Przeciwbólowe efekty morfiny, nefopamu, indometacyny i imipraminy u szczurów z lezją ośrodkowego układu serotoninergicznego
More details
Hide details
Department of Pharmacology, Medical University of Silesia, Zabrze, Poland
Corresponding author
Przemysław Nowak   

Katedra i Zakład Farmakologii SUM w Katowicach, 41-808 Zabrze, ul. H. Jordana 38, tel./faks: +(48 32) 272 26 83
Ann. Acad. Med. Siles. 2009;63:7-24
The aim of the present study was to examine the eff ect of the central serotoninergic lesion on the antinociceptive eff ects of morphine (5.0 mg/kg sc), nefopam (20 mg/kg ip), indomethacin (5.0 mg/kg ip) and imipramine (10 mg/kg ip) in the model of exteroceptive sensation - formalin test (chemical stimulus), and interoceptive sensation - writhing test (model of visceral pain). Furthermore monoamine synthesis rate after examined analgetics in the frontal cortex, thalamus, brain stem and spinal cord was assayed.

Material and Methods:
On the 3 rd day of postnatal life male rats were administered with 5.7-DHT (70 μg/10 μl in 0.1% ascorbic acid solution ICV; 35 μg/5 μl perside); control animals received vehicle (70 μg/10 μl of 0.1% ascorbic acid solution ICV). Rats continued to be housed until 8-10 weeks, for further experimentation.

It was shown that the central serotoninergic lesion slightly modified analgesia evoked by nefopam and indomethacin in formalin test but much more profound reduction in analgesia produced by morphine and indomethacin injection was observed in visceral model of nociception. In biochemical study it was shown that analgetics employed in this study (with exception of indomethacin) altered synthesis rate of serotonin (5-HT) and dopamine (DA) in the examined parts of the rats brain. The above indicates that besides serotoninergic pathway other monoaminergic systems (noradrenergic and dopaminergic) participate in the central mechanism of action of these drugs.

It is likely that similar nociception abnormalities may occur in patients with serotoninergic system dysfunction, so that it points out on the requirement of analgetics dosage adjustment.

Stein C., Clark J.D., Oh U., et al. Peripheral mechanisms of pain and analgesia. Brain Res. Rev. 2009; 60: 90-113.
Reynolds D.V. Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 1969; 164: 444 - 445.
Yoshimura M., Furue H. Mechanisms for the anti-nociceptive actions of the descending noradrenergic and serotonergic systems in the spinal cord. J. Pharmacol. Sci. 2006; 101: 107-117.
Mico J.A., Berrocoso E., Ortega-Alvaro A., Gibert-Rahola J., Rojas-Corrales M.O. The role of 5-HT1A receptors in research strategy for extensive pain treatment. Curr. Top. Med. Chem. 2006; 6: 1997-2003.
Rahman W., Suzuki R., Rygh L.J., et al. Descending serotonergic facilitation mediated through rat spinal 5HT3 receptors is unaltered following carrageenan infl ammation. Neurosci. Lett. 2004; 361: 229- 231.
Lu Y., Perl E.R. Selective action of noradrenaline and serotonin on neurones of the spinal superfi cial dorsal horn in the rat. J. Physiol. 2007; 582: 127-136.
Sawynok J. Topical and peripherally acting analgesics. Pharmacol. Rev. 2003; 55: 1-20.
Sawynok J. Topical analgesics in neuropathic pain. Curr. Pharm. Des. 2005; 11: 2995-3004.
Ge Y.X., Xin W.J., Hu N.W., Zhang T., Xu J.T., Liu X.G. Clonidine depresses LTP of C-fi ber evoked fi eld potentials in spinal dorsal horn via NO-cGMP pathway. Brain Res. 2006; 1118: 58-65.
Marazziti D., Rotondo A., Ambrogi F., Cassano G.B. Analgesia by nefopam: does it act through serotonin? Drugs Exp. Clin. Res. 1991; 17: 259-261.
