AMPAkines Have Novel Analgesic Properties in Rat Models of Persistent Neuropathic and Inflammatory Pain

Abstract

Background Novel analgesics that do not suppress the respiratory drive are urgently needed. Glutamate signaling through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors plays important roles in central pain circuits. AMPAkines augment AMPA receptor function and have been shown to stimulate the respiratory drive to oppose opioid-induced hypoventilation. However, their role in chronic pain states remains unknown. Methods We studied AMPAkines (CX546 and CX516) in rat spared nerve injury (SNI) model of neuropathic pain and Complete Freund’s Adjuvant (CFA) model of inflammatory pain. We measured the effect of AMPAkines on mechanical and cold allodynia. We also evaluated their effect on depressive symptoms of pain using the forced swim test, as time of immobility on this test has been used as a measure for behavioral despair, a feature of depression. Results We found that CX546, compared with DMSO control, reduced both mechanical and sensory allodynia in SNI(DMSO group, n = 9; CX546 group, n = 11) and CFA models (Both DMSO and CX546 groups, n=9). We found that CX546, compared with control, also reduced depressive symptoms of pain by decreasing immobility on the forced swim test in both SNI (both DMSO and CX546 groups, n = 8) and CFA models (both DMSO and CX546 groups, n = 10). Finally, we found that CX516, compared with control, also reduced mechanical and cold allodynia in the SNI model (both DMSO and CX516 groups, n = 10). Conclusions AMPAkines alleviate pain hypersensitivity as well as depression-like behaviors associated with long-lasting nerve injury and inflammatory insult.

AMPAkines Target the Nucleus Accumbens to Relieve Postoperative Pain

“…26,27,32,33,54,55 We have previously shown that systemic administration of CX546 can relieve both sensory hypersensitivity and depressive behaviors in response to chronic neuropathic pain and inflammatory pain in rats. 56 The pathogenesis and maintenance of acute postoperative and chronic pain, however, are different mechanistically at synaptic and circuit levels. 57 Hence, we wanted to test whether CX546 could also relieve acute postoperative pain in the PI model.…”

“…56 Thus, we used the FST to assess the effects of CX546 on the depressive symptoms associated with acute incisional pain (Fig. 1B).…”

“…17 We have previously shown that systemic infusion of CX546 can relieve both mechanical hypersensitivity and depression-like behaviors in this pain model. 56 Here we tested whether AMPA receptors in the NAc function as a pharmacological target of AMPAKines in this model of persistent postoperative pain (Fig. 6A).…”

“…Sample sizes were estimated based on previous experience with the same experimental designs. 17-19,29 All data were analyzed using GraphPad Prism Version 6 software (GraphPad, La Jolla, CA).…”

“…26-28 A previous study showed AMPAkines can relieve both sensory and affective symptoms of persistent pain. 29 However, it is not known whether AMPAkines can also relieve acute postoperative pain. If so, such drugs can be ideal analgesics in the postoperative setting to relieve pain and improve mood and at the same time to enhance the safety profile of sedatives commonly administered during or after surgery.…”