Locus coeruleus (LC) is considered to be the main source of norepinephrine in the central nervous system (CNS) and plays important role in relieving pain in the body. Changes in the activity of synaptic excitatory amino acid transporters (EAATs) would be an applicable way to regulate synaptic transmission in the LC. In the present study, we examined the role of astrocytic glutamate transporter−1 (GLT1) in the firing activity of LC neurons and the sensation of pain in rats. Male Wistar rats were divided into three control (CNT), ceftriaxone (CFT) and dihydrokainic acid (DHK) groups. Animals were given intraperitoneal injections for nine consecutive days after which the electrophysiological and behavioral experiments were performed to determine the single-unit activity of LC neurons and pain sensation. Results of this study revealed that CFT as a well−known up−regulator of GLT1 expression decreases the latency of pain sensation in rats but inhibition of GLT1 activity by DHK showed no significant effects. Furthermore, the results obtained by single-unit recording from LC showed a significant decrease in evoked response in CFT group compared to the CNT group. Therefore, this study suggests that GLT1 might be considered as a potential therapeutic target for pain modulation in the future.
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Bassi GS, Kanashiro A, Rodrigues GJ et al (2018) Brain stimulation differentially modulates nociception and inflammation in aversive and non-aversive behavioral conditions. Neuroscience 383:191–204
Bear M, Connors B, Paradios M (1996) The diffuse modularory system of the brain In: Neuroscience exploring the brain
Berridge CW, Waterhouse BD (2003) The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev 42:33–84
Bridges RJ, Esslinger CS (2005) The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes. Pharmacol Ther 107:271–285
Ennis M, Aston-Jones G, Shiekhattar R (1992) Activation of locus coeruleus neurons by nucleus paragigantocellularis or noxious sensory stimulation is mediated by intracoerulear excitatory amino acid neurotransmission. Brain Res 598:185–195
Fontana ACK (2015) Current approaches to enhance glutamate transporter function and expression. J Neurochem 134:982–1007
George P, Charles W (2007) The rat brain in stereotaxic coordinates. Qingchuan Zhuge Transl People’s Med Publ House, Beijing, p 32
George SA, Knox D, Curtis AL et al (2013) Altered locus coeruleus–norepinephrine function following single prolonged stress. Eur J Neurosci 37:901–909
Hamidi N, Nozad A, Milan HS et al (2019) Effect of ceftriaxone on paired-pulse response and long-term potentiation of hippocampal dentate gyrus neurons in rats with Alzheimer-like disease. Life Sci 238:116969
Hirata H, Aston-Jones G (1994) A novel long-latency response of locus coeruleus neurons to noxious stimuli: mediation by peripheral C-fibers. J Neurophysiol 71:1752–1761
Hirschberg S, Li Y, Randall A et al (2017) Functional dichotomy in spinal-vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats. Elife 6:e29808
Hu Y, Li W, Lu L et al (2010) An anti-nociceptive role for ceftriaxone in chronic neuropathic pain in rats. Pain 148:284–301
Jedema HP, Gold SJ, Gonzalez-Burgos G et al (2008) Chronic cold exposure increases RGS7 expression and decreases α2-autoreceptor-mediated inhibition of noradrenergic locus coeruleus neurons. Eur J Neurosci 27:2433–2443
Ji R-R, Chen G, Wang Z, et al (2020) Methods and kits for treating pain
Jones SL (1991) Descending noradrenergic influences on pain. Progress in brain research. Elsevier, The Netherland, pp 381–394
Kew JNC, Kemp JA (2005) Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology 179:4–29
Kiernan J, Rajakumar R (2013) Barr’s the human nervous system: an anatomical viewpoint. Lippincott Williams & Wilkins, Philadelphia
Kim K, Lee S-G, Kegelman TP et al (2011) Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol 226:2484–2493
Kimura M, Suto T, Eisenach JC, Hayashida K (2015) Down-regulation of astroglial glutamate transporter-1 in the locus coeruleus impairs pain-evoked endogenous analgesia in rats. Neurosci Lett 608:18–22
Lewerenz J, Maher P (2015) Chronic glutamate toxicity in neurodegenerative diseases—what is the evidence? Front Neurosci 9:469
