interaction. Collectively, these findings demonstrate a deleterious influence of non-physiological mTOR activation by constitutively active spinal 5-HT receptors upon painful and cognitive symptoms in neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT receptors with inverse agonists or disrupting the 5-HT receptor/mTOR interaction might be valuable strategies for the alleviation of neuropathic pain and cognitive co-morbidities.