Mayers A.G., Baldwin D.S. Antidepressants and their eff ect on sleep. Hum. Psychopharmacol. 2005; 20: 533-559.
Lesch K.P., Mössner R. Inactivation of 5HT transport in mice: modeling altered 5-HT homeostasis implicated in emotional dysfunction, aff ective disorders, and somatic syndromes. Handb. Exp. Pharmacol. 2006; 175: 417-456.
Gallup A.C., Gallup G.G. Yawning and thermoregulation. Physiol. Behav. 2008; 95: 10-16.
Compan V., Segu L., Buhot M.C., Daszuta A. Selective increases in serotonin 5-HT1B/1D and 5-HT2A/2C binding sites in adult rat basal ganglia following lesions of serotonergic neurons. Brain Res. 1998; 793: 103-111.
Dabrowska J., Nowak P., Brus R. Desensitization of 5-HT(1A) autoreceptors induced by neonatal DSP-4 treatment. Eur. Neuropsychopharmacol. 2007; 17: 129- 137.
Ferdyn-Drosik M., Jelito K., Korossy E., et al. Neonatal noradrenergic lesion aff ect central serotoninergic system in adult rats. Adv. Clin. Exp. Med. 2008; 17: 607-614.
Bortel A., Świerszcz M., Jaksz M., et al. Anxiety-like behaviour in neonatally DSP- 4 treated rats. Behavioural and biochemical studies. Ann. Acad. Med. Siles. 2007; 61: 485-491.
Bortel A., Nitka D., Słomian L., et al. Neonatal noradrenergic lesion with DSP-4 modifi es the convulsant eff ect of bicuculline and pentylenetetrazole in adult rats. Behavioral and biochemical studies. Ann. Acad. Med. Siles. 2008; 62: 46-52.
Bortel A., Słomian L., Nitka D., et al. Neonatal N-(-2-chloroethyl)-N-ethyl-2- bromobenzylamine (DSP-4) treatment modifi es the vulnerability to phenobarbital- and ethanol-evoked sedative-hypnotic eff ects in adult rats. Pharmacol. Rep. 2008; 60: 331-338.
Bortel A., Nowak P., Brus R. Neonatal DSP-4 treatment modifi es GABAergic neurotransmission in the prefrontal cortex of adult rats. Neurotox. Res. 2008; 13: 247- 252.
Adamus-Sitkiewicz B., Kőrössy E., Bojanek K., et al. Impairment in pain perception in adult rats treated with N-(-2-chloroethyl)- N-ethyl-2-bromobenzylamine (DSP-4) as neonates. Ann. Acad. Med. Siles. 2009; 63: 67-74.
Kőrössy E., Adamus-Sitkiewicz B., Nowak E., et al. Infl ammatory and visceral pain perception in rats lesioned with DSP-4 as neonates. Ann. Acad. Med. Siles. 2009; 63: 7-15.
Poveda R., Planas E., Pol O., Romero A., Sánchez S., Puig M.M. Interaction between metamizol and tramadol in a model of acute visceral pain in rats. Eur. J. Pain 2003; 7: 439-448.
Acton J., McKenna J.E., Melzack R. Amitriptyline produces analgesia in the formalin pain test. Exp. Neurol. 1992; 117: 94- 96.
León-Reyes M.R., Castańeda-Hernández G., Ortiz M.I. Pharmacokinetics and pharmacodynamics of diclofenac in the presence and absence of glibenclamide in the rat. J. Pharm. Pharm. Sci. 2008; 11: 68- 76.
Carlsson A., Davis J.N., Kehr W., Lindqvist M., Atack C.V. Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brain in vivo using an inhibitor of the aromatic amino acid decarboxylase. NaunynSchmiedebergs Arch. Pharmacol. 1972; 275: 153-168.
Nowak P., Bortel A., Dąbrowska J., et al. Histamine H(3) receptor ligands modulate L-dopa-evoked behavioral responses and L-dopa derived extracellular dopamine in dopamine-denervated rat striatum. Neurotox. Res. 2008; 13: 231-240.