Lockwood S, Dickenson AH (2019) What goes up must come down: insights from studies on descending controls acting on spinal pain processing. J Neural Transm 1–9
O’shea RD, (2002) Roles and regulation of glutamate transporters in the central nervous system. Clin Exp Pharmacol Physiol 29:1018–1023
Pajarillo E, Rizor A, Lee J et al (2019) The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: potential targets for neurotherapeutics. Neuropharmacology 161:107559
Rothstein J, Patel S, Regan M et al (2006) B-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73–77
Santenna C, Kumar S, Balakrishnan S et al (2019) A comparative experimental study of analgesic activity of a novel non-steroidal anti-inflammatory molecule–zaltoprofen, and a standard drug–piroxicam, using murine models. J Exp Pharmacol 11:85
Sawamura S, Kingery WS, Davies MF et al (2000) Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of $α$2B adrenoceptors. J Neurosci 20:9242–9251
Singewald N, Philippu A (1998) Release of neurotransmitters in the locus coeruleus. Prog Neurobiol 56:237–267
Smaga I, Fierro D, Mesa J, et al (2020) Molecular changes evoked by the beta-lactam antibiotic ceftriaxone across rodent models of substance use disorder and neurological disease. Neurosci Biobehav Rev
Stepanovic RM, Micov AM, Tomic MA et al (2014) Antihyperalgesic/antinociceptive effects of ceftriaxone and its synergistic interactions with different analgesics in inflammatory pain in rodents. Anesthesiol J Am Soc Anesthesiol 120:737–750
Sung B, Lim G, Mao J (2003) Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 23:2899–2910
Tian S-W, Yu X-D, Cen L, Xiao Z-Y (2019) Glutamate transporter GLT1 inhibitor dihydrokainic acid impairs novel object recognition memory performance in mice. Physiol Behav 199:28–32
Tsuruoka M, Willis WD Jr (1996) Bilateral lesions in the area of the nucleus locus coeruleus affect the development of hyperalgesia during carrageenan-induced inflammation. Brain Res 726:233–236
Van Bockstaele EJ, Garcia-Hernandez F, Fox K et al (2004) Expression of connexins during development and following manipulation of afferent input in the rat locus coeruleus. Neurochem Int 45:421–428
Vangaalen M, Kawahara H, Kawahara Y, Westerink BHC (1997) The locus coeruleus noradrenergic system in the rat brain studied by dual- probe microdialysis. Brain Res 763:56–62
Vazey EM, Moorman DE, Aston-Jones G (2018) Phasic locus coeruleus activity regulates cortical encoding of salience information. Proc Natl Acad Sci 115:E9439–E9448
Wang Y, Feng C, Wu Z et al (2008) Activity of the descending noradrenergic pathway after surgery in rats. Acta Anaesthesiol Scand 52:1336–1341
Weng H-R, Chen JH, Cata JP (2006) Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation. Neuroscience 138:1351–1360
Weng H-R, Chen JH, Pan ZZ, Nie H (2007) Glial glutamate transporter 1 regulates the spatial and temporal coding of glutamatergic synaptic transmission in spinal lamina II neurons. Neuroscience 149:898–907
West CHK, Boss-Williams KA, Ritchie JC, Weiss JM (2015) Locus coeruleus neuronal activity determines proclivity to consume alcohol in a selectively-bred line of rats that readily consumes alcohol. Alcohol 49:691–705
Williams JT, Henderson G, North RA (1985) Characterization of α2-adrenoceptors which increase potassium conductance in rat locus coeruleus neurones. Neuroscience 14:95–101
Xie Y-F, Wang J, Bonin RP (2018) Optogenetic exploration and modulation of pain processing. Exp Neurol 306:117–121
Zhao Z, Hiraoka Y, Ogawa H, Tanaka K (2018) Region-specific deletions of the glutamate transporter GLT1 differentially affect nerve injury-induced neuropathic pain in mice. Glia 66:1988–1998. https://doi.org/10.1002/glia.23452
Dr Ali Niapour for his valuable comments on IHC and all staff in the Laboratory of Neurophysiology at ArUMS.
This study is supported financially by the Research Vice-Chancellor of the School of Medicine, Ardabil University of Medical Sciences (GN062).
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Communicated by Sreedharan Sajikumar.
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Nozad, A., Hamidi, N. & Amani, M. The role of glutamate transporter-1 in firing activity of locus coeruleus neurons and nociception in rats. Exp Brain Res (2021). https://doi.org/10.1007/s00221-021-06065-0
- Locus coeruleus
- Single unit recording