EFFECT OF NONSELECTIVE AND SELECTIVE OPIOID RECEPTORS ANTAGONISTS ON ANTINOCICEPTIVE ACTION OF ACETAMINOPHEN [PART III]

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1 Copyright 2004 by Institute of Pharmacology Polish Academy of Sciences Polish Journal of Pharmacology Pol. J. Pharmacol., 2004, 56, ISSN EFFECT OF NONSELECTIVE AND SELECTIVE OPIOID RECEPTORS ANTAGONISTS ON ANTINOCICEPTIVE ACTION OF ACETAMINOPHEN [PART III] Magdalena Bujalska # Department of Pharmacodynamics, Medical University of Warszawa, Krakowskie Przedmieœcie 26/28, PL Warszawa, Poland Effect of nonselective and selective opioid receptors antagonists on antinociceptive action of acetaminophen [Part III]. M. BUJALSKA. Pol. J. Pharmacol., 2004, 56, The influence of naloxone (NAL), a competitive antagonist of, and receptors; D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH (CTOP), selective antagonist of -opioid receptors; nor-binaltorphimine (NOR-BNI), a potent and higly selective opioid receptor antagonist; naltrindole (NTI), a -opioid receptor antagonist and naltriben (NTB), a highly selective -opioid receptor antagonist on antinociceptive action of acetaminophen (ACETA) was studied in rats. NAL administered intraperitoneally (ip) or intracerebroventricularly (icv), and CTOP and NOR-BNI administered icv, markedly decreased the antinociceptive activity of the high dose of ACETA (400 mg/kg). Pretreatment with NTI (sc), as well as with naloxone (it), and NTB (it) slightly but significantly attenuated the ACETA antinociception. The possible involvement of the opioidergic systems in antinociceptive activity of ACETA is discussed. Key words: acetaminophen, antinociception, opioidergic systems correspondence; mbujalski@profilsp.com.pl

2 M. Bujalska Abbreviations: ACETA acetaminophen, C control, CNS central nervous system, CTOP D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH, NAL naloxone, NOR-BNI nor-binaltrophimine, NSAIDs nonsteroidal anti-inflammatory drugs, NTB naltriben, NTI naltrindol INTRODUCTION Acetaminophen (ACETA), an active metabolite of phenacetin, is a commonly used non-opioid drug. In spite of the numerous investigations, the mechanism of ACETA action is still poorly definied and has not been satisfactorily explained. This drug, as other non-steroidal anti-inflammatory drugs (NSAIDs), produces analgesic and antipyretic effect. However, unlike other NSAIDs, ACETA administered at therapeutic doses has little or no antiinflammatory and antiplatelet activity as well as does not share the typical side effect profile with other NSAIDs, such as damage of gastrointestinal tract, induction of aspirin astma etc. Therefore, ACETA has widely replaced acetylsalicylic acid (ASA) and other salicylates in the treatment of mild to moderate pain conditions not associated with inflammatory processes, such as headache, toothache and dysmenorrhoea [2, 8, 9, 14, 21]. The results obtained in previous study suggested that both cyclooxygenase (COX) and nitric oxide syntase (NOS) systems were involved in the antinociception produced by orally (po) administered ACETA [5]. Among various mechanisms of action, it was suggested that endogenous opioidergic system may be involved in antinociceptive activity of ACETA [20]. However, the results of other studies concerning the influence of opioid receptors on ACETA antinociception are controversial and contradictory [7, 18]. These differences may depend on many reasons e.g.: a kind of nociceptive stimuli, a range of administered doses, a route of drug aplication, as well as a presence or a lack of inflammation [3, 6, 15, 18, 20]. Naloxone (NAL) is a competitive antagonist of,, and sigma ( ) receptors, D-Phe-Cys-Tyr-D- Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP) is a selective ligand of -opioid receptors, nor-binaltorphimine (NOR-BNI) potently and higly selectively blocks opioid receptor, naltrindole (NTI) is a -opioid receptor antagonist, and naltriben (NTB) is a highly selective 2 -opioid receptor antagonist. The ways of administration of selective -, - or -opioid receptor antagonist and the applied doses were chosen on the ground of references. It was, therefore, of interest to investigate the effects of the abovementioned drugs on the antinociceptive activity of ACETA. MATERIALS and METHODS Animals This study was performed according to the guidelines and after approval of the Local Ethics Committee for Experiments on Animals in Warszawa. Male Wistar rats weighing g housed at the room temperature of 20 ± 2 C under 12 h light-dark cycle were used. Animals had a free access to food and water. Food was limited 12 h before the experimental session. The animals were used for experimentation only once. All groups consisted of 6 rats. Drugs The following drugs were used: ACETA and NAL purchased from Polfa, Poland; NOR-BNI synthetized by A.W. Lipkowski (Institute of Industrial Chemistry in Warszawa, Poland); CTOP, NTB and NTI were purchased from Research Biochemicals Incorporated (RBI), USA. ACETA was suspended in 0.1% solution of methylcellulose. CTOP, % Analgesia Time (min) Fig. 1. Influence of naloxone (NAL) at a dose of 1 mg/kg ip on ± SEM. ACETA vs. NAL+ACETA ** p 0.01 * p 0.05; F (95%) : 3.68; F (99%) : Pol. J. Pharmacol., 2004, 56,