Nowak P., Jochem J., Żwirska-Korczala K., et al. Ontogenetic noradrenergic lesion alters histaminergic activity in adult rats. Neurotox. Res. 2008; 13:79-83.
Li J.Y., Wong C.H., Huang E.Y., et al. Modulations of spinal serotonin activity aff ect the development of morphine tolerance. Anesth. Analg. 2001; 92: 1563- 1568.
Nakazawa T., Yamanishi Y., Kaneko T. A comparative study of monoaminergic involvement in the antinociceptive action of E-2078, morphine and U-50,488E. J. Pharmacol. Exp. Ther. 1991; 257: 748-753.
Giordano J., Barr G.A. Eff ects of neonatal spinal cord serotonin depletion on opiate-induced analgesia in tests of thermal and mechanical pain. Brain Res. 1988; 469: 121-127.
Jones C.K., Peters S.C., Shannon H.E. Effi cacy of duloxetine, a potent and balanced serotonergic and noradrenergic reuptake inhibitor, in infl ammatory and acute pain models in rodents. J. Pharmacol. Exp. Ther. 2005; 312: 726-732.
Piston D., Wang S., Feng Y., et al. The role of cyclooxygenase-2/prostanoid pathway in visceral pain induced liver stress response in rats. Chin. Med. J. (Engl). 2007; 120: 1813-1819.
Grauer S.M., Tao R., Auerbask S.B. Morphine induces an increase in extracellular serotonin in the rat diencephalon. Brain Res. 1992; 599: 277–282.
Tao R., Auerbach S.B. Increased extracellular serotonin in rat brain after systemic or intraraphe administration of morphine. J. Neurochem. 1994; 63: 517–524.
Xu W., Cui X., Han J.S. Spinal serotonin IA and IC/2 receptors mediate supraspinal mu opioid-induced analgesia. Neuroreport 1994; 5: 2665–2668.
Mori T., Kawano K., Shishikura T. 5- HT3-receptor antagonist inhibits visceral pain diff erently in chemical and mechanical stimuli in rats. J. Pharmacol. Sci. 2004; 94: 73-76.
Schul R., Frenk H. The role of serotonin in analgesia elicited by morphine in the periaqueductal gray matter. Brain Res. 1991; 556: 353–357.
Guiard B.P., El Mansari M., Merali Z., Blier P. Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions. Int. J. Neuropsychopharmacol. 2008; 11: 625-639.
Kurihara T., Nonaka T., Tanabe T. Acetic acid conditioning stimulus induces longlasting antinociception of somatic infl ammatory pain. Pharmacol. Biochem. Behav. 2003; 74: 841-849.
Korzeniewska-Rybicka I., Płaźnik A. Role of serotonergic and noradrenergic systems in a model of visceral pain. Pol. J. Pharmacol. 2001; 53: 475-480.
Baker D.E. Rationale for using serotonergic agents to treat irritable bowel syndrome. Am. J. Health-Syst. Pharm. 2005; 62: 700–713.
Gershon M.D. Nerves, refl exes, and the enteric nervous system. J. Clin. Gastroenterol. 2005; 39: S184–193.
Björkman R. Central antinociceptive eff ects of non-steroidal anti-infl ammatory drugs and paracetamol. Experimental studies in the rat. Acta Anaesthesiol. Scand. Suppl. 1995; 103: 1-44.
Świerszcz M., Nowak P., Bałasz M., Walawander I., Ksaperski J., Skaba D., Nowak E., Szkilnik R.: Eff ect of neonatal serotonin depletion on morphine-, nefopam-, indomethacin-, and imipramine-induced analgesia in tests of thermal and mechanical pain in adult rats. Adv. Clin. Exp. Med. 2010, 19, 33-41.
Giambalvo C.T. Snodgrass SR. Eff ect of p-chloroamphetamine and 5,7-dihydroxytryptamine on rotation and dopamine turnover. Brain Res. 1978; 149: 453-467.
Johnston C.A., Moore K.E. The eff ect of morphine on 5-hydroxytryptamine synthesis and metabolism in the striatum, and several discrete hypothalamic regions of the rat brain. J. Neural. Transm. 1983; 57: 65-73.
