AMPAkines Target the Nucleus Accumbens to Relieve Postoperative Pain

Abstract

Background AMPAkines augment the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the brain to increase excitatory outputs. These drugs are known to relieve persistent pain. However, their role in acute pain is unknown. Furthermore, a specific molecular and anatomic target for these novel analgesics remains elusive. Methods The authors studied the analgesic role of an AMPAkine, CX546, in a rat paw incision (PI) model of acute postoperative pain. The authors measured the effect of AMPAkines on sensory and depressive symptoms of pain using mechanical hypersensitivity and forced swim tests. The authors asked whether AMPA receptors in the nucleus accumbens (NAc), a key node in the brain’s reward and pain circuitry, can be a target for AMPAkine analgesia. Results Systemic administration of CX546 (n = 13), compared with control (n = 13), reduced mechanical hypersensitivity (50% withdrawal threshold of 6.05 ± 1.30 g [mean ± SEM] vs. 0.62 ± 0.13 g), and it reduced depressive features of pain by decreasing immobility on the forced swim test in PI-treated rats (89.0 ± 15.5 vs. 156.7 ± 18.5 s). Meanwhile, CX546 delivered locally into the NAc provided pain-relieving effects in both PI (50% withdrawal threshold of 6.81 ± 1.91 vs. 0.50 ± 0.03 g; control, n = 6; CX546, n = 8) and persistent postoperative pain (spared nerve injury) models (50% withdrawal threshold of 3.85 ± 1.23 vs. 0.45 ± 0.00 g; control, n = 7; CX546, n = 11). Blocking AMPA receptors in the NAc with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione inhibited these pain-relieving effects (50% withdrawal threshold of 7.18 ± 1.52 vs. 1.59 ± 0.66 g; n = 8 for PI groups; 10.70 ± 3.45 vs. 1.39 ± 0.88 g; n = 4 for spared nerve injury groups). Conclusions AMPAkines relieve postoperative pain by acting through AMPA receptors in the NAc.

AMPAkines and morphine provide complementary analgesia

“…High-impact AMPAkines such as CX546 are more potent, but they have a narrower therapeutic window. In our current study, we did not observe any behavioral side effects or evidence of hyperexcitability with a systemic dose of 10mg/kg, and previous studies using this and similar doses have also shown the safety of this dose in rats [12, 13, 19, 20]. Nevertheless, in the future, it will be important to study the analgesic properties of newer low-impact AMPAkines which are more clinically applicable.…”

“…AMPAkines are known to improve memory and cognition [6] and have been studied in a variety of neuropsychiatric diseases [11]. Two recent studies have shown that AMPAkines can relieve acute and chronic pain in several animal models, and the sites of action for these receptors are likely in the brain [12, 13]. Interestingly, AMPAkines are also known to increase the respiratory drive to antagonize hypoventilation in the context of opioids [14].…”

“…It is not known, however, if AMPAkines and opioids can provide complementary analgesia. Furthermore, while previous studies have identified the nucleus accumbens as a potential target for AMPAkines [12], other brain regions that are known to produce descending inhibitory control of nociception, such as the prefrontal cortex (PFC), may also emerge as important therapeutic targets.…”

“…1A). The dosage of 10mg/kg was chosen based on previous dose-response experiments, which showed this dose to be able to provide near-maximal analgesia with no observed side effects [12, 13, 19, 20]. …”

Reward Circuitry Plasticity in Pain Perception and Modulation

“…In this circuitry, dopamine midbrain neurons, especially those connecting the VTA to the NAc and the NAc shell to the striatum (striato-nigro-striatal pathway) are considered the key elements ( Elman and Borsook, 2016 ). Not surprisingly, dysfunction of the VTA-NAc mesolimbic pathway has been associated with depression ( Russo and Nestler, 2013 ; Su et al, 2016 ) and neuropathic pain ( Ozaki et al, 2002 ; Taylor et al, 2015 ). Remarkably, previous studies have evidenced a dual behavior of those dopaminergic neurons, since a phasic burst occurs in response to an unexpected reward while a phasic firing inhibition occurs when an expected reward is not received ( Fields et al, 2007 ; Schultz, 2007 ).…”