Advances in Clinical and Experimental Medicine
2015, vol. 24, nr 3, May-June, p. 419–427
Publication type: original article
Impairment in Pain Perception in Adult Rats Lesioned as Neonates with 5.7-Dihydroxytryptamine
1 Beskid Oncology Center, John Paul II City Hospital in Bielsko-Biała, Poland
2 Department of Basic Medical Sciences, Public Health Faculty, Medical University of Silesia, Bytom, Poland
3 Toxicology and Drug Addiction Division, Department of Toxicology and Occupational Health Protection, Public Health Faculty, Medical University of Silesia, Katowice, Poland
Background. Whereas some studies have demonstrated the essential role of 5-hydroxytryptamine (5-HT) in tramadol and acetaminophen analgesia, other research has presented conflicting results. To dispel doubts, some aspects of the involvement of 5-HT in the antinociceptive properties of these drugs remain to be clarified.
Objectives. The aim of this study was to determine whether the serotoninergic system dysfunction produced by neonatal 5-HT lesion in rats may affect the antinociceptive effects of tramadol and acetaminophen administered in adulthood.
Material and Methods. Three days after birth, the control rats were pretreated with desipramine HCl (20 mg/kg i.p.) 30 min before intraventricular saline – vehicle injection. A separate group received 5.7-DHT; 2 × 35 µg in each lateral ventricle. At the age of 8 weeks, 5-HT and 5-hydroxyidoleaceticacid (5-HIAA) concentrations were determined in the thalamus and spinal cord by an HPLC/ED method. The antinociceptive effects of tramadol (20 mg/kg i.p.) or acetaminophen (100 mg/kg i.p.) were evaluated by a battery of tests.
Results. 5.7-DHT lesioning was associated with a reduction in 5-HT and 5-HIAA content of the thalamus (> 85% and > 90%) and spinal cord (> 58% and 70%). Neonatal 5.7-DHT treatment produced a significant reduction in the antinociceptive effect of tramadol in the hot plate, tail-immersion, paw withdrawal and writhing tests. In the formalin hind paw test, the results were ambiguous. 5-HT lesion was also associated with a decrease in the analgesic effect of acetaminophen in the hot plate and writhing tests. A similar relationship wasn’t found in the other assessments conducted with the use of acetaminophen.
Conclusion. The present study provides evidence that (1) an intact serotoninergic system is required for the adequate antinociceptive action of tramadol, and (2) the serotoninergic system exerts a negligible influence on acetaminophen-induced analgesia in rats. We hypothesize that similar abnormalities in nociception may occur in patients with 5-HT dysfunction (e.g. depression), so these results should be complied in analgesic dosage adjustment.
tramadol, acetaminophen, serotonin, lesion, rats.
- Argoff C: Mechanisms of pain transmission and pharmacologic management. Curr Med Res Opin 2011, 27, 2019– –2031.
- Brus R, Nowak P, Szkilnik R, Mikolajun U, Kostrzewa RM: Serotoninergics attenuate hyperlocomotor activity in rats. Potential new therapeutic strategy for hyperactivity. Neurotox Res 2004, 6, 317–325.
- Lopez-Gimenez JF, Vilaro MT, Milligan G: Morphine desensitization, internalization, and down-regulation of the mu opioid receptor is facilitated by serotonin 5-hydroxytryptamine2A receptor coactivation. Mol Pharmacol 2008, 74, 1278–1291.
- Korossy E, Świerszcz M, Nowak E, Beśka M, Bałasz M, Nowak P, Szkilnik R: Antinociceptive effects of morphine, nefopam, indomethacin and imipramine in rats with lesion of the central serotoninergic system. Ann Acad Med Siles 2009, 63, 7–24.
- Świerszcz M, Nowak P, Bałasz A, Walawender I, Kasperski J, Skaba D, Nowak E, Szkilnik R: Effect of neonatal serotonin depletion on morphine-, nefopam-, indomethacinand imipramine-induced analgesia in tests of thermal and mechanical pain in adult rats. Adv Clin Exp Med 2010, 19, 33–41.
- Roczniak W, Wróbel J, Dolczak L, Nowak P: Influence of central noradrenergic system lesion on the serotoninergic 5-HT3 receptor mediated analgesia in rats. Adv Clin Exp Med 2013, 22, 629–638.
- Reeves RR, Burke RS: Tramadol: basic pharmacology and emerging concepts. Drugs Today (Barc) 2008, 44, 827– –836.
- Girard P, Coppé MC, Verniers D, Pansart Y, Gillardin JM: Role of catecholamines and serotonin receptor subtypes in nefopam-induced antinociception. Pharmacol Res 2006, 54, 195–202.
- Beśka M, Walawender I, Kasperski J, Skaba D, Nowak P, Reichman-Warmuz G, Szkilnik R: Biological peculiarities of the analgesic drug nefopam in rats. Adv Clin Exp Med 2010, 19, 21–31.
- Dharmshaktu P, Tayal V, Kalra BS: Efficacy of antidepressants as analgesics: a review. J Clin Pharmacol 2012, 52, 6–17.
- Dogrul A, Seyrek M, Akgul EO, Cayci T, Kahraman S, Bolay H: Systemic paracetamol-induced analgesic and antihyperalgesic effects through activation of descending serotonergic pathways involving spinal 5-HT₇ receptors. Eur J Pharmacol 2012, 677, 93–101.
- Ohayon MM: Pain sensitivity, depression, and sleep deprivation: links with serotoninergic dysfunction. J Psychiatr Res 2009, 43, 1243–1245.
