Acta Neurol Belg DOI 10.1007/s13760-013-0272-9
ORIGINAL ARTICLE
Blockade of cannabinoid CB1 and CB2 receptors does not prevent the antipruritic effect of systemic paracetamol Gulis Saglam • Ozgur Gunduz • Ahmet Ulugol
Received: 22 November 2013 / Accepted: 17 December 2013 Ó Belgian Neurological Society 2013
Paracetamol has been used extensively for the treatment of pain and fever for more than a century; however, its
mechanism of action is not fully understood and currently widely discussed. Its analgesic and antipyretic actions seem to resemble those of the nonsteroidal anti-inflammatory drugs, but, unlikely, does not exert any anti-inflammatory activity and does not produce cyclooxygenase-related unwanted effects [1, 2]. Pruritus is an unpleasant sensation that provokes the desire to scratch. Similar to pain sensation, participation of various neuronal receptors in the spinal cord and transmission via spinothalamic pathways to brain are proposed for pruritus. Accordingly, antipruritic therapies are now suggested to expand from the skin to the central nervous system [3–5]. Ho¨gestatt et al. [6] suggested that paracetamol, following deacetylation to p-aminophenol, is transformed to AM404 in the brain and the spinal cord after a fatty acid amide hydrolase (FAAH)-dependent conjugation with arachidonic acid. Correspondingly, cannabinoid CB1 receptors have been indicated to mediate systemic and local antinociceptive effects of paracetamol [7, 8]. Furthermore, FAAH-dependent metabolism into AM404 and reinforcement of descending serotonergic pathways by the endocannabinoid system through activation of CB1 receptors by this metabolite are suggested to participate in paracetamol analgesia [9]. Taking into account the similarities that itch and pain sensations share, the purpose of the present study was to investigate whether blockade of cannabinoid CB1 and CB2 receptors participates in the antipruritic activity of paracetamol in mice.
Presented in ‘‘Pain in Europe VIII, 8th Congress of the European Federation of IASP Chapters’’, Florence, Italy, 9–12 October, 2013.
Methods
G. Saglam O. Gunduz A. Ulugol (&) Department of Medical Pharmacology, Faculty of Medicine, Trakya University, 22030 Edirne, Turkey e-mail: [email protected]
Female Balb/c mice (Center of the Laboratory Animals, Trakya University), weighing 20–30 g, were used. Animals were maintained under 12–12 h light–dark cycles at a
Abstract Cannabinoid CB1 receptors have been shown to mediate the antinociceptive, but not the hypothermic, action of the worldwide used analgesic, paracetamol. Since itch and pain sensations share many similarities, the purpose of the present study was to investigate whether blockade of cannabinoid CB1 and CB2 receptors participates in the antipruritic activity of paracetamol in mice. Scratching behavior was induced by intradermal serotonin injection into the rostral part of the back of the mice. After serotonin administration, scratching of the injected site by the hind paws were videotaped and counted for 30 min. Serotonin-induced scratching behavior was attenuated with high-dose paracetamol (300 mg/kg). The CB1 receptor antagonist, AM-251 (1 mg/kg), and the CB2 receptor antagonist, SR-144528 (1 mg/kg), did not alter the antiscratching behavioral effect of paracetamol. Our results indicate that, in contrast to its antinociceptive action, but similar to its hypothermic effect, cannabinoid receptors are not involved in the antipruritic activity of paracetamol. Keywords Paracetamol Cannabinoid receptors AM-251 SR-144528 Pruritus
Introduction
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Acta Neurol Belg
Fig. 1 Effects of different doses (30, 100, 300 mg/kg) of paracetamol on serotonin-induced scratches (*P \ 0.05, n = 9 for each group)
temperature of 21 ± 2 °C; water and food were provided ad libitum. This study was performed according to the guidelines of the Ethical Committee of the International Association for the Study of Pain, and the experimental protocols were approved by the local ‘‘Animal Care Ethics Committee’’. Paracetamol was purchased from Sigma, SR144528 from Cayman, and serotonin hydrochloride and AM-251 from Tocris. Paracetamol was dissolved in saline, while AM-251 and SR-144528 in 20 % DMSO, 1 % Tween 80, 1 % ethanol, and 78 % saline. Scratching behavior was induced by intradermal injection of 50 lg/50 lL of serotonin into the rostral part of the back of the mice. After serotonin administration, scratching of the injected site by the hind paws were videotaped and counted for 30 min. The mice typically showed several scratches per second and such response was counted as one bout of scratching. After testing different doses of paracetamol (30, 100, 300 mg/kg, i.p.), the effect of the CB1 receptor antagonist, AM-251 (1 mg/kg, i.p.), and the CB2 receptor antagonist, SR-144528 (1 mg/kg, i.p.), on the antipruritic effects of paracetamol was studied. Paracetamol was administered 30 min before serotonin injection, and cannabinoid antagonists were given 30 min before paracetamol. Drug doses and treatment times were chosen from previous studies [7, 8, 10]. Hind leg scratching counts were normally distributed (Bartlett’s test). Thus, to compare the data of the groups, analysis of variance (ANOVA), followed by Bonferroni t test, was carried out. Values of P \ 0.05 were considered to be significant. All data are expressed as mean ± SEM.