Strömbom U., Svensson T.H. Antagonism of morphine-induced central stimulation in mice by small doses of catecholamine- receptor agonists. J. Neural. Transm. 1978; 42: 169-179.
Rosland J.H., Hole K. The eff ect of nefopam and its enantiomers on the uptake of 5-hydroxytryptamine, noradrenaline and dopamine in crude rat brain synaptosomal preparations. J. Pharm. Pharmacol. 1990; 42: 437-438.
Girard P., Coppé M.C., Verniers D., Pansart Y., Gillardin J.M. Role of catecholamines and serotonin receptor subtypes in nefopam-induced antinociception. Pharmacol Res 2006; 54:195-202.
Esposito E., Romandini S., Merlo-Pich E., Mennini T., Samanin R. Evidence of the involvement of dopamine in the analgesic eff ect of nefopam. Eur. J. Pharmacol. 1986; 128: 157-164.
Hunskaar S., Fasmer O.B., Broch O.J., Hole K. Involvement of central serotonergic pathways in nefopam-induced antinociception. Eur. J. Pharmacol. 1987; 138: 77-82.
Karolewicz B., Paul I.A., Antkiewicz- Michaluk L. Eff ect of NOS inhibitor on forced swim test and neurotransmitters turnover in the mouse brain. Pol. J. Pharmacol. 2001; 53: 587-596.
Fuller R.W., Snoddy H.D., Robertson D.W. Mechanisms of eff ects of d-fenfl uramine on brain serotonin metabolism in rats: uptake inhibition versus release. Pharmacol. Biochem. Behav. 1988; 30: 715- 721.
Coluzzi F., Mattia C. Mechanism-based treatment in chronic neuropathic pain: the role of antidepressants. Curr. Pharm. Des. 2005; 11: 2945-2960.
Courteix C., Bardin M., Chantelauze C., Lavarenne J., Eschalier A. Study of the sensitivity of the diabetes-induced pain model in rats to a range of analgesics. Pain 1994; 57: 153-160.
Zarrindast M.R., Baghdadi B., Sahebgharani M. Potentiation of imipramine-induced antinociception by nicotine in the formalin test. Eur. Neuropsychopharmacol. 2004; 14: 71-76.
Rojas-Corrales M.O., Casas J., Moreno- Brea M.R., Gibert-Rahola J., Micó J.A. Antinociceptive eff ects of tricyclic antidepressants and their noradrenergic metabolites. Eur. Neuropsychopharmacol. 2003; 13: 355-363.
Nayebi A.R., Hassanpour M., Rezazadeh H. Eff ect of chronic and acute administration of fl uoxetine and its additive eff ect with morphine on the behavioural response in the formalin test in rats. J. Pharm. Pharmacol. 2001; 53: 219-225.
Aoki M., Tsuji M., Takeda H., Harada Y., Nohara J., Matsumiya T., Chiba H. Antidepressants enhance the antinociceptive eff ects of carbamazepine in the acetic acidinduced writhing test in mice. Eur. J. Pharmacol. 2006; 550: 78-83.
Sierralta F., Pinardi G., Miranda H.F. Eff ect of p-chlorophenylalanine and alpha- methyltyrosine on the antinociceptive eff ect of antidepressant drugs. Pharmacol. Toxicol. 1995; 77: 276-280.
Pini L.A., Vitale G., Sandrini M. The role of serotonin brain receptors in the analgesic eff ect of phenazone. Drugs Exp. Clin. Res. 1993; 19: 13-18.
Pini L.A., Sandrini M., Vitale G. Involvement of brain serotonergic system in the antinociceptive action of acetylsalicylic acid in the rat. Infl amm. Res. 1995; 44: 30- 35.
Vitale G., Pini L.A., Ottani A., Sandrini M. Eff ect of acetylsalicylic acid on formalin test and on serotonin system in the rat brain. Gen. Pharmacol. 1998; 31: 753- 758.
Journals System - logo
Scroll to top