3 OPIOIDERGIC SYSTEM(S) AND ANTINOCICEPTIVE ACTIVITY OF ACETAMINOPHEN % Analgesia % Analgesia Time (min) Fig. 2. Influence of naloxone (NAL) at a dose of 10 g icv on ± SEM. ACETA vs. NAL+ACETA ** p 0.01; F (95%) : 3.8; F (99%) : 6.7 NAL, NTB, NTI were dissolved in redistilled water. ACETA was applied per os (po) via the gastric tube at the dose of 400 mg/kg, CTOP was given intracerebroventricularly (icv) [1, 34] at g, NAL was administered icv and intrathecally (it) at 10 g or intraperitoneally (ip) at 1 mg/kg [13], NOR-BNI was injected icv at 7 g [34], NTB was given it at 1.0 g [29, 33] and NTI was administered subcutaneously (sc) at 1 mg/kg [13]. Control animals received 0.1% solution of methylcellulose or redistilled water, respectively. Intrathecal administration It injections of drugs were based on the method described for mice by Hylden and Wilcox [11] as modified by Stachura and Herman [28] for rats. At the time of injection, an animal was held firmly by the pelvis girdle with one hand. The Hamilton syringe was held at an angle of about 20 above the vertebral column with the other hand. Then, the tip of the needle (No. 25) was placed onto one side of the L 5 -L 6 intervertebral space. The syringe was tilted to about 10, and the needle was introduced 5 mm deep into the vertebral column canal. The drugs were injected in a volume of 3 l, and the needle was rotated during its withdrawal. Fig. 3. Influence of naloxone (NAL) at a dose of 10 g it on ± SEM. ACETA vs. NAL+ACETA ** p 0.01; F (95%) : 3.68; F (99%) : 6.36 Intracerebroventricular administration Icv administration of drugs was based on the method described by Noble and Wurtman [16] modified by Robinson et al. [23]. The animals were anaesthetized with pentobarbital (Vetbutal, Polfa) at a dose of 30 mg/kg. The polyethylene cannula was permanently implanted into the right lateral ventricle, 4 mm deep from the dura, 2 mm lateral to the crossing of the sagital and coronal sutures, according to the procedure described by Strada et al. [30]. Animals were then placed in separate cages. The experiment began on the fifth day after cannulation. The drugs were administered using a Hamilton syringe. Experimental methods The changes in nociceptive thresholds were estimated using a mechanical stimuli (the modification of the Randall and Selitto paw withdrawal test) [22]. For mechanical stimulation, a progressively increased pressure was applied to the dorsal surface of the rat s paw (expressed in g) using an analgesimeter (Ugo-Basile). Percent of analgesia was calculated according to the following formula: ISSN

4 M. Bujalska Fig. 4. Influence of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr- NH (CTOP) at a dose of g icv on antinociceptive activity of acetaminophen (ACETA) po at a dose of 400 mg/kg in Randall-Selitto test. Values are means ± SEM. ACETA vs. CTOP+ACETA ** p 0.01; F (95%) : 3.74; F (99%) : 6.51 % analgesia = 100 x B 100 A A pressure (in g) at the time 0. B pressure (in g) 15, 30, 60, 75, 90, 120, 150 and 180 min after ACETA administration. NAL (ip, it and icv) was applied 30 min before ACETA (po). NTI (sc) and NTB (it) were given 10 min before ACETA (po), CTOP (icv) and NOR-BNI (icv) 15 min before ACETA. Statistics All results were expressed as the mean ± SEM. Statistical significance was determined by means of ANOVA (multiple comparisons). A value of p 0.05 was considered as significant. All statistical calculations were performed with the use of computer programs described by Tallarida and Murray [31]. RESULTS Influence of NAL (nonselective opioid receptor antagonist) on antinociceptive activity of ACETA NAL administered alone at 1 mg/kg ip, 10 g icv and 10 g it did not influence the nociceptive threshold. Fig. 5. Influence of nor-binaltrophimine (NOR-BNI) at a dose of 7 g icv on antinociceptive activity of acetaminophen (ACETA) po at a dose of 400 mg/kg in Randall-Selitto test. Values are means ± SEM. ACETA vs. NOR-BNI+ACETA ** p 0.01; F (95%) : 3.68; F (99%) : 6.36 Ip or icv pretreatment with NAL markedly decreased the antinociceptive activity of ACETA at 400 mg/kg dose (Fig. 1 and 2). However, pretreatment with NAL it only slightly but significantly modified ACETA antinociception (Fig. 3). Effect of CTOP, NOR-BNI, NTI, NTB on antinociceptive activity of ACETA At the used doses, none of the investigated opioid receptor antagonists (CTOP, NOR-BNI, NTI, NTB) produced any changes in the nociceptive threshold in Randall-Selitto model. In animals pretreated with CTOP icv and NOR-BNI icv, antinociceptive action of ACETA was significantly decreased (Fig. 4 and 5). As shown in Figures 6 and 7, after pretreatment with NTI sc as well as with NTB it, antinociception produced by 400 mg/kg of ACETA was also decreased but this effect was not so pronouced. DISCUSSION As demonstrated in the previous study, ACETA administered po increased the nociceptive threshold for both mechanical and chemical stimuli [5]. However, this effect was not dose-dependent. In both models, the existence of ceiling dose of ACETA (400 mg/kg) was observed above which the action of the drug was not intensified. Moreover, the results obtained in previous study [5] indi- 542 Pol. J. Pharmacol., 2004, 56,

