Nonsteroid anti-inflammatory drugs (NSAIDs) are major drugs against inflammation and pain. They are well known inhibitors of cyclooxygenases (COXs). However, many studies indicate that they may also act on other targets. Acidosis is observed in inflammatory conditions such as chronic joint inflammation, in tumors and after ischemia, and greatly contributes to pain and hyperalgesia. Administration of NSAIDs reduces low-pH-induced pain. The acid sensitivity of nociceptors is associated with activation of H(+)-gated ion channels. Several of these, cloned recently, correspond to the acid-sensing ion channels (ASICs) and others to the vanilloid receptor family. This paper shows (1) that ASIC mRNAs are present in many small sensory neurons along with substance P and isolectin B4 and that, in case of inflammation, ASIC1a appears in some larger Abeta fibers, (2) that NSAIDs prevent the large increase of ASIC expression in sensory neurons induced by inflammation, and (3) that NSAIDs such as aspirin, diclofenac, and flurbiprofen directly inhibit ASIC currents on sensory neurons and when cloned ASICs are heterologously expressed. These results suggest that the combined capacity to block COXs and inhibit both inflammation-induced expression and activity of ASICs present in nociceptors is an important factor in the action of NSAIDs against pain.

The TREK-1 channel is a temperature-sensitive, osmosensitive and mechano-gated K þ channel with a regulation by Gs and Gq coupled receptors. This paper demonstrates that TREK-1 qualifies as one of the molecular sensors involved in pain perception. TREK-1 is highly expressed in small sensory neurons, is present in both peptidergic and nonpeptidergic neurons and is extensively colocalized with TRPV1, the capsaicin-activated nonselective ion channel.Mice with a disrupted TREK-1 gene are more sensitive to painful heat sensations near the threshold between anoxious warmth and painful heat. This phenotype is associated with the primary sensory neuron, as polymodal C-fibers were found to be more sensitive to heat in single fiber experiments. Knockout animals are more sensitive to low threshold mechanical stimuli and display an increased thermal and mechanical hyperalgesia in conditions of inflammation. They display a largely decreased pain response induced by osmotic changes particularly in prostaglandin E 2 -sensitized animals. TREK-1 appears as an important ion channel for polymodal pain perception and as an attractive target for the development of new analgesics.

Tissue acidosis is an important feature of inflammation. It is a direct cause of pain and hyperalgesia. Protons activate sensory neurons mainly through acid-sensing ion channels (ASICs) and the subsequent membrane depolarization that leads to action potential generation. We had previously shown that ASIC transcript levels were increased in inflammatory conditions in vivo. We have now found that this increase is caused by the proinflammatory mediators NGF, serotonin, interleukin-1, and bradykinin. A mixture of these mediators increases ASIC-like current amplitude on sensory neurons as well as the number of ASIC-expressing neurons and leads to a higher sensory neuron excitability. An analysis of the promoter region of the ASIC3 encoding gene, an ASIC specifically expressed in sensory neurons and associated with chest pain that accompanies cardiac ischemia, reveals that gene transcription is controlled by NGF and serotonin.

Nerve growth factor (NGF) is a key element of inflammatory pain. It induces hyperalgesia by up-regulating the transcription of genes encoding receptors, ion channels, and neuropeptides. Acid-sensing ion channel 3 (ASIC3), a depolarizing sodium channel gated by protons during tissue acidosis, is specifically expressed in sensory neurons. It has been associated to cardiac ischemic and inflammatory pains. We previously showed that low endogenous NGF was responsible for ASIC3 basal expression and high NGF during inflammation increased ASIC3 expression parallely to the development of neuron hyperexcitability associated with hyperalgesia. NGF is known to activate numerous signaling pathways through trkA and p75 receptors. We now show that (i) NGF controls ASIC3 basal expression through constitutive activation of a trkA/phospholipase C/protein kinase C pathway, (ii) high inflammatory-like NGF induces ASIC3 overexpression through a trkA/JNK/ p38MAPK pathway and a p75-dependent mechanism as a transcriptional switch, and (iii) NGF acts through AP1 response elements in ASIC3 encoding gene promoter. These new data indicate potential targets that could be used to develop new treatments against inflammatory pain.Inflammation is a major source of pain characterized by spontaneity of painful sensations and hypersensitivity. Among proinflammatory mediators, nerve growth factor (NGF) 1 is a key signal in inflammatory pain (1-4). It induces lasting sensitization of sensory neurons by changing transcription levels of pain genes such as the genes coding for preprotachykinin A (precursor of substance P), calcitonin gene-related peptide (5), tetrodotoxin-resistant voltage-dependent sodium channels (6, 7), and acid-sensing ion channels (ASICs) (8, 9). These changes generate neuronal hypersensitivity and spontaneous activity known as peripheral sensitization. Moreover, NGF induces changes at the dorsal horn neuron level and then central sensitization. This potentiation of the sensory tract leads to hyperalgesia (i.e. enhanced responses to noxious stimuli) and allodynia (i.e. innocuous stimuli produce pain), thus producing clinical pain (10).During inflammation, extracellular pH drops to values below pH 6 (11, 12) due to the leak of intracellular contents, hypoxic metabolism, and related lactic acid production. Acidosis is an important source of pain. In humans it produces non-adapting nociceptor excitation (13) and contributes to hyperalgesia and allodynia in inflammation (14 -16). Protons directly activate nociceptors (17) by gating depolarizing cationic channels (18,19) corresponding to the ASICs (20, 21). ASICs are sodium channels belonging to the ENaC/DEG family and six isoforms (ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4) have been isolated that associate to form functional homo-or heterotetramers (22-29). Among these, ASIC3 is a serious candidate as a pain sensor. First, ASIC3 is specific to dorsal root ganglia (DRG) neurons and is expressed by nociceptors (9). Second, ASIC3 displays a biphasic current with a fast activate...

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The persistence of pain after surgery increases the recovery interval from surgery to a normal quality of life. AYX1 is a DNA-decoy drug candidate designed to prevent post-surgical pain following a single intrathecal injection. Tissue injury causes a transient activation of the transcription factor EGR1 in the dorsal root ganglia-dorsal horn network, which then triggers changes in gene expression that induce neuronal hypersensitivity. AYX1 is a potent, specific inhibitor of EGR1 activity that mimics the genomic EGR1-binding sequence. Administered in the peri-operative period, AYX1 dose dependently prevents mechanical hypersensitivity in models of acute incisional (plantar), inflammatory (CFA), and chronic neuropathic pain (SNI) in rats. Furthermore, in a knee surgery model evaluating functional measures of postoperative pain, AYX1 improved weight-bearing incapacitance and spontaneous rearing compared to control. These data illustrate the potential clinical therapeutic benefits of AYX1 for preventing the transition of acute to chronic post-surgical pain.

Aims  Lamotrigine, an antiepileptic drug, is cleared from the systemic circulation mainly by glucuronidation. The possibility of changes in the pharmacokinetics of lamotrigine in plasma owing to hepatic dysfunction has been evaluated. Methods  Thirty‐six subjects, including 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers received a single 100 mg dose of lamotrgine. Blood samples were taken for 7 days in all subjects, except nine with severe cirrhosis, who had a 29 day blood sampling period. Results  The pharmacokinetics of lamotrigine were comparable between the patients with moderate cirrhosis (corresponding to Child‐Pugh grade A) and the healthy subjects. Plasma oral clearance mean ratios (90% confidence interval) in patients with severe cirrhosis without or with ascites (corresponding, respectively, to Child‐Pugh grade B and C) to healthy subjects were, respectively, 60% (44%, 83%) and 36% (25%, 52%). Plasma half‐life mean ratios (90% confidence interval) in these two patient groups to healthy subjects were, respectively, 204% (149%, 278%) and 287% (202%, 408%). Conclusions  Lamotrigine administered as a single oral dose of 100 mg was well tolerated in all groups. Initial, escalation and maintenance doses should generally be reduced by approximately 50 or 75% in patients with Child‐Pugh Grade B or C cirrhosis. Escalation and maintenance doses should be adjusted according to clinical response.

Voltage-gated potassium channels that activate near the neuronal resting membrane potential are important regulators of excitation in the nervous system, but their functional diversity is still not well understood. For instance, Kv12.2 (ELK2, KCNH3) channels are highly expressed in the cerebral cortex and hippocampus, and although they are most likely to contribute to resting potassium conductance, surprisingly little is known about their function or regulation. Here we demonstrate that the auxiliary MinK (KCNE1) and MiRP2 (KCNE3) proteins are important regulators of Kv12.2 channel function. Reduction of endogenous KCNE1 or KCNE3 expression by siRNA silencing, significantly increased macroscopic Kv12.2 currents in Xenopus oocytes by around 4-fold. Interestingly, an almost 9-fold increase in Kv12.2 currents was observed with the dual injection of KCNE1 and KCNE3 siRNA, suggesting an additive effect. Consistent with these findings, over-expression of KCNE1 and/or KCNE3 suppressed Kv12.2 currents. Membrane surface biotinylation assays showed that surface expression of Kv12.2 was significantly increased by KCNE1 and KCNE3 siRNA, whereas total protein expression of Kv12.2 was not affected. KCNE1 and KCNE3 siRNA shifted the voltages for half-maximal activation to more hyperpolarized voltages, indicating that KCNE1 and KCNE3 may also inhibit activation gating of Kv12.2. Native co-immunoprecipitation assays from mouse brain membranes imply that KCNE1 and KCNE3 interact with Kv12.2 simultaneously in vivo, suggesting the existence of novel KCNE1-KCNE3-Kv12.2 channel tripartite complexes. Together these data indicate that KCNE1 and KCNE3 interact directly with Kv12.2 channels to regulate channel membrane trafficking.