Results Paracetamol attenuated serotonin-induced scratching at the highest dose used (300 mg/kg, P \ 0.05, Fig. 1). The CB1
123
Fig. 2 Effects of the CB1 receptor antagonist, AM-251 (1 mg/kg), and the CB2 receptor antagonist, SR-144528 (1 mg/kg), on attenuation of serotonin-induced scratches by paracetamol (300 mg/kg) (*P \ 0.05, n = 9 for each group)
receptor antagonist, AM-251 (1 mg/kg), and the CB2 receptor antagonist, SR-144528 (1 mg/kg), at doses that did not exert any effect on their own, did not alter the antiscratching behavioral activity of paracetamol (Fig. 2).
Discussion The analgesic action of paracetamol is not totally elucidated; it seems to be far beyond a peripheral local effect and involves many central nervous system structures. A number of mechanisms have been proposed to explain this central action of paracetamol. Among these, inhibition of central cyclooxygenase [11], modulation of opioid and serotonergic system [12, 13], and inhibition of nitric oxide synthase [14] appear to play important roles. In addition, the necessity of cannabinoid CB1 receptors and the contribution of endocannabinoid system in paracetamol analgesia have been discovered [7, 8, 15]. Accordingly, involvement of CB1 receptors followed by reinforcement of descending inhibitory pathways has been shown to participate in paracetamol-induced analgesia [9]. On the other hand, in contrast to the contribution of cannabinoid system to paracetamol analgesia, cannabinoids and cannabinoid CB1 receptors have been shown not to be involved in paracetamol-induced hypothermia [16, 17]. Little is known about the effect of nonsteroidal antiinflammatory drugs on pruritus, especially when the central nervous system is the target for their site of action. Both tenoxicam and diclofenac have been shown to decrease opioid-induced pruritus scores significantly [18, 19]. Recently, antipruritic effects of paracetamol and some
Acta Neurol Belg
other nonsteroidal anti-inflammatory drugs have also been shown [20, 21]; these antipruritic effects have been indicated to be independent of the cannabinoid system. Similarly, our findings indicate that paracetamol attenuates scratching behavior with its higher doses, but antagonism of cannabinoid CB1 and CB2 receptors does not affect this antipruritic effect of paracetamol. As mentioned earlier, itch and pain sensations contain many similarities. Recent researches indicate that cannabinoid receptor agonists tend to decrease scratching behavior and reveal FAAH inhibitors as a novel target to treat pruritus [22, 23]. Taken together, similar to pain researches, cannabinoid receptor antagonists, especially CB1 receptor antagonists, could be expected to mediate the antipruritic effect of paracetamol. However, unlike its antinociceptive but similar to its hypothermic effect, blockade of cannabinoid CB1 and CB2 receptors did not prevent the antipruritic activity of paracetamol. It should also be taken into consideration that the cannabinoid system might be involved in this antipruritic action of paracetamol when other itch models or different routes of administration are employed. Acknowledgments This work was supported by a grant from Trakya University Research Council (TUBAP-2012/186). Conflict of interest report.
The authors have no conflicts of interests to
References 1. Blough ER, Wu M (2011) Acetaminophen: beyond pain and fever-relieving. Front Pharmacol 2:1–6 2. Tippana E, Hamunen K, Kontinen V, Kalso E (2013) The effect of paracetamol and tropisetron on pain: experimental studies and a review of published data. Basic Clin Pharmacol Toxicol 112:124–131 3. Cevikbas F, Steinhoff M, Ikoma A (2011) Role of spinal neurotransmitter receptors in itch: new insights into therapies and drug development. CNS Neurosci Ther 17:742–749 4. Ross SE (2011) Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease. Curr Opin Neurobiol 21:880–887 5. Schmelz M (2010) Itch and pain. Neurosci Biobehav R 34:171–176 6. Ho¨gestatt ED, Jo¨nsson BA, Ermund A, Andersson DA, Bjo¨rk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM (2005) Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 280:31405–31412
7. Dania M, Guindon J, Lambert C, Beaulieu P (2007) The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors. Eur J Pharmacol 573: 214–215 8. Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A (2006) The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors. Eur J Pharmacol 531:280–281 9. Mallet C, Daulhac L, Bonnefont J et al (2008) Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain 139:190–200 10. Elmas P, Ulugol A (2013) Involvement of cannabinoid CB1 receptors in the antinociceptive effect of dipyrone. J Neural Transm 120:1533–1538 11. Flower RJ, Vane JR (1972) Inhibition of prostaglandin synthetase in brain explains antipyretic activity of paracetamol (4-Acetamidophenol). Nature 240:410–411 12. Bujalska M (2004) Effect of nonselective and selective opioid receptors antagonists on antinociceptive action of acetaminophen [Part III]. Pol J Pharmacol 56:539–545 13. Pini LA, Sandrini M, Vitale G (1996) The antinociceptive action of paracetamol is associated with changes in the serotonergic system in the rat brain. Eur J Pharmacol 308:31–40 14. Ryu YS, Lee JH, Seok JH et al (2000) Acetaminophen inhibits iNOS gene expression in RAW 264.7 macrophages: differential regulation of NF-kappa B by acetaminophen and salicylates. Biochem Bioph Res Co 272:758–764 15. Dogrul A, Seyrek M, Akgul EO, Cayci T, Kahraman S, Bolay H (2012) Systemic paracetamol-induced analgesic and anti-hyperalgesic effects through activation of descending serotonergic pathways involving spinal 5-HT7 receptors. Eur J Pharmacol 677:93–101 16. Ayoub SS, Pryce G, Seed MP, Bolton C, Flower RJ, Baker D (2011) Paracetamol-induced hypothermia is independent of cannabinoids and transient receptor potential vanilloid-1 and is not mediated by AM404. Drug Metab Dispos 39:1689–1695 17. Corley G, Rawls SM (2009) Opioid, cannabinoid CB1 and NOP receptors do not mediate APAP-induced hypothermia in rats. Pharmacol Biochem Behav 92:503–507 18. Colbert S, O’Hanlon DM, Chambers F, Moriarty DC (1999) The effect of intravenous tenoxicam on pruritus in patients receiving epidural fentanyl. Anaesthesia 54:76–80 19. Colbert S, O’Hanlon DM, Galvin S, Chambers F, Moriarty DC (1999) The effect of rectal diclofenac on pruritus in patients receiving intrathecal morphine. Anaesthesia 54:948–952 20. Dogrul A, Ilkaya F, Seyrek M, Yesilyurt O, Akar A (2012) The evaluation of antipruritic effect of paracetamol and its metabolite AM404 in an acute allergenic mice model. In: 6th European Congress of Pharmacology, Granada, Spain 21. Yesilyurt O, Seyrek M, Gunduz O, Ilkaya F, Akar A, Ulugol A, Dogrul A (2012) Does cannabinoid system represent a new therapeutic target for pruritus based on compound 48/80-induced itch model. In: 14th World Congress on Pain, Milan, Italy 22. Darmani NA, Pandya DK (2000) Involvement of other neurotransmitters in behaviors induced by the cannabinoid CB1 receptor antagonist SR 141716A in naive mice. J Neural Transm 107:931–945 23. Schlosburg JE, Kinsey SG, Lichtman AH (2009) Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation. AAPS J 11:39–44
123
ORIGINAL ARTICLE
Blockade of cannabinoid CB1 and CB2 receptors does not prevent the antipruritic effect of systemic paracetamol Gulis Saglam • Ozgur Gunduz • Ahmet Ulugol
Received: 22 November 2013 / Accepted: 17 December 2013 Ó Belgian Neurological Society 2013
Paracetamol has been used extensively for the treatment of pain and fever for more than a century; however, its
