**1. Introduction**

Nociception refers to *"neural processes of encoding and processing noxious stimuli"* as defined by the International Association for the Study of Pain. Noxious stimuli are *"actually or potentially tissue damaging events"* that need to act on nociceptors in order to cause pain. Accordingly, nociceptors are viewed as *"sensory receptors that are capable of transducing and encoding noxious stimuli"*. As such, nociceptors are peripheral nerve endings of first order nociceptive neurons; these are part of the peripheral nervous system with neuronal cell bodies located mostly in dorsal root ganglia and with central neurites projecting to second order nociceptive neurons located in the dorsal horn of the spinal cord [1].

Noxious stimuli that impinge on nociceptors comprise mechanical forces, temperature changes (heat and cold), and chemical agents (e.g., protons and plant-derived irritants such as capsaicin, menthol, or isothiocyanates). Apart from acting directly on nociceptors, such injurious impact may lead to inflammation, as do infections. This pathologic response is characterized by the release of a plethora of mediators from various types of cells including, amongst others, macrophages, mast cells, immune cells, platelets and the nociceptive neurons themselves [2]. Together, these mediators are called inflammatory soup and lead to an increased responsiveness of nociceptive neurons. This latter mechanism is known as sensitization and forms the pathophysiological basis of allodynia and hyperalgesia: pain in response to a non-nociceptive stimulus and increased pain sensitivity, respectively [1].

Constituents of the inflammatory soup comprise protons, nucleotides and nucleosides, enzymes (proteases), fatty acid derivatives (prostanglandins), biogenic amines (histamine, noradrenaline, and serotonin), cytokines, chemokines, neurotrophins and other peptides (bradykinin, endothelin, and tachykinins) [3]. These multifarious endogenous agents influence nociceptor signaling through a variety of different receptors:


Hence, most of the influence of the inflammatory soup on nociceptors is mediated by GPCRs [3]. The common outcome of the separate actions of the single components contained in the inflammatory soup is sensitization of nociceptors, as mentioned above. The prime task of nociceptors is the transformation of noxious stimuli into action potentials that are propagated along the neurites of nociceptive neurons from the periphery to the spinal cord. Accordingly, sensitization means that this transformation of noxious stimuli into action potentials is facilitated, and this may occur through one of two possible mechanisms: reduction in the action potential threshold or increased responses to suprathreshold stimuli. In principle, these two pathophysiological alternatives underlie the clinical phenomena of allodynia and hyperalgesia, respectively [1]. Consequently, this review summarizes how activation of certain GPCRs can impinge on either of these two mechanisms underlying the sensitization of nociceptors.

Obviously, the transformation of noxious stimuli into action potentials relies on the coordinated operation of a variety of ion channels. Therefore, inflammatory mediators must ultimately act on the function of these ion channels to be able to sensitize nociceptors. In this regard, the present review summarizes signaling mechanisms that link an activation of GPCRs to changes in ion channel function in nociceptors.

When dealing with GPCRs expressed in peripheral nociceptive neurons, one must take into account that not all of them subserve stimulatory actions that in the end lead to sensitization. Several of these GPCRs mediate inhibitory effects which rather diminish than enhance neuronal excitability. For the sake of comprehensiveness, such inhibitory receptors are considered as well.