- Brus R, Kostrzewa RM, Perry KW, Fuller RW: Supersensitization of the oral response to SKF 38393 in neonatal 6-hydroxydopamine-lesioned rats is eliminated by neonatal 5,7-dihydroxytryptamine treatment. J Pharmacol Exp Ther 1994, 268, 231–237.
- Nowak P, Nitka D, Kwieciński A, Jośko J, Drab J, Pojda-Wilczek D, Kasperski J, Kostrzewa RM, Brus R: Neonatal co-lesion by DSP-4 and 5,7-DHT produces adulthood behavioral sensitization to dopamine D(2) receptor agonists. Pharmacol Rep 2009, 61, 311–408.
- Jośko J, Drab J, Nowak P, Szkilnik R, Körossy E, Boroń D, Brus H, Kostrzewa RM, Brus R: Thioperamide, an H₃ receptor antagonist prevents [³H]glucose uptake in brain of adult rats lesioned as neonates with 5,7-dihydroxytryptamine. Neurotox Res 2011, 20, 93–96.
- O’Callaghan JP, Holtzman SG: Quantification of the analgesic activity of narcotic antagonists by a modified hotplate procedure. J Pharmacol Exp Ther 1975, 192, 497–505.
- Korossy-Mruk E, Kuter K, Nowak P, Szkilnik R, Rykaczewska-Czerwinska M, Kostrzewa RM, Brus R: Neonatal DSP-4 treatment modifies antinociceptive effects of the CB1 receptor agonist methanandamide in adult rats. Neurotox Res 2013, 23, 39–48.
- Nowak P, Kowalińska-Kania M, Nowak D, Kostrzewa RM, Malinowska-Borowska J: Antinociceptive effects of H₃ (R-methylhistamine) and GABA(B) (baclofen)-receptor ligands in an orofacial model of pain in rats. Neurotox Res 2013, 24, 258–264.
- Nowak P, Szczerbak G, Biedka I, Drosik M, Kostrzewa RM, Brus R: Effect of ketanserin and amphetamine on nigrostriatal neurotransmission and reactive oxygen species in Parkinsonian rats. In vivo microdialysis study. J Physiol Pharmacol 2006, 57, 583–597.
- Szkilnik R, Brus R, Malinowska-Borowska J, Nowak D, Waliczek M, Kostrzewa RM, Nowak P: Ontogenetic manganese exposure with perinatal 6-OHDA lesioning alters behavioral responses of rats to dopamine D1 and D2 agonist treatments. Environ Toxicol Pharmacol 2014, 37, 28–36.
- Yanarates O, Dogrul A, Yildirim V, Sahin A, Sizlan A, Seyrek M, Akgül O, Kozak O, Kurt E, Aypar U: Spinal 5-HT7 receptors play an important role in the antinociceptive and antihyperalgesic effects of tramadol and its metabolite, O-Desmethyltramadol, via activation of descending serotonergic pathways. Anesthesiology 2010, 112, 696–710.
- Rojas-Corrales MO, Ortega-Alvaro A, Gibert-Rahola J, Roca-Vinardell A, Micó JA: Pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine(1A/1B) antagonist, enhances the analgesic effect of tramadol. Pain 2000, 88, 119–124.
- Dürsteler C, Mases A, Fernandez V, Pol O, Puig MM: Interaction between tramadol and two anti-emetics on nociception and gastrointestinal transit in mice. Eur J Pain 2006, 10, 629–638.
- Oliva P, Aurilio C, Massimo F, Grella A, Maione S, Grella E, Scafuro M, Rossi F, Berrino L: The antinociceptive effect of tramadol in the formalin test is mediated by the serotonergic component. Eur J Pharmacol 2002, 445, 179–185.
- Yalcin I, Coubard S, Bodard S, Chalon S, Belzung C: Effects of 5,7-dihydroxytryptamine lesion of the dorsal raphe nucleus on the antidepressant-like action of tramadol in the unpredictable chronic mild stress in mice. Psychopharmacology 2008, 200, 497–507.
- Toussaint K, Yang XC, Zielinski MA, Reigle KL, Sacavage SD, Nagar S, Raffa RB: What do we (not) know about how paracetamol (acetaminophen) works? J Clin Pharm Ther 2010, 35, 617–638.
- Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF: The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology 2013, 21, 201–232.
- Pini LA, Sandrini M, Vitale G: The antinociceptive action of paracetamol is associated with changes in the serotonergic system in the rat brain. Eur J Pharmacol 1996, 308, 31–40.
- Bonnefont J, Alloui A, Chapuy E, Clottes E, Eschalier A: Orally administered paracetamol does not act locally in the rat formalin test: evidence for a supraspinal, serotonin-dependent antinociceptive mechanism. Anesthesiology 2003, 99, 976–981.
- Tjolsen A, Lund A, Hole K: Antinociceptive effect of paracetamol in rats is partly dependent on spinal serotonergic systems. Eur J Pharmacol 1991, 193, 193–201.
- Sandrini M, Pini LA, Vitale G: Differential involvement of central 5-HT1B and 5-HT3 receptor subtypes in the antinociceptive effect of paracetamol. Inflamm Res 2003, 52, 347–352.
- Fiebich BL, Candelario-Jalil E, Mantovani M, Heinzmann M, Akundi RS, Hüll M, Knörle R, Schnierle P, Finkenzeller G, Aicher B: Modulation of catecholamine release from rat striatal slices by the fixed combination of aspirin, paracetamol and caffeine. Pharmacol Res 2006, 53, 391–396.
- Courade JP, Caussade F, Martin K, Besse D, Delchambre C, Hanoun N, Hamon M, Eschalier A, Cloarec A: Effects of acetaminophen on monoaminergic systems in the rat central nervous system. Naunyn Schmiedebergs Arch Pharmacol 2001, 364, 534–537.