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...