Mechanisms of Sensitization Receptors

In addition to the thermo- and mechanoreceptors described above, a vast array of chemoreceptors has been identified that contribute to that activation and/or sensitization of nociceptive neurons (34). Chemoreceptors are most often described in terms of the compounds or agonists that activate them, such as glutamate receptors or substance P receptors. They are also classified according to whether they are directly coupled to ion channels (ionotropic receptors) or to second-messenger pathways (metabotropic receptors). Metabotropic receptors are further subclassified according to the second-messenger pathway(s) initiated following receptor activation. The largest family of metabotropic receptors is the guanine nucleotide-binding protein (G-protein)-coupled receptors. Additional metabotropic receptor families include those bearing intrinsic protein tyro-sine kinase domains (i.e., Trk receptors), receptors that associate with cytosolic tyrosine kinases (i.e., non-tyrosine kinase receptors such as cytokine receptors and integrins), and protein serine/threonine kinases [i.e., transforming growth factor (TGF)-P receptors].

Unlike mechano- or thermotransduction, which ultimately must result in neuronal activation, chemoreceptors may be either excitatory or inhibitory. A number of factors impact whether or under what conditions a receptor will be excitatory or inhibitory. For example, in most neurons in adult animals, the ionotropic y-aminobutyric acid (GABA) receptor (GABAA receptor) is inhibitory. The GABAA receptor is a Cl_ channel and because the concentration of intracellular Cl_ is usually low and the concentration of extracellular Cl_ is generally high, the equilibrium potential for Cl_ is usually below action potential threshold. However, following tissue injury, the intracellular concentration of Cl_ may be increased as a result of changes in the expression of Cl_ transporters (110). Consequently, activation of GABAA receptors may result in membrane depolarization sufficient for action potential generation. Similarly, because the concentration of intracellular Cl_ is always relatively high in primary afferent neurons, a decrease in action potential threshold may enable GABAA receptor activation to generate action potentials in primary afferents (83).

Different chemoreceptors preferentially couple to different second-messenger pathways (see below). Thus, a common mechanism influencing whether a receptor will be excitatory or inhibitory is the second-messenger pathway activated by a particular receptor. In primary afferent neurons, adenosine A2 receptors appear to couple to stimulatory G-proteins, resulting in the activation of adenylate cyclase, an increase in cyclic adenosine monophosphate (cAMP), the activation of protein kinase A (PKA) and ultimately nociceptor sensitization (111,112). In contrast, adenosine A1 receptors appear to couple to inhibitory G-proteins, resulting in the inhibition of adenylate cyclase, a decrease in cAMP and PKA activity and a reversal of sensi-tization (111). The relative balance between excitatory and inhibitory processes will depend on a number of factors, including receptor properties (i.e., binding affinity for transmitter or ligand), relative receptor density, and the history of the neuron. The balance between excitation and inhibition is further complicated in the CNS, where there is excitatory and inhibitory neural circuitry that is influenced by excitatory and inhibitory receptor activation.

Recent evidence suggests that two additional factors critically impact receptor function. The first of these is the ability of receptors or receptor subunits to form complexes. There are a number of ionotropic receptors that are assembled from a number of distinct receptor subunits. For example of GABAA receptors, which are composed of two a, two b, and a single y subunit (most commonly). Several receptors particularly relevant for nociception may be assembled from either multiples of the same subunit (homomultimers) or multiples of different subunits (heteromultimers). For example, ionotropic ATP receptors (referred to as P2X receptors) may be formed from homomultimers of P2X2 or P2X3 as well as heteromultimers of P2X2/3 (113). Importantly, the biophysical properties and/or pharmacology of heteromultimers are distinct. Therefore, the stoichiometry of subunit assembly will impact the properties of evoked currents. Recently, the issue has proven to be even more complex, as there are at least preliminary data of functional interaction between distinct ionotropic receptor subtypes. For example, there is evidence of functional interaction between ATP receptors (P2X5) and proton receptors (ASIC3), which dramatically alters proton activation of the ASIC3 receptor (114). The issue is complicated still further by evidence to suggest that G-protein-coupled receptors form functional interactions that influence receptor affinity, signaling, and trafficking (115-117).

"Receptor trafficking'' is a term used to describe processes underlying receptor localization, internalization, and reinsertion in neuronal membranes. While many of the mechanisms underlying receptor trafficking have yet to be fully elucidated, it is clear that these processes play a critical role in neural plasticity and therefore are likely to contribute to both peripheral and central sensitization observed following tissue injury (118,119).

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