mechanism of action is not fully understood and currently widely discussed. Its analgesic and antipyretic actions seem to resemble those of the nonsteroidal anti-inflammatory drugs, but, unlikely, does not exert any anti-inflammatory activity and does not produce cyclooxygenase-related unwanted effects [1, 2]. Pruritus is an unpleasant sensation that provokes the desire to scratch. Similar to pain sensation, participation of various neuronal receptors in the spinal cord and transmission via spinothalamic pathways to brain are proposed for pruritus. Accordingly, antipruritic therapies are now suggested to expand from the skin to the central nervous system [3–5]. Ho¨gestatt et al. [6] suggested that paracetamol, following deacetylation to p-aminophenol, is transformed to AM404 in the brain and the spinal cord after a fatty acid amide hydrolase (FAAH)-dependent conjugation with arachidonic acid. Correspondingly, cannabinoid CB1 receptors have been indicated to mediate systemic and local antinociceptive effects of paracetamol [7, 8]. Furthermore, FAAH-dependent metabolism into AM404 and reinforcement of descending serotonergic pathways by the endocannabinoid system through activation of CB1 receptors by this metabolite are suggested to participate in paracetamol analgesia [9]. Taking into account the similarities that itch and pain sensations share, the purpose of the present study was to investigate whether blockade of cannabinoid CB1 and CB2 receptors participates in the antipruritic activity of paracetamol in mice.
Presented in ‘‘Pain in Europe VIII, 8th Congress of the European Federation of IASP Chapters’’, Florence, Italy, 9–12 October, 2013.
Methods
G. Saglam O. Gunduz A. Ulugol (&) Department of Medical Pharmacology, Faculty of Medicine, Trakya University, 22030 Edirne, Turkey e-mail: [email protected]
Female Balb/c mice (Center of the Laboratory Animals, Trakya University), weighing 20–30 g, were used. Animals were maintained under 12–12 h light–dark cycles at a
Abstract Cannabinoid CB1 receptors have been shown to mediate the antinociceptive, but not the hypothermic, action of the worldwide used analgesic, paracetamol. Since itch and pain sensations share many similarities, the purpose of the present study was to investigate whether blockade of cannabinoid CB1 and CB2 receptors participates in the antipruritic activity of paracetamol in mice. Scratching behavior was induced by intradermal serotonin injection into the rostral part of the back of the mice. After serotonin administration, scratching of the injected site by the hind paws were videotaped and counted for 30 min. Serotonin-induced scratching behavior was attenuated with high-dose paracetamol (300 mg/kg). The CB1 receptor antagonist, AM-251 (1 mg/kg), and the CB2 receptor antagonist, SR-144528 (1 mg/kg), did not alter the antiscratching behavioral effect of paracetamol. Our results indicate that, in contrast to its antinociceptive action, but similar to its hypothermic effect, cannabinoid receptors are not involved in the antipruritic activity of paracetamol. Keywords Paracetamol Cannabinoid receptors AM-251 SR-144528 Pruritus
Introduction
123
Acta Neurol Belg
Fig. 1 Effects of different doses (30, 100, 300 mg/kg) of paracetamol on serotonin-induced scratches (*P \ 0.05, n = 9 for each group)
temperature of 21 ± 2 °C; water and food were provided ad libitum. This study was performed according to the guidelines of the Ethical Committee of the International Association for the Study of Pain, and the experimental protocols were approved by the local ‘‘Animal Care Ethics Committee’’. Paracetamol was purchased from Sigma, SR144528 from Cayman, and serotonin hydrochloride and AM-251 from Tocris. Paracetamol was dissolved in saline, while AM-251 and SR-144528 in 20 % DMSO, 1 % Tween 80, 1 % ethanol, and 78 % saline. Scratching behavior was induced by intradermal injection of 50 lg/50 lL of serotonin into the rostral part of the back of the mice. After serotonin administration, scratching of the injected site by the hind paws were videotaped and counted for 30 min. The mice typically showed several scratches per second and such response was counted as one bout of scratching. After testing different doses of paracetamol (30, 100, 300 mg/kg, i.p.), the effect of the CB1 receptor antagonist, AM-251 (1 mg/kg, i.p.), and the CB2 receptor antagonist, SR-144528 (1 mg/kg, i.p.), on the antipruritic effects of paracetamol was studied. Paracetamol was administered 30 min before serotonin injection, and cannabinoid antagonists were given 30 min before paracetamol. Drug doses and treatment times were chosen from previous studies [7, 8, 10]. Hind leg scratching counts were normally distributed (Bartlett’s test). Thus, to compare the data of the groups, analysis of variance (ANOVA), followed by Bonferroni t test, was carried out. Values of P \ 0.05 were considered to be significant. All data are expressed as mean ± SEM.
