Neuropharmacology and Analgesia Systemic paracetamol-induced analgesic and antihyperalgesic effects through activation of descending serotonergic pathways involving spinal 5-HT 7 receptors Ahmet Dogrul a, ⁎, Melik Seyrek a , Emin Ozgur Akgul b , Tuncer Cayci b , Serdar Kahraman c , Hayrunnisa Bolay d a Department of Pharmacology, Gulhane Academy of Medicine, 06010, Ankara, Turkey b Department of Biochemistry, Gulhane Academy of Medicine, 06010, Ankara, Turkey c Department of Neurosurgery, Gulhane Academy of Medicine, 06010, Ankara, Turkey d Department of Neurology, Gazi Medical Faculty, Ankara, Turkey abstract article info Article history: Received 27 August 2011 Received in revised form 1 December 2011 Accepted 9 December 2011 Available online 21 December 2011 Keywords: Acetaminophen Paracetamol Analgesia Serotonin 5-HT 7 Spinal Hyperalgesia Postoperative pain Descending Incision Although some studies have shown the essential role of descending serotonergic pathways and spinal 5- HT 1A , 5-HT 2A , or 5-HT 3 receptors in the antinociceptive effects of paracetamol, other studies have presented conflicting results, and the particular subtype of spinal 5-HT receptors involved in paracetamol-induced an- algesia remains to be clarified. Recent studies have demonstrated the importance of spinal 5-HT 7 receptors in descending serotonergic pain inhibitory pathways. In this study, we investigated the role of descending sero- tonergic pathways and spinal 5-HT 7 receptors compared with 5-HT 3 and 5-HT 2A receptors in the antinocicep- tive and antihyperalgesic effects of paracetamol. Tail-flick, hot plate and plantar incision tests were used to determine nociception in male BALB/c mice. Lesion of serotonergic bulbospinal pathways was performed by intrathecal (i.th.) injection of 5,7-dihydroxytryptamine (5,7-DHT), and spinal 5-HT levels were measured by HPLC. To evaluate the particular subtypes of the spinal 5-HT receptors, the selective 5-HT 7 , 5-HT 3 and 5- HT 2A receptor antagonists SB 269970, ondansetron and ketanserin, respectively, were given i.th. after oral ad- ministration of paracetamol. Oral paracetamol (200, 400 and 600 mg/kg) elicits dose-dependent antinocicep- tive and antihyperalgesic effects. I.th. pretreatment with 5,7-DHT (50 μg) sharply reduced 5-HT levels in the spinal cord. Depletion of spinal 5-HT totally abolished the antinociceptive and antihyperalgesic effects of paracetamol. I.th. injection of SB 2669970 (10 μg) blocked the antinociceptive and antihyperalgesic effects of paracetamol, but ondansetron and ketanserin (10 μg) did not. Our findings suggest that systemic adminis- tration of paracetamol may activate descending serotonergic pathways and spinal 5-HT 7 receptors to produce a central antinociceptive and antihyperalgesic effects. © 2011 Elsevier B.V. All rights reserved. 1. Introduction Oral paracetamol is one of the most commonly used pain relievers, and the recent introduction of an intravenous paracetamol formula- tion has increased its use in postoperative and perioperative settings (Smith, 2009; Toussaint et al., 2010). Although one of the primary mechanisms of paracetamol-induced analgesic and antihyperalgesic effects relies on cyclooxygenase inhibition, experimental studies have shown that other mechanisms contribute to the effects of para- cetamol on nociception as well (Anderson, 2008; Bonnefont et al., 2007; Hamza and Dionne, 2009; Smith, 2009). Preclinical and clinical studies have indicated that there exists a central serotonergic mecha- nism for paracetamol-induced analgesia (Anderson, 2008; Smith, 2009). Descending serotonergic pathways make up one of the main endogenous analgesic systems and various analgesic drug actions are associated with the activation of these pathways (Dogrul and Seyrek, 2006, 2009; Rahman et al., 2011; Roca-Vinardell et al., 2003; Seyrek et al., 2010;Toussaint et al., 2010). The marked attenuation of the antinociceptive effects of systemic paracetamol in animals de- pleted of spinal 5-HT provides evidence that paracetamol induces antinociceptive effects by reinforcing descending serotonergic path- ways that inhibit nociceptive transmission in the spinal cord (Mallet et al., 2008; Tjolsen et al., 1991). Descending serotonergic (5-hydroxytryptamine, 5-HT) pathways are known to modulate spinal nociceptive processes via seven 5-HT re- ceptor families (5-HT 1–7 )(Millan, 2002). Although some studies have reported on the contribution of spinal 5-HT 1A , 5-HT 2A , and 5-HT 3 recep- tors to the antinociceptive effects of paracetamol (Bonnefont et al., 2005; Courade et al., 2001b; Mallet et al., 2008; Roca-Vinardell et al., 2003), other studies have provided conflicting results. For example, while i.th. administration of tropisetron, a selective 5-HT 3 receptor an- tagonist blocked antinociceptive effects of paracetamol in paw pressure European Journal of Pharmacology 677 (2012) 93–101 ⁎ Corresponding author at: Department of Pharmacology, Gulhane Academy of Medicine, 06018-Etlik, Ankara, Turkey. Tel.: +90 312 3044767; fax: +90 312 3042150. E-mail address: dogrula@gata.edu.tr (A. Dogrul). 0014-2999/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2011.12.016 Contents lists available at SciVerse ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar