Amitriptyline suppresses neuroinflammation and up-regulates glutamate transporters in morphine-tolerant rats

Abstract

The present study was performed to evaluate the effects of the tricyclic antidepressant amitriptyline on morphine tolerance in rats. Male Wistar rats were implanted with two intrathecal (i.t.) catheters with or without a microdialysis probe, then received a continuous i.t. infusion of saline (control) or morphine (15 microg/h) and/or amitriptyline (15 microg/h) for 5 days. The results showed that amitriptyline alone did not produce an antinociceptive effect, while morphine alone induced antinociceptive tolerance and down-regulation of spinal glutamate transporters (GLAST, GLT-1, and EAAC1) in the rat spinal cord dorsal horn. Co-administration of amitriptyline with morphine attenuated morphine tolerance and up-regulated GLAST and GLT-1 expression. On day 5, morphine challenge (10 microg/10 microl) resulted in a significant increase in levels of the excitatory amino acids (EAAs), aspartate and glutamate, in CSF dialysates in morphine-tolerant rats. Amitriptyline co-infusion not only markedly suppressed this morphine-evoked EAA release, but also preserved the antinociceptive effect of acute morphine challenge at the end of infusion. Glial cells activation and increased cytokine expression (TNFalpha, IL-1beta, and IL-6) in the rat spinal cord were induced by the 5-day morphine infusion and these neuroimmune responses were also prevented by amitriptyline co-infusion. These results show that amitriptyline not only attenuates morphine tolerance, but also preserves its antinociceptive effect. The mechanisms involved may include: (a) inhibition of pro-inflammatory cytokine expression, (b) prevention of glutamate transporter down-regulation, and even up-regulation of glial GTs GLAST and GLT-1 expression, with (c) attenuation of morphine-evoked EAA release following continuous long-term morphine infusion.

GluN2B N-methyl-D-aspartate receptor and excitatory amino acid transporter 3 are upregulated in primary sensory neurons after 7 days of morphine administration in rats

“…Sustained morphine administration leads to a down-regulation of glutamate transporters, especially the glial transporters GLAST and GLT1, resulting in elevation of extracellular glutamate [53; 69]. In the DRG this additional glutamate is associated with a NMDAR mediated increased excitability of sensory neurons [44].…”

The association between spinal cord trauma-sensitive miRNAs and pain sensitivity, and their regulation by morphine

“…However, administration of morphine in the acute phase of a spinal contusion injury in rats has been shown to significantly attenuate locomotor function and increase expression of chronic pain symptoms (Hook et al, 2007; Hook et al, 2009). The increased chronic pain associated with morphine administration has been attributed to the activation of astrocytes and microglia by morphine and inhibition of analgesic effects by increased expression of pro-inflammatory cytokines TNF, IL-1, and IL-6 (Cui et al, 2006; Johnston et al, 2004; Raghavendra et al, 2002; Song and Zhao, 2001; Tai et al, 2006). Accordingly, the application of an interleukin-1 receptor antagonist prior to intrathecal morphine prevents the maladaptive effects of morphine on neuropathic pain and functional recovery (Hook et al, 2011).…”

Salvia officinalis L. attenuates morphine analgesic tolerance and dependence in rats: possible analgesic and sedative mechanisms

“…Glial cells activation and increased cytokine (TNFa, IL-1, andIL-6) expression are also involved in morphine tolerance and dependence so that suppression of neuroinflammation could be helpful in the prevention of morphine withdrawal responses and morphine analgesic tolerance (35,36). It is well known that SO and its components have potent anti-inflammatory effects in different animal models of inflammation (11,14,15 (37) demonstrated that some SO constituents such as 1, 8-cineole, borneol, camphor, and thujone exert anti-inflammatory effects through inhibition of IL-6 and IL-8.…”