Results Paracetamol attenuated serotonin-induced scratching at the highest dose used (300 mg/kg, P \ 0.05, Fig. 1). The CB1
123
Fig. 2 Effects of the CB1 receptor antagonist, AM-251 (1 mg/kg), and the CB2 receptor antagonist, SR-144528 (1 mg/kg), on attenuation of serotonin-induced scratches by paracetamol (300 mg/kg) (*P \ 0.05, n = 9 for each group)
receptor antagonist, AM-251 (1 mg/kg), and the CB2 receptor antagonist, SR-144528 (1 mg/kg), at doses that did not exert any effect on their own, did not alter the antiscratching behavioral activity of paracetamol (Fig. 2).
Discussion The analgesic action of paracetamol is not totally elucidated; it seems to be far beyond a peripheral local effect and involves many central nervous system structures. A number of mechanisms have been proposed to explain this central action of paracetamol. Among these, inhibition of central cyclooxygenase [11], modulation of opioid and serotonergic system [12, 13], and inhibition of nitric oxide synthase [14] appear to play important roles. In addition, the necessity of cannabinoid CB1 receptors and the contribution of endocannabinoid system in paracetamol analgesia have been discovered [7, 8, 15]. Accordingly, involvement of CB1 receptors followed by reinforcement of descending inhibitory pathways has been shown to participate in paracetamol-induced analgesia [9]. On the other hand, in contrast to the contribution of cannabinoid system to paracetamol analgesia, cannabinoids and cannabinoid CB1 receptors have been shown not to be involved in paracetamol-induced hypothermia [16, 17]. Little is known about the effect of nonsteroidal antiinflammatory drugs on pruritus, especially when the central nervous system is the target for their site of action. Both tenoxicam and diclofenac have been shown to decrease opioid-induced pruritus scores significantly [18, 19]. Recently, antipruritic effects of paracetamol and some
Acta Neurol Belg
other nonsteroidal anti-inflammatory drugs have also been shown [20, 21]; these antipruritic effects have been indicated to be independent of the cannabinoid system. Similarly, our findings indicate that paracetamol attenuates scratching behavior with its higher doses, but antagonism of cannabinoid CB1 and CB2 receptors does not affect this antipruritic effect of paracetamol. As mentioned earlier, itch and pain sensations contain many similarities. Recent researches indicate that cannabinoid receptor agonists tend to decrease scratching behavior and reveal FAAH inhibitors as a novel target to treat pruritus [22, 23]. Taken together, similar to pain researches, cannabinoid receptor antagonists, especially CB1 receptor antagonists, could be expected to mediate the antipruritic effect of paracetamol. However, unlike its antinociceptive but similar to its hypothermic effect, blockade of cannabinoid CB1 and CB2 receptors did not prevent the antipruritic activity of paracetamol. It should also be taken into consideration that the cannabinoid system might be involved in this antipruritic action of paracetamol when other itch models or different routes of administration are employed. Acknowledgments This work was supported by a grant from Trakya University Research Council (TUBAP-2012/186). Conflict of interest report.
