br Conclusion The HT receptor family is

Conclusion The 5-HT receptor family is complex, and one may ask as does Bryan Roth et al. [205] whether this is useless iso 1 synthesis (i.e. too much redundancy) or an embarrassment of the riches (i.e. many potential targets to choose from to affect normal or pathological function); molecular biology has largely confirmed, but also significantly enlarged the suspected diversity and stopped discussions about too much complexity or redundancy of 5-HT receptors. It still remains to be seen which functions some of the many subtypes play in health and/or disease (e.g. 5-ht5 receptors). There are multiple links between 5-HT receptors and disease, as illustrated by a large list of medications active at one or the other receptors and/or 5-HT transporters or metabolizing enzymes, other drugs being active at several receptors at the time, as illustrated by various antipsychotics/antidepressants. The complexity of the system is probably even larger than suspected, as illustrated by the great number of splices variants for some receptors (e.g. 5-HT4 or 5-HT7) or even editing variants (e.g. 5-HT2C). It is beyond the scope of this short review to address the impact of genetic variations on 5-HT receptor or transporter function in health and disease (see [206]). Similarly, complexity is also contributed by GPCR interacting proteins and other chaperones, endogenous modulating proteins such as 5-HT moduline [68] or oleamide, homo and/or heterodimerisation ([70]; see also Breitwieser, 2004) (which may explain some features of the still orphan receptors such as 5-HT1P). There is room for more 5-HT3 receptors, in light of the recent cloning of further subunits, especially when considering what nature has done with nicotine, GABA or glutamate receptors. Cross talk between some of these ligand-gated channel receptors cannot be excluded given structural similarities and especially since a number of drugs share similar affinities for 5-HT3 and nicotine alpha7 receptors. It will be interesting to revisit various 5-HT receptor models which have been proposed based on sequence alignments with rhodopsin, now that a high resolution structure/crystal of the beta2 adrenoceptor has been reported by Kobilka and collaborators (see [207], [208]).
Introduction Paracetamol (acetaminophen) has been extensively studied as analgesic for pain relief in many clinical settings but its mechanism of action still is under considerable debate. Paracetamol crosses the blood brain barrier and many reports indicate that paracetamol exerts its antinociceptive activity not only peripherally, but also within the central nervous system (CNS) (Courad et al., 2001). In addition, paracetamol also exhibits antinociceptive effects in tests that are reputed to be sensitive only to central analgesics, as hot-plate test and tail-flick test (Pinardi et al., 2003, Sandrini et al., 2007), and intracerebroventricular or intrathecal administration of paracetamol have also been shown to provide antinociception (Alloui et al., 2002, Raffa et al., 2004). Paracetamol has been shown to act as a selective COX-2 inhibitor in the CNS, where the concentration of tissue peroxides is low unlike at sites of inflammation (Hinz et al., 2008, Lee et al., 2007). Also, the analgesic effects of paracetamol are attenuated by drugs that act via inhibition of serotonergic, opioid and cannabinoid systems (Pickering et al., 2006, Toussaint et al., 2010) suggesting that a number of neurotransmitter system may be involved in the central antinociceptive mechanism of paracetamol, in particular, serotonergic pathways. In support of this, different studies have shown that action of paracetamol is significantly reduced when lesions are produced in the serotonergic pathway or by inhibiting synthesis of serotonin (5-HT) in animal models (Sandrini et al., 2003, Tiippana et al., 2013). Conversely, paracetamol treatment induces a significant increase in 5-HT levels in the brainsterm (Courade et al., 2001). Another hypothesis that has surfaced is that the analgesic action of systemically administered paracetamol could be attributed to spinal 5-HT (5-HT3 and 5-HT7) receptors mediated the enhanced neurotransmitter release in the descending serotonergic pathway, which is responsible for modulation of pain at the spinal level (Dogrul et al., 2012). However, other studies report a serotonergic facilitatory modulation onto the spinal cord through 5-HT3 in different pain models (Bannister et al., 2015, Sikandar et al., 2012).