5 OPIOIDERGIC SYSTEM(S) AND ANTINOCICEPTIVE ACTIVITY OF ACETAMINOPHEN Fig. 6. Influence of naltrindole (NTI) at a dose of 1 mg/kg sc on ± SEM. ACETA vs. NTI+ACETA ** p 0.01; F (95%) : 3.59; F (99%) : 6.11 cated that mechanism(s) of ACETA action was complex and both COX as well as NOS systems were involved in antinociception produced by this compound. As reported recently [4], ACETA possesses both peripheral as well as central antinociceptive action. The results of the present study also confirmed that opioidergic system was engaged in the mechanism of ACETA action. These observations are in agreement with results obtained by Pini et al. [20] who also noted that antinociceptive effect of higher dose of ACETA (400 mg/kg) was reversed by nonselective opioid receptor antagonist (NAL iv) in the hot-plate test and in the first phase of the formalin test. Furthermore, Sandrini et al. [24, 25, 26] reported the potentiation of antinociception of morphine when it was co-administered with a relatively low dose of ACETA (100 mg/kg). Analysis of the available literature data indicates some similarities in the antinociceptive action of ACETA and morphine. Both drugs administered icv produced the inhibition of the spinal reflex, evoked by nociceptive stimulus possibly by activation of the descending antinociceptive pathway, which leads to the increase in serotonin release in the dorsal horn [10]. Since morphine is the well-known agonist of -receptor, in the present work, we investigated the type of opioid receptors involved in the antinociceptive activity of ACETA. The results of this study indicate that the antinociceptive activity of Fig. 7. Influence of naltriben (NTB) at a dose of 1 g it on antinociceptive activity of acetaminophen (ACETA) po at a dose ± SEM. ACETA vs. NTB+ACETA ** p 0.01 * p 0.05 high doses of ACETA is attenuated by and and, to a lesser extent, also by antagonists. This seemed to confirm that opioidergic system(s) participated in ACETA-induced analgesia. It is, however, hard to believe that ACETA acts directly on opioidergic receptors since Pelissier et al. [18] were unable to demonstrated ACETA affinity for these receptors in vitro. Furthermore, in experiments of Carlsson et al. [7] intravenously administered naloxone did not antagonize the ACETA-induced supression of neuronal activity in ventro-medial thalamus produced by nociceptive stimulation of the sciatic nerve. It may be, therefore, suggested that ACETA activates opioidergic system indirectly via still unknown mechanism or mechanisms. In this respect, it is of interest to note that Sandrini et al. [24, 25] demonstrated the decrease in dynorphin levels in the cerebral cortex after administration of ACETA at 400 mg/kg. In the present study, it was demonstrated that opioid receptors localized in the brain can be involved in the ACETA-induced antinociception. Moreover, the available data confirm that antinociception induced by supraspinal administration of receptor agonists is mediated by dynorphin release, which directly influences this type of receptors [17]. Therefore, it can be speculated that analgesic activity of ACETA, at least partially, depends on dynorphin release. It is commonly known that serotonergic (5-HT) systems originating in the raphe nuclei are involved ISSN

