TRPV1 has been originally cloned as the heat and capsaicin receptor implicated in acute pain signalling, while further research has shifted the focus to its importance in chronic pain caused by inflammation and associated with this TRPV1 sensitization. However, accumulating evidence suggests that, apart from pain signalling, TRPV1 subserves many other unrelated to nociception functions in the nervous system. In the brain, TRPV1 can modulate synaptic transmission via both pre- and postsynaptic mechanisms and there is a functional crosstalk between GABA receptors and TRPV1. Other fundamental processes include TRPV1 role in plasticity, microglia-to-neuron communication, and brain development. Moreover, TRPV1 is widely expressed in the peripheral tissues, including the vasculature, gastrointestinal tract, urinary bladder, epithelial cells, and the cells of the immune system. TRPV1 can be activated by a large array of physical (heat, mechanical stimuli) and chemical factors (e.g., protons, capsaicin, resiniferatoxin, and endogenous ligands, such as endovanilloids). This causes two general cell effects, membrane depolarization and calcium influx, thus triggering depending on the cell-type diverse functional responses ranging from neuronal excitation to secretion and smooth muscle contraction. Here, we review recent research on the diverse TRPV1 functions with focus on the brain, vasculature, and some visceral systems as the basis of our better understanding of TRPV1 role in different human disorders.

The endocannabinoid system is gaining steadily increasing research interest as its important role in the regulation of many fundamental physiological processes becomes more and more evident. One area which received particularly significant attention concerns targeting the endocannabinoid system as a useful strategy in pain control, especially in refractory, difficult to treat cases of chronic pain. Apart from the classical targets of cannabinoids, the CB1 and CB2 receptors, several members of the large TRP family of Ca2+-permeable cation channels have been designated as “ionotropic cannabinoid receptors” to highlight their role in cannabinoid signalling. The most notable in this connection are TRPV1-4, TRPA1 and TRPM8 channels. Intriguingly, all of them are also important for the detection of noxious stimuli of various origin and pain transduction. Thus, the aim of this review was to summarise the current knowledge of the endocannabinoid system, including its components, and its physiological and pathophysiological roles with focus on synaptic transmission and pain, then progress to an overview of “painful” TRPs with focus on their targeting by cannabinoids, and finally to discuss possible cellular mechanisms linking nociceptive and cannabinoid signalling with TRP channels. We conclude that several TRP subtypes not only function as an integral part of the endocannabinoid system, but also represent promising molecular constituents for pain alleviation with the use of endo- and phytocannabinoids, especially when these channels are upregulated/sensitized under inflammatory conditions.

Serotonin (5-HT) is involved in the control of various behaviors inAplysia californica, including reproduction, feeding, locomotion, circadian rhythm, synaptic plasticity, and synaptic growth. The large variety of functions of 5-HT is mediated by different receptor subtypes that are coupled to different second-messenger systems. Here, we report the cloning of a cDNA coding for anAplysiaG-protein-coupled 5-HT receptor (5-HT_ap1). Its deduced amino acid sequence resembles those of the 5-HT₁receptor subfamily. When expressed in stable cell lines, 5-HT_ap1exhibits high-affinity binding for the serotonergic radioligand [N-methyl-³H]lysergic acid diethylamide. This binding is competed by several 5-HT agonists and antagonists, and the pharmacological profile of inhibition has some similarities with those of 5-HT₁and 5-HT₇receptors. Application of 5-HT or its agonists 5-carboxamidotryptamine maleate and (±)-8-hydroxy-2-(di-n-propyl-amino) tetralin hydrobromide on cells transformed with 5-HT_ap1produced a dose-dependent inhibition of forskolin-stimulated cAMP accumulation. 5-HT_ap1is thus negatively coupled to adenylate cyclase. The production of antiserum against the 5-HT_ap1receptor allowed us to examine its expression in animal tissues. The receptor protein is detected in every tissue examined, although it seems only weakly expressed in some samples. The receptor is also found in every ganglia of the nervous system, both in the sheath and in the neurons. 5-HT_ap1mRNA is absent from the sheath, indicating that the protein observed there is probably located on the nerve terminals.

Acid-sensing ion channels (ASICs) are Na+-permeable ion channels activated by protons and predominantly expressed in the nervous system. ASICs act as pH sensors leading to neuronal excitation. At least eight different ASIC subunits (including ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, ASIC4, ASIC5) are encoded by five genes (ASIC1-ASIC5). Functional ASICs assembled in the plasma membrane are homo- or heteromeric trimers. ASIC1a-containing trimers are of particular interest as, in addition to sodium ions, they also conduct calcium ions and thus can trigger or regulate multiple cellular processes. ASICs are widely but differentially expressed in the central and peripheral nervous systems. In the mammalian brain, a majority of neurons express at least one ASIC subunit. Several recent reviews have summarized findings of the role of ASICs in the peripheral nervous system, particularly in nociception and proprioception, and the structure-function relationship of ASICs. However, there is little coverage on recent findings regarding the role of ASICs in the brain. Here we review and discuss evidence regarding the roles of ASICs: (i) as postsynaptic receptors activated by protons coreleased with glutamate at glutamatergic synapses; (ii) as modulators of synaptic transmission at glutamatergic synapses and GABAergic synapses; (iii) in synaptic plasticity, memory and learning; (iv) in some pathologies such as epilepsy, mood disorders and Alzheimer's disease.