The low extracellular pH of inflamed or ischemic tissues enhances painful sensations by sensitizing and activating the vanilloid receptor 1 (TRPV1). We report here that activation of TRPV1 results in a marked intracellular acidification in nociceptive dorsal root ganglion neurons and in a heterologous expression system. A characterization of the underlying mechanisms revealed a Ca 2؉ -dependent intracellular acidification operating at neutral pH and an additional as yet unrecognized direct proton conductance through the poorly selective TRPV1 pore operating in acidic extracellular media. Large organic cations permeate through the activated TRPV1 pore even in the presence of physiological concentrations of Na ؉ , Mg 2؉ , and Ca 2؉ . The wide pore and the unexpectedly high proton permeability of TRPV1 point to a proton hopping permeation mechanism along the water-filled channel pore. In acidic media, the high relative proton permeability through TRPV1 defines a novel proton entry mechanism in nociceptive neurons.During ischemia or inflammation, pain sensation is augmented by the acidic extracellular pH (pH ext ). 1 A␦-and C-fiber neurons sense extracellular acid by means of two different classes of cation channels, namely TRPV1, the founding member of the vanilloid receptor-like transient receptor potential channel family (1, 2), and the acid-sensing ion channels (ASIC) (3, 4). Both channel types are expressed in small diameter dorsal root ganglion (DRG) neurons, and their role in mediating inflammatory hyperalgesia has been proven by gene deletion techniques (5-7). TRPV1, a poorly selective cation channel, integrates multiple pain-inducing stimuli, including noxious heat, vanilloids, and acidic extracellular pH (1, 8 -10). Inflammatory mediators such as bradykinin, serotonin, histamine, or prostaglandins further stimulate TRPV1 activity either by protein kinase C-dependent signals (11-13), by a release from a phosphatidylinositol 4,5-bisphosphate-dependent inhibition (14,15), by formation of 12-lipoxygenase products (16), or by a protein kinase A-mediated recovery from inactivation (17). Furthermore, extracellular acidification shifts the activation of TRPV1 toward lower temperature or ligand thresholds by protonation of an amino acid located in the vicinity of the pore loop (18). Although the role of the external pH ext in modulating TRPV1 activity is well established, a possible impact of TRPV1 activation on the intracellular pH has not been studied.A Ca 2ϩ influx component through activated voltage-or ligand-gated cation channels has been recognized to lower the intracellular pH (pH i ) in neurons or in neuroendocrine cells (19,20). We therefore asked the question whether activation of the Ca 2ϩ -permeable TRPV1 may also mediate intracellular acidification in native rat dorsal root ganglion neurons or in a heterologous expression system. Our results provide evidence for two independent TRPV1-mediated acidification signals, including an as yet unrecognized direct proton conductance through the activated TRPV1 p...

Opioids have long been thought to act exclusively within the central nervous system. An increasing number of studies recently reported the existence of opioid receptors outside the central nervous system and therefore suggested that opioids are also able to produce analgesic effects in the periphery. Such effects are particularly prominent under painful inflammatory conditions, both in animals and in humans. During inflammatory processes, opioid receptors are transported from dorsal root ganglia towards the peripheral sensory nerve endings. At the same time, immune cells containing endogenous opioid peptides accumulate within the inflamed tissue. Environmental stimuli (e.g. stress) as well as releasing agents (e.g. corticotropin releasing factor, cytokines) can liberate these opioid peptides to interact with the neuronal opioid receptors and elicit local analgesia. The inflammation-induced activation of opioid production and the release of endogenous opioids from immune cells may lead to novel approaches for the development of peripherally acting analgesics. Clinical investigation now focuses on the development of new peripheral opioid agonists as well as on ways to stimulate the endogenous analgesic system in order to induce effective peripheral analgesia with reduced central side effects typically associated with opioids.

Butyrate, a physiologically occurring agent, has been reported to decrease constitutively high expressed p53 levels in transformed cells. To elucidate whether butyrate also inhibits DNA-damage-induced p53 response we investigated the eects of butyrate and the anticancer drug mitomycin C in normal C3H10T1/2 cells harbouring wild-type p53. In comparison with p53-de®cient ®broblasts we examined p53 protein level, cell cycle arrest, dierentiation, and apoptosis. Butyrate induced G1 phase arrest, dierentiation, and p53-independent increase in p21 waf1/cip1 protein. Moreover, butyrate induced p53-independent apoptosis, which was, as well as p53-mediated apoptosis, associated with a dose-dependent increase in Bax and c-Myc protein. Pretreatment with butyrate repressed dose-dependently mitomycin-C-induced p53 accumulation and interfered with p53-dependent cell cycle arrest. Butyrate further partially inhibited p53-mediated apoptosis, but low doses of butyrate were more eective than higher concentrations. This was re¯ected in an enhanced decrease in c-Myc and Bax protein in response to mitomycin C with low concentrations of butyrate. Our data indicate that the dierentiation stimulus of butyrate, in association with p21 waf1/cip1 induction, and apoptosis, may explain antineoplastic eects of butyrate. Co-carcinogenic features of butyrate may result from inhibition of p53-mediated DNA damage response.

In long-term treatment opioids seem to have only minimal side-effects compared with other analgesics and co-analgesics.Nevertheless, some risks have to be considered. While immunosuppression, neurotoxicity, teratogenity, tolerance and addiction are clinically not relevant or very rare, cognitive impairment, sedation and obstipation may have a clinical impact.However, these symptoms can usually be managed by adjuvant medication and patient education. Treatment of non-malignant pain with opioids can only be considered on an individual basis. Scientific evidence for general treatment with opioids, treatment of specific pain syndromes or treatment with certain opioids is not available. In conclusion, only recommendations regarding opioid treatment for certain chronic pain syndromes can be made. In only a minority of patients can a long-term analgesic effect be expected.Therefore, careful evaluation of alternative options of pain management is necessary before opioid therapy is started. With standardized documentation responders may be distinguished from non-responders. For clinical practice of long-term opioid therapy in non-malignant pain a specialized knowledge in pain management is a prerequisite. Future studies with more sophisticated methodology will be necessary to advocate more precise guidelines.However, the therapeutic recommendations from the DGSS consensus conference allow a safer,well structured and validated use of opioids for chronic non-malignant pain.

Adequate control of postoperative pain does not only improve patient satisfaction, but is also indicated from a medical point of view. Besides conventional non-opioid analgesics and opioids, more sophisticated analgesia concepts like intravenous patient-controlled analgesia (PCA) and epidural analgesia may be indicated. Modalities and practical aspects of these concepts are discussed and briefly described. It is believed that the effectiveness of improved analgesia will be increased by integrating analgesia concepts into a multimodal approach of intensified mobilisation, early enteral nutrition and frequent respiratory therapy of the postoperative patient. In conclusion, there is good evidence of improved analgesia from PCA and epidural analgesia. Data on outcome improvement by analgesia is still contradictory, but improvement of patient satisfaction is without doubt.