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: The authors 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. They measured the effect of AMPAkines on mechanical and cold allodynia. They 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: The authors found that CX546, compared with dimethyl sulfoxide (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). They 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, they 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 behavior associated with long-lasting nerve injury and inflammatory insult.

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The involvement of NMDA and AMPA receptors in the mechanism of antidepressant-like action of zinc in the forced swim test

Amino Acids ◽

10.1007/s00726-009-0412-y ◽

2009 ◽

Vol 39 (1) ◽

pp. 205-217 ◽

Cited By ~ 56

Author(s):

B. Szewczyk ◽

E. Poleszak ◽

M. Sowa-Kućma ◽

A. Wróbel ◽

S. Słotwiński ◽

...

Keyword(s):

Ampa Receptors ◽

Forced Swim Test ◽

Swim Test ◽

Forced Swim

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A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats

Anesthesiology ◽

10.1097/aln.0b013e31822f16ae ◽

2011 ◽

Vol 115 (4) ◽

pp. 812-821 ◽

Cited By ~ 96

Author(s):

Jing Wang ◽

Yossef Goffer ◽

Duo Xu ◽

David S. Tukey ◽

D. B. Shamir ◽

...

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Forced Swim Test ◽

Preference Test ◽

Sucrose Preference ◽

Spared Nerve Injury ◽

Chronic Neuropathic Pain ◽

Swim Test ◽

Forced Swim ◽

Sucrose Preference Test

Background Chronic pain is associated with depression. In rodents, pain is often assessed by sensory hypersensitivity, which does not sufficiently measure affective responses. Low-dose ketamine has been used to treat both pain and depression, but it is not clear whether ketamine can relieve depression associated with chronic pain and whether this antidepressant effect depends on its antinociceptive properties. Methods The authors examined whether the spared nerve injury model of neuropathic pain induces depressive behavior in rats, using sucrose preference test and forced swim test, and tested whether a subanesthetic dose of ketamine treats spared nerve injury-induced depression. Results Spared nerve injury-treated rats, compared with control rats, showed decreased sucrose preference (0.719 ± 0.068 (mean ± SEM) vs. 0.946 ± 0.010) and enhanced immobility in the forced swim test (107.3 ± 14.6s vs. 56.2 ± 12.5s). Further, sham-operated rats demonstrated depressive behaviors in the acute postoperative period (0.790 ± 0.062 on postoperative day 2). A single subanesthetic dose of ketamine (10 mg/kg) did not alter spared nerve injury-induced hypersensitivity; however, it treated spared nerve injury-associated depression-like behaviors (0.896 ± 0.020 for ketamine vs. 0.663 ± 0.080 for control rats 1 day after administration; 0.858 ± 0.017 for ketamine vs. 0.683 ± 0.077 for control rats 5 days after administration). Conclusions Chronic neuropathic pain leads to depression-like behaviors. The postoperative period also confers vulnerability to depression, possibly due to acute pain. Sucrose preference test and forced swim test may be used to compliment sensory tests for assessment of pain in animal studies. Low-dose ketamine can treat depression-like behaviors induced by chronic neuropathic pain.

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Involvement of NMDA and AMPA receptors in the antidepressant-like activity of antidepressant drugs in the forced swim test

Pharmacological Reports ◽

10.1016/s1734-1140(13)71080-6 ◽

2013 ◽

Vol 65 (4) ◽

pp. 991-997 ◽

Cited By ~ 23

Author(s):

Małgorzata Wolak ◽

Agata Siwek ◽

Bernadeta Szewczyk ◽

Ewa Poleszak ◽

Andrzej Pilc ◽

...

Keyword(s):

Ampa Receptors ◽

Forced Swim Test ◽

Antidepressant Drugs ◽

Swim Test ◽

Forced Swim

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Involvement of AMPA receptors in the antidepressant-like effects of lithium in the mouse tail suspension test and forced swim test

Neuropharmacology ◽

10.1016/j.neuropharm.2007.11.002 ◽

2008 ◽

Vol 54 (3) ◽

pp. 577-587 ◽

Cited By ~ 77

Author(s):

Todd D. Gould ◽

Kelley C. O'Donnell ◽

Eliot R. Dow ◽

Jing Du ◽

Guang Chen ◽

...

Keyword(s):

Ampa Receptors ◽

Forced Swim Test ◽

Tail Suspension Test ◽

Tail Suspension ◽

Swim Test ◽

Forced Swim ◽

Suspension Test

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AMPAkines Target the Nucleus Accumbens to Relieve Postoperative Pain

Anesthesiology ◽

10.1097/aln.0000000000001336 ◽

2016 ◽

Vol 125 (5) ◽

pp. 1030-1043 ◽

Cited By ~ 8

Author(s):

Chen Su ◽

Hau Yeuh Lin ◽

Runtao Yang ◽

Duo Xu ◽

Michelle Lee ◽

...

Keyword(s):

Nucleus Accumbens ◽

Postoperative Pain ◽

Nerve Injury ◽

Ampa Receptors ◽

Forced Swim Test ◽

Spared Nerve Injury ◽

Mechanical Hypersensitivity ◽

Withdrawal Threshold ◽

Forced Swim ◽

Rat Paw

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.

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