Spinal upregulation of glutamate transporter GLT-1 by ceftriaxone: therapeutic efficacy in a range of experimental nervous system disorders

Abstract

Glutamate neurotransmission is highly regulated, largely by glutamate transporters. In the spinal cord, the glutamate transporter GLT-1 is primarily responsible for glutamate clearance. Downregulation of GLT-1 can occur in activated astrocytes, and is associated with increased extracellular glutamate and neuroexcitation. Among other conditions, astrocyte activation occurs following repeated opioids and in models of chronic pain. If GLT-1 downregulation occurs in these states, GLT-1 could be a pharmacological target for improving opioid efficacy and controlling chronic pain. The present studies explored whether daily intrathecal treatment of rats with ceftriaxone, a β-lactam antibiotic that upregulates GLT-1 expression, could prevent development of hyperalgesia and allodynia following repeated morphine, reverse pain arising from central or peripheral neuropathy, and reduce glial activation in these models. Ceftriaxone pre-treatment attenuated the development of hyperalgesia and allodynia in response to repeated morphine, and prevented associated astrocyte activation. In a model of multiple sclerosis (experimental autoimmune encephalomyelitis; EAE), ceftriaxone reversed tactile allodynia and halted the progression of motor weakness and paralysis. Similarly, ceftriaxone reversed tactile allodynia induced by chronic constriction nerve injury (CCI). EAE and CCI each significantly reduced the expression of membrane-bound, dimerized GLT-1 protein in lumbar spinal cord, an effect normalized by ceftriaxone. Lastly, ceftriaxone normalized CCI- and EAE-induced astrocyte activation in lumbar spinal cord. Together, these data indicate that increasing spinal GLT-1 expression attenuates opioid-induced paradoxical pain, alleviates neuropathic pain, and suppresses associated glial activation. GLT-1 therefore may be a therapeutic target that could improve available treatment options for patients with chronic pain.

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

“…Opioid-induced elevations in GFAP expression by astrocytes after long-term drug exposure has since been observed repeatedly using mRNA (Marie-Claire et al, 2004;Raghavendra et al, 2004a;Tawfik et al, 2005), protein (Tawfik et al, 2005;Wen et al, 2008;Mika et al, 2009;Ramos et al, 2010), and immunohistochemistry quantification of protein (Alonso et al, 2007). However, some studies have failed to show opioid-induced GFAP up-regulation for reasons that are unclear (Horvath et al, 2010a).…”

Targeting the Overproduction of Peroxynitrite for the Prevention and Reversal of Paclitaxel-Induced Neuropathic Pain

“…Experimental test substances or their vehicle were given either subcutaneously (s.c., 0.2 ml), orally by gavage ( p.o., 0.2 ml) or by intrathecal injection (10 l followed by a 10 l flush with sterile physiological saline) in rats chronically implanted with intrathecal cannulas using the L5/L6 lumbar approach, as described previously by us and others (Størkson et al, 1996;Ledeboer et al, 2007;Doyle et al, 2010;Muscoli et al, 2010) and commonly used for drug delivery (SchoenigerSkinner et al, 2007;Doyle et al, 2010;Muscoli et al, 2010;Ramos et al, 2010). Test compounds were administered from day 0 (D0) (30 min before the first intraperitoneal injection of the chemotherapeutic agent) to D15 or were given once on D16.…”

Glutamate Transporter Activators as Anti-Nociceptive Agents

“…The interest in anti-nociceptive effects of GLT-1 up-regulation adds to the widespread interest in utilizing spinal GLT-1 up-regulation in a wide range of CNS disorders mediated by enhanced glutamatergic neurotransmission [8]. Down regulation of GLT-1 occurs in activated astrocytes; seen often following chronic opioid therapy and in chronic pain models.…”

“…Down regulation of GLT-1 occurs in activated astrocytes; seen often following chronic opioid therapy and in chronic pain models. Efficacy has been demonstrated after intraspinal ceftriaxone in 1) hyperalgesia and allodynia following chronic morphine [8], 2) pain following peripheral neuropathy, inflammation or spinal cord injury [20,21,34] 3) tactile hyperalgesia and progression of motor weakness and paralysis in animal models of multiple sclerosis [8]. There are also ongoing studies regarding the efficacy of GLT-1 up-regulation in other conditions mediated by enhanced extracellular glutamate such as Alzheimer's disease, Huntington's disease, epilepsy, amyotrophic lateral sclerosis and the regulation of addictive behaviors [35][36][37][38][39].…”

“…Studies suggest that this transporter is responsible for the removal of over 90% of extracellular glutamate by rapidly removing it from the synaptic cleft after release from pre-synaptic terminals [7]. Since glutamate is the major excitatory neurotransmitter released in the first central synapse of the pain-transmitting afferent neurons, and perhaps from non-neuronal sources, augmentation of GLT-1 activity may be an important target of pain management strategies [8]. Indeed, substances that augment glutamate transporter function alleviate nociception and glutamate transporter blockers worsen pain [9][10][11][12][13][14].…”