Korean J Anesthesiol.  2019 Feb;72(1):60-67. 10.4097/kja.d.18.00022.

Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models

• Kim Y
• Kwon SY
• Jung HS
• Park YJ
• Kim YS
• In JH
• Choi JW
• Kim JA
• Joo JD

• KMID: 2438623
• DOI: http://doi.org/10.4097/kja.d.18.00022

Abstract

BACKGROUND
The pain-relief properties of tricyclic antidepressants can be attributed to several actions. Recent observations suggest that adenosine is involved in the antinociceptive effect of amitriptyline. The A3 adenosine receptor (A3AR) is the only adenosine subtype overexpressed in inflammatory and cancer cells. This study was performed to investigate the role of A3AR in the anti-nociceptive effect of amitriptyline.
METHODS
Spinal nerve-ligated neuropathic pain was induced by ligating the L5 and L6 spinal nerves of male Sprague-Dawley rats. The neuropathic rats were randomly assigned to one of the following three groups (8 per group): a neuropathic pain with normal saline group, a neuropathic pain with amitriptyline group, and a neuropathic pain with amitriptyline and 3-ethyl-5-benzyl- 2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS) group. Amitriptyline or saline was administered intraperitoneally and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191), an A3AR antagonist, was injected subcutaneously immediately before amitriptyline administration. The level of extracellular signal-regulated kinase P44/42 (ERK1/2), cyclic AMP response element-binding protein (CREB), and proinflammatory cytokines were assessed using immunoblotting or reverse-transciption polymerase chain reaction.
RESULTS
Amitriptyline increased the mechanical withdrawal threshold of the neuropathic rats. The level of phospho-ERK1/2 and phospho-CREB proteins, and proinflammatory cytokines produced by spinal nerve ligation were significantly reduced by amitriptyline administration. However, the use of MRS-1191 before amitriptyline administration not only reduced the threshold of mechanical allodynia, but also increased the signaling protein and proinflammatory cytokine levels, which were reduced by amitriptyline.
CONCLUSIONS
The results of this study suggest that the anti-nociceptive effect of amitriptyline involves the suppression of ERK1/2 and CREB signaling proteins, and A3AR activation also affects the alleviation of the inflammatory response.

Keyword

Adenosine A3; Amitriptyline; Cyclic AMP response element-binding protein; Cytokine; Mitogen-activated protein kinase

MeSH Terms

Adenosine
Amitriptyline*
Animals
Antidepressive Agents, Tricyclic
Cyclic AMP Response Element-Binding Protein
Cytokines*
Humans
Hyperalgesia
Immunoblotting
Ligation
Male
Neuralgia*
Phosphotransferases
Polymerase Chain Reaction
Rats*
Rats, Sprague-Dawley
Receptors, Purinergic P1
Spinal Nerves
Adenosine
Amitriptyline
Antidepressive Agents, Tricyclic
Cyclic AMP Response Element-Binding Protein
Cytokines
Phosphotransferases
Receptors, Purinergic P1