Amitriptyline Suppresses Neuroinflammation-dependent Interleukin-10-p38 Mitogen-activated Protein Kinase-Heme Oxygenase-1 Signaling Pathway in Chronic Morphine-infused Rats

Abstract

These results suggest that the antiinflammatory effect of amitriptyline on morphine tolerance, probably acting by increasing IL-10 expression, is mediated by p38 mitogen-activated protein kinase heme oxygenase-1 signal transduction cascade.

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

“…IL-1␤ is elevated by morphine (Johnston et al, 2004;Bokhari et al, 2009;Cao et al, 2010), in a ceramide synthase- , sphingosine kinase- (Muscoli et al, 2010), MEK-, and CGRP- ) dependent manner; this effect could be blocked by ibudilast (Hutchinson et al, 2009a), propentofylline (Raghavendra et al, 2004a), and amitriptyline (Tai et al, 2006;Tai et al, 2009), as well as by the blockade of TNF-␣ (etanercept) (Shen et al, 2011). IL-6 elevation after morphine (Johnston et al, 2004;Dave and Khalili, 2010) is dependent on sphingosine kinase (Muscoli et al, 2010), p38, CGRP , and TLR2 and could also be blocked by etanercept (Shen et al, 2011), naltrexone (Bokhari et al, 2009), amitriptyline (Tai et al, 2006;Tai et al, 2009), and propentofylline (Raghavendra et al, 2004a). Finally, morphine elevation of TNF-␣ (Johnston et al, 2004) is dependent on TLR2 , ceramide synthase ), p38, and CGRP ) and is sensitive to amitriptyline (Tai et al, 2006;Tai et al, 2009), naltrexone (Bokhari et al, 2009), naloxone, and ␤-funaltrexamine (Sawaya et al, 2009).…”

“…IL-6 elevation after morphine (Johnston et al, 2004;Dave and Khalili, 2010) is dependent on sphingosine kinase (Muscoli et al, 2010), p38, CGRP , and TLR2 and could also be blocked by etanercept (Shen et al, 2011), naltrexone (Bokhari et al, 2009), amitriptyline (Tai et al, 2006;Tai et al, 2009), and propentofylline (Raghavendra et al, 2004a). Finally, morphine elevation of TNF-␣ (Johnston et al, 2004) is dependent on TLR2 , ceramide synthase ), p38, and CGRP ) and is sensitive to amitriptyline (Tai et al, 2006;Tai et al, 2009), naltrexone (Bokhari et al, 2009), naloxone, and ␤-funaltrexamine (Sawaya et al, 2009). Other nonclassic opioid ligands such as (ϩ)-morphine, (ϩ)-methadone and morphine-3-glucuronide are also capable of inducing upregulation of IL-1␤, IL-6, and TNF-␣ (Hutchinson et al, 2010a;Lewis et al, 2010), suggesting a possible role for nonclassic opioid pathways in inducing opioid proinflammatory responses.…”

Psychiatric comorbidity in the treatment of patients with inflammatory bowel disease

“…Amitriptyline also acts on α1-adrenoceptors to produce anti-inflammatory effects [64] . Due to its effects on the inhibitory cytokine interleukin-10, amitriptyline has been reported to suppress neuroinflammation [66] . Furthermore, antidepressants have anti-inflammatory effects by considerably decreasing the production of nitric oxide (NO) and umor necrosis factor-alpha (TNFα) in microglia and astrocyte cultures at mRNA levels [65] .…”

“…They can inhibit the degradation of IκB, the nuclear translocation of the p65 subunit of NF-κB. Therefore, NF-κB cannot transmigrate into the nucleus to bind with DNA to promote the expression of gene regions [66] . Antidepressants can also inhibit the phosphorylation of p38 mitogen-activated protein kinase in lipopolysaccharide-stimulated microglia cells [65] .…”

“…Antidepressants can also inhibit the phosphorylation of p38 mitogen-activated protein kinase in lipopolysaccharide-stimulated microglia cells [65] . This phosphorylation can induce the associated inflammatory gene expression to produce the proinflammatory cytokines and NO, which may be attenuated or inhibited by antidepressants [66] . NO can also induce ROS; therefore, it can increase intestinal damage and, with cytokine production, prolong the development of IBD.…”