Neuropathic animals display increased sensitivity to the

Neuropathic animals display increased sensitivity to the anti-nociceptive effect of baclofen and whilst the number and affinity of GABAB Dabrafenib sale in the dorsal horn are not altered (Smith et al., 1994; Zemoura et al., 2016), GABAB receptors subunits (B1 and B2) are both down-regulated in sensory neurons after nerve injury (Engle et al., 2012) and GABAB1 down-regulation in nociceptive neurons is a likely contributor to reduced GABA-mediated inhibition of nociceptive input in the dorsal horn. Allosteric modulators of GABAB receptors such as rac-BHFF, have not shown efficacy in neuropathic mice and suggest a limited role for that GABAB-mediated mechanisms under this condition (Zemoura et al., 2016). On a more positive note, baclofen has shown anti-hyperlagesic effects in cancer induced bone pain (CIBP) which is poorly managed with currently available analgesics including opioids. GABAB receptors undergo down regulation in the dorsal horn of CIBP rats where they are expressed mainly by neurons. Interestingly, prolonged treatment with baclofen restored receptor expression (Zhou et al., 2017). Whether GABAB allosteric modulators are effective analgesic in CIBP remains to be explored.
Conclusion In conclusion, over the past three decades the research on GABA biology and pharmacology has been a fascinating voyage. From the intuition of Norman Bowery on the existence of a second receptor for GABA to the definition of GABAB molecular mechanisms, patterns of expression and potent modulatory functions within the CNS, we are now harnessing this science for innovative approaches to the therapeutic management of pain. In this review I have brought together this knowledge which has stemmed from Bowery's discovery with the excitement and awareness that his legacy would be fulfilled by the development of novel analgesics able to activate the GABAB receptor.
Acknowledgements Research in MM lab is currently supported by the Arthritis Research UK (grant number 20020), Medical Research Council (MR/M023893/1) European commission FP7/2007-2013 under grant agreement 602133 and under grant agreement grant 603191.
Introduction Muscarinic acetylcholine receptors are densely expressed in the striatum and are vigorously involved in the regulation of striatal neuronal activity (Levey et al., 1991, Hersch et al., 1994). Among five subtypes of muscarinic receptors (M1–5), muscarinic 4 (M4) receptors have drawn particular attention. This receptor is a principal muscarinic receptor subtype expressed in postsynaptic striatal neurons. More specifically, M4 receptors are expressed in striatonigral projection neurons, one of two subpopulations of medium spiny projection neurons in the striatum (Ince et al., 1997, Santiago and Potter, 2001). As a typical G protein-coupled receptor (GPCR), the M4 receptor is coupled to Gαi/o proteins. Through Gαi/o proteins, M4 receptors inhibit adenylyl cyclase and thereby reduce cAMP formation and protein kinase A (PKA) activity (Wess, 1996). It is generally viewed that the M4-mediated cholinergic transmission interacts with other local transmitters to maintain neuronal homeostasis and synaptic plasticity, although underlying molecular mechanisms are poorly understood. Dopamine is another important transmitter in the striatum. By interacting with dopamine D1 receptors and D2 receptors, two major dopamine receptor subtypes in the striatum, dopamine achieves its various local actions. In details, D1 and D2 receptors are segregated into two subpopulations of striatal projection neurons, i.e., D1 receptors expressed in striatonigral neurons and D2 receptors present in striatopallidal neurons (Gerfen et al., 1990, Aubert et al., 2000, Bertran-Gonzalez et al., 2010). Both dopamine receptors are GPCRs. Activation of Gαs/Golf-coupled D1 receptors and Gαi/o-coupled D2 receptors stimulates and inhibits the cAMP-PKA pathway, respectively (Neve et al., 2004). Given the fact that D1 and M4 receptors are coexpressed in striatonigral neurons while they oppositely regulate the cAMP-PKA pathway, the two receptors are thought to form a balance at the PKA level to control the responsibility of the PKA-dependent effectors to changing synaptic input.