Mechanisms of Sensitization SecondMessenger Pathways

Molecules released or activated following ligand binding to a receptor that leads to changes in cellular processes are referred to as second messengers. The sequence of cellular events associated with the release/activation of second messengers is referred to as a second-messenger pathway. Second-messenger pathways underlie the sensitization of both peripheral and central neurons. The detail to which many of these pathways have been elucidated is extraordinary, and far beyond the scope of the present chapter. Nevertheless, several general concepts have arisen from detailed analysis of second-messenger pathways that are particularly important to the understanding of pain and sensitization. These include the duration of a second-messenger-mediated change in cellular processes, the history of the neuron, cross talk between second-messenger pathways, and the influence of target of innervation.

A primary function of second-messenger-mediated signaling pathways is that they enable the amplification of cellular events in terms of the magnitude of the event, its cellular distribution, and its duration. The duration of an event is tightly regulated and depends both on the second-messenger pathway utilized and on the presence of cellular processes responsible for the termination/reversal of the event. There are second-messenger-mediated events that occur on the millisecond-to-minute time scale, other events that occur over minutes to hours and others still that may require days or longer. Classical second-messenger-signaling pathways involve the activation of PKA or protein kinase C (PKC). These two kinases appear to be critical for the initiation of inflammatory hyperalgesia (120-122) as well as changing the properties of ion channels thought to underlie inflammatory hyperalgesia (123). It has long been known that activation of PKC may involve the activation of phospholipase C (PLC), which cleaves phospha-tidylinositol 4,5-bisphosphate (PIP2), resulting in the liberation of diacylglycerol (DAG) and inositol trisphosphate (IP3). Liberated IP3 causes the release of Ca2+ from internal stores, and DAG and Ca2+ may act as coactivators of PKC. More recently, it has been demonstrated that PIP2 may directly regulate the activity of specific ion channels. Consequently, PLC-mediated cleavage of PIP2 may result in the activation of some ion channels (124) or the inhibition of others (125). More recently, a number of additional, rapid second-messenger cascades have been identified that underlie sensitization of nociceptive afferents, including the nitric oxide (NO)/ guanylate cyclase (GC)/protein kinase G (PKG) pathway (126), ceramide sphingomyelinase pathway (127), and at least two myelin-associated protein kinase (MAPK) pathways, including extracellular signal-related/mitogen-activated potein kinase (ERK) (128) and p38 (66). Some of the kinase-mediated changes in nociceptor excitability are relatively short lived as the apparent result of phosphatase activity. However, in the face of limited phosphatase activity, some of the kinase-mediated changes in excitability may last many tens of minutes. While not well documented in nociceptive systems, there is evidence of changes in ion channel and/or receptor distribution following the activation of specific second-messenger pathways (129). These changes appear to involve cytoskeletal proteins and may last for minutes to hours.

Even longer-lasting changes appear to ultimately reflect changes in protein synthesis. Changes in transcription and translation have both been documented and may be driven by a number of distinct second-messenger pathways (34). Time-dependent activation of second-messenger pathways in a series of different cell types, developing over many days, appears to underlie the maintenance of pain observed, following nerve injury (130).

Cross talk between second-messenger pathways appears to be the norm and is a phenomenon that has important implications for the interpretation of experiments designed to characterize second-messenger pathways mediating the sensitization of nociceptive neurons. "Cross talk'' is the term used to describe the observation that the activation of one second-messenger pathway may lead to modulation and/or activation of a second pathway. This sort of interaction may occur at a number of levels starting from the receptor and ending at the effector molecule. Interactions between PKA- and PKC-dependent pathways have been well documented and depend on the actions of a number of different second messengers including G-protein subunits, adenylate cyclase isoforms, and Ca2+ (131). Interestingly, a relatively novel mechanism of interaction between PKA and PKC pathways was recently identified and actually occurs upstream of activation of PKA. An increase in cAMP in a subpopulation of nociceptive neurons results in the activation of a cAMP-activated guanine exchange factor (Epac) in addition to, and/or instead of, the activation of PKA (132). Epac, in turn, appears to mediate the activation of two phospholipases, PLC and PLD, both of which are critical for the activation of an isoform of PKC. An example of an interaction that occurs at the effector level is the kinase-mediated modulation of BK channels, depending on the splice variant of the a subunit of the BK channel (slo); the ability of PKA to phosphorylate the channel may depend on whether the channel has been phosphorylated by PKC (133).

Several lines of evidence indicate that the second-messenger pathway(s) activated by an inflammatory mediator in naive tissue may not be the same second-messenger pathway activated by the inflammatory mediator in tissue previously injured, thereby highlighting the importance of "history" on the response to injury. Importantly, the response of an organism to reinjury may be exacerbated or prolonged (22,134). Evidence that this change in the response to reinjury may reflect a change in second-messenger coupling was suggested by data from a model employing two inflammatory insults (22). In naive tissue, administration of the inflammatory mediator PGE2 results in nociceptor sensitization mediated by the activation of PKA- and PKG-dependent second-messenger cascades. This sensitization appears to last for approximately 60 minutes. However, in tissue previously inflamed, PGE2 results in hyperalgesia lasting more than 24 hours that appears to be mediated by the activation of a PKC-dependent pathway (22).

The observation that activation of the NO/GC/PKG pathway may produce different results depending on whether inflammation is present provides another example of the influence of "history" on second-messenger signaling. The NO pathway is involved in the modulation of afferent activity, underlying the action of bradykinin (135,136) and PGE2 (137), where in naive tissue activation of this pathway appears to mediate nociceptor sensitization via modulation of a VGSC (137). In the presence of persistent inflammatory hyperalgesia, however, the NO pathway appears to mediate the antinociceptive effects of peripheral opioids via activation of a potassium channel (138).

The role of NO-dependent pathways in the modulation of afferent excitability also illustrates the importance of target of innervation on the mechanisms underlying injury-induced changes in nociception as different subpopulations of afferents that are either sensitized, inhibited, or unaffected by the activation of NO-dependent pathways (139). For example, intradermal activation of this pathway is pronociceptive, suggesting that intradermal afferents are sensitized, following the activation of this pathway (139). Conversely, subcutaneous activation of this pathway is antinociceptive (139), suggesting that activation of this pathway can decrease the excitability of cutaneous afferents. The suggestion that both populations of neurons may innervate the same site in some tissues comes from the observation that there are subpopulations of dural afferents that could be distinguished according to whether they were sensitized, inhibited, or unaffected by NO (140).

Second-messenger-mediated pathways leading to long-term changes in neuronal properties involve changes in protein synthesis and therefore engage translational and transcriptional machinery. A number of second-messenger pathways underlying short-term changes in neuronal properties, such as those associated with Ca2+ influx or MAPK activation are also involved in mediating changes in protein synthesis. Activity-mediated Ca2+ influx is clearly involved in initiating changes in protein synthesis (97). Much more widely studied, however, is the impact of neurotrophic factors such as nerve growth factor (NGF) and glial-derived neurotrophic factor. Molecules such as NGF were originally shown to activate specific receptors, forming a trophic factor/receptor complex, which was internalized, transported back to the cell body, and translocated into the nucleus where it was thought to regulate transcriptional activity through binding to DNA at specific sites (141). More recently, it has been shown that these signaling molecules are able to initiate a number of distinct second-messenger cascades (142) and that downstream targets such as ERK and p38 are also involved in regulating transcriptional and translational machinery (66,143).

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