The spinal cord is the first relay site in the transmission of nociceptive information from the periphery to the brain. Sensory signals are transmitted from the periphery by primary afferent fibres into the dorsal horn of the spinal cord, where these afferents synapse with intrinsic spinal dorsal horn neurones. Spinal projection neurones then convey this information to higher centres in the brain, where non-noxious and noxious signals can be perceived. During nociceptive transmission, the output of the spinal cord is dependent on various spinal mechanisms which can either increase or decrease the activity of dorsal horn neurones. Such mechanisms include local excitatory and inhibitory interneurones, N-methyl-D-aspartate receptor activation, and descending influences from the brainstem, which can be both inhibitory and excitatory in nature. After nerve injury or conditions of inflammation, shifts can occur in these excitatory and inhibitory mechanisms which modulate spinal excitability, often resulting in the heightened response of dorsal neurones to incoming afferent signals, and increased output to the brain, a phenomenon known as central sensitization. In this review, we consider the ways in which spinal cord activity may be altered in chronic pain states. In addition, we discuss the spinal mechanisms which are targeted by current analgesics used in the management of chronic pain.

Here, we show that phosphatidylinositol 3-kinase (PI3K) is a key player in the establishment of central sensitization, the spinal cord phenomenon associated with persistent afferent inputs and contributing to chronic pain states. We demonstrated electrophysiologically that PI3K is required for the full expression of spinal neuronal wind-up. In an inflammatory pain model, intrathecal administration of LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], a potent PI3K inhibitor, dose-dependently inhibited pain-related behavior. This effect was correlated with a reduction of the phosphorylation of ERK (extracellular signal-regulated kinase) and CaMKII (calcium/calmodulin-dependent protein kinase II). In addition, we observed a significant decrease in the phosphorylation of the NMDA receptor subunit NR2B, decreased translocation to the plasma membrane of the GluR1 (glutamate receptor 1) AMPA receptor subunit in the spinal cord, and a reduction of evoked neuronal activity as measured using c-Fos immunohistochemistry. Our study suggests that PI3K is a major factor in the expression of central sensitization after noxious inflammatory stimuli.

G q protein-coupled receptor stimulation increases sarcolemmal Na ؉ /H؉ exchanger (NHE1) activity in cardiac myocytes by an ERK/RSK-dependent mechanism, most likely via RSK-mediated phosphorylation of the NHE1 regulatory domain. Adenosine A 1 receptor stimulation inhibits this response through a G i proteinmediated pathway, but the distal inhibitory signaling mechanisms are unknown. In cultured adult rat ventricular myocytes (ARVM), the A 1 receptor agonist cyclopentyladenosine (CPA) inhibited the increase in NHE1 phosphorylation induced by the ␣ 1 -adrenoreceptor agonist phenylephrine, without affecting activation of the ERK/RSK pathway. CPA also induced significant accumulation of the catalytic subunit of type 2A protein phosphatase (PP2A c ) in the particulate fraction, which contained the cellular NHE1 complement; this effect was abolished by pretreatment with pertussis toxin to inactivate G i proteins. Confocal immunofluorescence microscopic imaging of CPA-treated ARVM revealed significant co-localization of PP2A c and NHE1, in intercalated disc regions. In an in vitro assay, purified PP2A c dephosphorylated a GST-NHE1 fusion protein containing aa 625-747 of the NHE1 regulatory domain, which had been pre-phosphorylated by recombinant RSK; such dephosphorylation was inhibited by the PP2A-selective phosphatase inhibitor endothall. In intact ARVM, the ability of CPA to attenuate the phenylephrine-induced increase in NHE1 phosphorylation and activity was lost in the presence of endothall. These studies reveal a novel role for the PP2A holoenzyme in adenosine A 1 receptor-mediated regulation of NHE1 activity in ARVM, the mechanism of which appears to involve G i protein-mediated translocation of PP2A c and NHE1 dephosphorylation.The cardiac sarcolemmal Na ϩ /H ϩ exchanger (NHE) 2 is a membrane glycoprotein encoded by the NHE1/SLC9A1 gene (1), which is one of nine known members of the solute carrier 9 (SLC9) gene family (2). The sarcolemmal NHE contributes significantly to the control of intracellular pH (pH i ) in cardiac myocytes, particularly in response to intracellular acidosis (3). Although basal activity of the sarcolemmal NHE is low under physiological conditions (3), increased exchanger activity and resultant increases in intracellular [Na ϩ ] and/or pH i may mediate inotropic responses to neurohormonal stimuli, such as endothelin 1 (4), angiotensin II (5), and ␣ 1 -adrenoreceptor (␣ 1 -AR) agonists (6). Increased sarcolemmal NHE activity, as a result of the release and autocrine/paracrine actions of angiotensin II and endothelin 1 (7) or by an independent mechanism (8), may also underlie the slow increase in force development that occurs in response to myocardial stretch.With respect to cardiac pathophysiology, there is strong evidence that sarcolemmal NHE activity contributes to myocardial injury and dysfunction during ischemia and reperfusion. Thus, NHE1-selective pharmacological inhibitors, such as cariporide, have been shown to be cardioprotective in this setting in numerous animal studies (see revi...

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Peripheral inflammation or nerve injury induces a primary afferent barrage into the spinal cord, which can cause N-methyl -aspartate (NMDA) receptor-dependent alterations in the responses of dorsal horn sensory neurons to subsequent afferent inputs. This plasticity, such as “wind-up” and central sensitization, contributes to the hyperexcitability of dorsal horn neurons and increased pain-related behavior in animal models, as well as clinical signs of chronic pain in humans, hyperalgesia and allodynia. Binding of NMDA receptor subunits by the scaffolding protein postsynaptic density protein-95 (PSD-95) can facilitate downstream intracellular signaling and modulate receptor stability, contributing to synaptic plasticity. Here, we show that spinal delivery of the mimetic peptide Tat-NR2B9c disrupts the interaction between PSD-95 and NR2B subunits in the dorsal horn and selectively reduces NMDA receptor-dependent events including wind-up of spinal sensory neurons, and both persistent formalin-induced neuronal activity and pain-related behaviors, attributed to central sensitization. Furthermore, a single intrathecal injection of Tat-NR2B9c in rats with established nerve injury-induced pain attenuates behavioral signs of mechanical and cold hypersensitivity, with no effect on locomotor performance. Thus, uncoupling of PSD-95 from spinal NR2B-containing NMDA receptors may prevent the neuronal plasticity involved in chronic pain and may be a successful analgesic therapy, reducing side effects associated with receptor blockade.