6 M. Bujalska in analgesic activity of opioids [35]. Moreover, morphine administered to periaqueductal grey matter (PAG) increases spinal release of serotonin. A selective lesion of serotonergic neurons in a brainstem or a damage of descending pathways originating in nucleus raphe magnus and project to the dorsal horn of spinal cord decrease the antinociceptive activity of morphine, as well [12]. On the other hand, descending serotonergic system seemed to be engaged in ACETA produced antinociception since lesion of descending serotonergic pathway abolished analgesic activity of this drug [32]. Furthermore, ACETA antinociception was attenuated by tropisetron, a relatively selective 5-HT 3 receptor antagonist [18, 19]. Therefore, it cannot be excluded that ACETA modified the activity of opioidergic system or systems via serotonergic mechanism. In this study, selective antagonist of receptor (CTOP) administered supraspinally decreased antinociceptive activity of ACETA. Therefore, it can be speculated, that descending serotonergic pathway participates in antinociceptive activity of ACETA mediated by supraspinal receptor. This study also indicates that 2 receptors at the spinal cord level may be partly engaged in the mechanism of antinociceptive activity of high doses of ACETA. Possibly, this receptor may be stimulated by another still not defined ACETAactivated antinociceptive pathway. Autor suggests that it could be the -endorphin bulbospinal pathway. Interestingly enough, Tseng et al. [34] have demonstrated that supraspinal -endorphin antinociception is mediated by stimulation of epsilon receptors, which causes release of Met-enkephalin, acting on the 2 receptor in the spinal cord. The results of this study indicate that opioidergic systems are involved in antinociceptive activity of ACETA. However, it cannot be excluded that ACETA acts on some presently unknown link between opioidergic and serotonergic systems. REFERENCES 1. Bartolome JV, Chang KJ, Bartolome MB: The inhibition of ornithine decarboxylase activity in developing rat tissues by central nervous system beta-endorphin is mediated by mi-opioid receptors, but not by delta- or epsilon-opioid receptors. Eur J Pharmacol, 1995, 284, Bianchi M, Panerai AE: The dose-related effects of paracetamol on hyperalgesia and nociception in the rat. Br J Pharmacol, 1996, 117, Björkman R: Central antinociceptive effects of nonsteroidal anti-inflammatory drugs and paracetamol. Acta Anaesthesiol Scand, 1995, 39, Suppl 103, Bujalska M: Effect of cyclooxygenase and NO synthase inhibitors administered centrally on antinociceptive action of acetaminophen (Part II). Pol J Pharmacol, 2003, 55, Bujalska M, Gumu³ka WS: Effect of cyclooxygenase and NO synthase inhibitors on antinociceptive action of acetaminophen. Pol J Pharmacol, 2001, 53, Carlsson KH, Jurna I: Central analgesic effect of paracetamol manifested by depression of nociceptive activity in thalamic neurones of the rat. Neurosci Lett, 1987, 77, Carlsson KH, Monzel W, Jurna I: Depression by morphine and the non-opioid analgesic agents, metamiol (dipyrone), lysine acetylsalicylate and paracetamol, of activity in rat thalamus neurones evoked by electrical stimulation of nociceptive afferents. Pain, 1988, 32, Clissold SP: Paracetamol and phenacetin. Drugs, 1986, 32, Suppl 4, Day RO, Graham GG, Whelton A: The position of paracetamol in the world of analgesics. Am J Ther, 2000, 7, Flether D, Benoist JM, Gautron M, Guibaud G: Isobolographic analysis of interactions between intravenous morphine, propacetamol and diclofenac in carrageenininjected rats. Anesthesiology, 1997, 87, Hylden JLK, Wilcox GL: Intrathecal morphine in mice: a new technique. Eur J Pharmacol, 1980, 67, Jensen TS: Opioids in the brain: supraspinal mechanism in pain control. Acta Anaesthesiol Scand, 1997, 41, Kayser V: Endogenous opioid systems in the modulation of pain: behavioral studies in rat models of persistent hyperalgesia. Proceedings of the World Congress on Pain, Progress in Pain Reserch and Management, Vol. 2, Ed. Gebhart GF, Hammond DL, Jensen TS, IASP Press, Seattle, Meredith TJ, Goulding R: Paracetamol. Postgrad Med J, 1980, 56, Molke Jensen F, Dahl JB, Frigast C: Direct spinal effect of intrathecal acetaminophen on visceral noxious stimulation in rabits. Acta Anaesthesiol Scand, 1992, 36, Noble EP, Wurtman RJ: A simple and rapid method for injecting H3-norepinephrine into the lateral ventricle of the rat brain. Life Sci, 1967, 6, Ohsawa M, Mizoguchi H, Narita M, Chu M, Nagase H, Tseng LF: Differential mechanisms mediating descending pain controls for antinociception induced by supraspinally administered endomorphin-1 and endomorphin-2 in the mouse. J Pharmacol Exp Ther, 2000, 294, Pelissier T, Alloui A, Caussade F, Dubray C, Cloarec A, Lavarenne J, Echalier A: Paracetamol exerts a spinal antinociceptive effect involving an indirect inter- 544 Pol. J. Pharmacol., 2004, 56,

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