The authors have no conflicts of interests to
References 1. Blough ER, Wu M (2011) Acetaminophen: beyond pain and fever-relieving. Front Pharmacol 2:1–6 2. Tippana E, Hamunen K, Kontinen V, Kalso E (2013) The effect of paracetamol and tropisetron on pain: experimental studies and a review of published data. Basic Clin Pharmacol Toxicol 112:124–131 3. Cevikbas F, Steinhoff M, Ikoma A (2011) Role of spinal neurotransmitter receptors in itch: new insights into therapies and drug development. CNS Neurosci Ther 17:742–749 4. Ross SE (2011) Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease. Curr Opin Neurobiol 21:880–887 5. Schmelz M (2010) Itch and pain. Neurosci Biobehav R 34:171–176 6. Ho¨gestatt ED, Jo¨nsson BA, Ermund A, Andersson DA, Bjo¨rk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM (2005) Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem 280:31405–31412
7. Dania M, Guindon J, Lambert C, Beaulieu P (2007) The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors. Eur J Pharmacol 573: 214–215 8. Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A (2006) The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors. Eur J Pharmacol 531:280–281 9. Mallet C, Daulhac L, Bonnefont J et al (2008) Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. Pain 139:190–200 10. Elmas P, Ulugol A (2013) Involvement of cannabinoid CB1 receptors in the antinociceptive effect of dipyrone. J Neural Transm 120:1533–1538 11. Flower RJ, Vane JR (1972) Inhibition of prostaglandin synthetase in brain explains antipyretic activity of paracetamol (4-Acetamidophenol). Nature 240:410–411 12. Bujalska M (2004) Effect of nonselective and selective opioid receptors antagonists on antinociceptive action of acetaminophen [Part III]. Pol J Pharmacol 56:539–545 13. Pini LA, Sandrini M, Vitale G (1996) The antinociceptive action of paracetamol is associated with changes in the serotonergic system in the rat brain. Eur J Pharmacol 308:31–40 14. Ryu YS, Lee JH, Seok JH et al (2000) Acetaminophen inhibits iNOS gene expression in RAW 264.7 macrophages: differential regulation of NF-kappa B by acetaminophen and salicylates. Biochem Bioph Res Co 272:758–764 15. Dogrul A, Seyrek M, Akgul EO, Cayci T, Kahraman S, Bolay H (2012) Systemic paracetamol-induced analgesic and anti-hyperalgesic effects through activation of descending serotonergic pathways involving spinal 5-HT7 receptors. Eur J Pharmacol 677:93–101 16. Ayoub SS, Pryce G, Seed MP, Bolton C, Flower RJ, Baker D (2011) Paracetamol-induced hypothermia is independent of cannabinoids and transient receptor potential vanilloid-1 and is not mediated by AM404. Drug Metab Dispos 39:1689–1695 17. Corley G, Rawls SM (2009) Opioid, cannabinoid CB1 and NOP receptors do not mediate APAP-induced hypothermia in rats. Pharmacol Biochem Behav 92:503–507 18. Colbert S, O’Hanlon DM, Chambers F, Moriarty DC (1999) The effect of intravenous tenoxicam on pruritus in patients receiving epidural fentanyl. Anaesthesia 54:76–80 19. Colbert S, O’Hanlon DM, Galvin S, Chambers F, Moriarty DC (1999) The effect of rectal diclofenac on pruritus in patients receiving intrathecal morphine. Anaesthesia 54:948–952 20. Dogrul A, Ilkaya F, Seyrek M, Yesilyurt O, Akar A (2012) The evaluation of antipruritic effect of paracetamol and its metabolite AM404 in an acute allergenic mice model. In: 6th European Congress of Pharmacology, Granada, Spain 21. Yesilyurt O, Seyrek M, Gunduz O, Ilkaya F, Akar A, Ulugol A, Dogrul A (2012) Does cannabinoid system represent a new therapeutic target for pruritus based on compound 48/80-induced itch model. In: 14th World Congress on Pain, Milan, Italy 22. Darmani NA, Pandya DK (2000) Involvement of other neurotransmitters in behaviors induced by the cannabinoid CB1 receptor antagonist SR 141716A in naive mice. J Neural Transm 107:931–945 23. Schlosburg JE, Kinsey SG, Lichtman AH (2009) Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation. AAPS J 11:39–44
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