Epigenetic modulation of mGlu2 receptors by histone deacetylase inhibitors in the treatment of inflammatory pain.

Knowing that expression of metabotropic glutamate 2 (mGlu2) receptors in the dorsal root ganglia is regulated by acetylation mechanisms, we examined the effect of two selective and chemically unrelated histone deacetylase (HDAC) inhibitors, N-(2-aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl)aminomethyl]benzamide (MS-275) and suberoylanilide hydroamic acid (SAHA), in a mouse model of persistent inflammatory pain. Although a single subcutaneous injection of MS-275 (3 mg/kg) or SAHA (5-50 mg/kg) was ineffective, a 5-day treatment with either of the two HDAC inhibitors substantially reduced the nociceptive response in the second phase of the formalin test, which reflects the development of central sensitization in the dorsal horn of the spinal cord. Analgesia was abrogated by a single injection of the mGlu2/3 receptor antagonist (alphaS)-alpha-amino-alpha-[(1S,2S)-2-carboxycyclopropyl]-9H-xantine-9-propanoic acid (LY341495; 1 mg/kg, i.p.), which was inactive per se. Both MS-275 and SAHA up-regulated the expression of mGlu2 receptors in the dorsal root ganglion (DRG) and spinal cord under conditions in which they caused analgesia, without changing the expression of mGlu1a, mGlu4, or mGlu5 receptors. Induction of DRG mGlu2 receptors in response to SAHA was associated with increased acetylation of p65/RelA on lysine 310, a process that enhances the transcriptional activity of p65/RelA at nuclear factor-kappaB-regulated genes. Transcription of the mGlu2 receptor gene is known to be activated by p65/RelA in DRG neurons. We conclude that HDAC inhibition produces analgesia by up-regulating mGlu2 receptor expression in the DRG, an effect that results from the amplification of NF-kappaB transcriptional activity. These data provide the first evidence that HDAC inhibitors cause analgesia and suggest that HDACs are potential targets for the epigenetic treatment of pain.

Pregabalin in the treatment of chronic pain: an overview.

Chronic 'pathological' pain is sustained by mechanisms of peripheral and central sensitization, which are being increasingly investigated at the molecular and cellular levels. The molecular determinants of nociceptive sensitization are natural targets for potential analgesic drugs used in the treatment of different forms of pain. Most of these determinants are common to all forms of chronic pain, and it is therefore not surprising that drugs specifically targeted for the treatment of neuropathic pain are effective in relieving nociceptive inflammatory pain and vice versa. The molecular mechanisms of sensitization that occur in peripheral nociceptors and the dorsal horns of the spinal cord are putative targets for context-dependent drugs, i.e. drugs that are able to discriminate between 'normal' and 'pathological' pain transmission. Among these, pregabalin and gabapentin bind to the alpha(2)delta subunit of voltage-sensitive Ca2+ channels, which sustain the enhanced release of pain transmitters at the synapses between primary afferent fibres and second-order sensory neurons under conditions of chronic pain. Pregabalin in particular represents a remarkable example of a context-dependent analgesic drug that acts at a critical step of nociceptive sensitization. Preclinical and clinical data suggest that pregabalin is more than a structural and functional analogue of gabapentin and may be effective in the treatment of nociceptive inflammatory pain that is resistant to gabapentin.

Influence of esophageal varices and spontaneous portal-systemic shunts on postprandial splanchnic hemodynamics.

OBJECTIVE: The aim of the study was to assess postprandial splanchnic hemodynamic changes in cirrhosis in relation to variceal status. METHODS: In 9 healthy controls and 56 patients with liver cirrhosis, stratified according to variceal status and presence of spontaneous portal-systemic shunts, the portal vein diameter and flow velocity, the congestion index of the portal vein, and the resistive index of the superior mesenteric artery (SMA-RI) were studied by Doppler ultrasound before and 30, 60, and 120 min after the intake of a standard meal. Comparison of postprandial parameters with basal ones was done within each group by paired t test and among groups by ANOVA and Duncan test. RESULTS: Healthy controls and cirrhotic patients without varices showed similar significant splanchnic hemodynamic changes, namely a reduction of SMA-RI (-13% at 30 min) and a consequent increase in portal vein diameter (respectively, +32% and +17% in the two groups) and velocity (+66% and +51%). A significant reduction of SMA-RI was also found in patients with varices, irrespective of the variceal size (range, -7 to -11%), but the expected portal vein dilation and velocity increase were progressively blunted with the increase of variceal size (range, 0-5% for diameter and 5-19% for velocity). Patients with spontaneous portal-systemic shunts showed a response similar to that of patients with large varices. Significant modification of the congestion index of the portal vein did not occur in any group. CONCLUSIONS: Our results show that the hemodynamic response to meal in patients with liver cirrhosis is influenced by the presence and size of esophageal varices and the presence of spontaneous portal-systemic shunts.

Hepatitis C virus in elderly patients with chronic liver diseases.

Between January 1993 and July 1994, 141 consecutive patients were recruited, all above 50 years of age, affected by chronic liver diseases (CLD), in order to evaluate the prevalence of hepatitis C virus (HCV). The overall prevalence of HCV alone was 50.3% (71 out of 141 patients) which increased to 70.1% when considered together with the alcoholism (28 out of 141 patients). Contrastingly, the prevalence of hepatitis B and D virus (HBV and HDV) was low (17%, 24 patients). Mean age of HCV patients was significantly higher than the mean age of HBV/HDV patients (p < 0.001). There was a significant difference (p < 0.05) between the mean age of the group of patients with only HCV and those where the disease was associated with alcoholism. Our data indicate that HCV is by far the most frequent cause of CLD in elderly patients in our geographical area. The mean age of HCV-induced CLD patients was significantly higher than the mean age of HBV/HDV patients, due to the slower evolution of HCV. The severity of liver damage increases if HCV is associated with alcoholism, as shown by the lower age of these subjects. HCV induced liver cirrhosis often develops into carcinoma (in 5 out of 51 patients in our series, 9.8%) and may be a result of the longer duration of the disease. This seems to be the only factor aggravating the otherwise slow evolution of HCV. Our data suggest the necessity of long term monitoring of elderly patients with HCV-induced CLD.

Recombinant interferon alpha therapy in elderly patients with chronic hepatitis C without cirrhosis.

We administered a 24 week cycle of recombinant interferon alpha (r-IFNa) treatment (6 MU twice per week) to 18 patients over 50 years and 20 patients under 50 years affected by chronic hepatitis C without cirrhosis in order to evaluate the efficacy of, and tolerance to r-IFNa. Liver histology and serum alanine aminotransferase (ALT) values prior to treatment were overlapping in the two groups. Complete response was achieved in 2 patients of the first group (11%) and 12 of the second (60%, p < 0.01) and was defined as normalization of ALT values during treatment. Sustained response was defined as persisting normal ALT values 6 months after the end of treatment and was observed in 2 patients of the group above 50 years of age and in 8 patients of the younger group. Partial response was observed in 8 patients (44.5%) of the older group and 2 patients (10%) of the younger group; it was defined as a more than 50% ALT reduction compared to the values before the treatment. No statistically significant correlation was observed between the pretreatment histological picture and type of response. Tolerance to treatment was good in both group and none of the patients presented side effects necessitating suspension of treatment.