Analgesic tolerance and cross-tolerance to the bifunctional opioid/neuropeptide FF receptors agonist EN-9 and µ-opioid receptor ligands at the supraspinal level in mice.

The chimeric peptide EN-9 was reported as a κ-opioid/neuropeptide FF receptors bifunctional agonist that modulated chronic pain with no tolerance. Many lines of evidence have shown that the effect of the κ-opioid receptor is mediated by not only its specific activation but also downstream events participation, especially interaction with the µ-opioid receptor pathway in antinociception and tolerance on most occasions. The present study investigated the acute and chronic cross-tolerance of EN-9 with µ-opioid receptor agonist EM-2, DAMGO, and morphine after intracerebroventricularly (i.c.v) injection in the mouse tail-flick test. In the acute tolerance test, EN-9 showed symmetrical acute cross-tolerance to DAMGO but no cross-tolerance to EM2. In the chronic tolerance test, EN-9 had no tolerance after eight days of repeated administration. However, EN-9 illustrated complete cross-tolerance to morphine and symmetrical cross-tolerance to EM2. In addition, inhibition of NPFF receptor could induce the tolerance development of EN-9. These findings indicated that supraspinal EN-9-induced antinociception contains additional components, which are mediated by the downstream µ-opioid receptor pathway both in acute and chronic treatment, whereas the subtypes of µ-opioid receptor or NPFF system pathway involved in antinociceptive effects induced by EN-9 are complex. Identifying the receptor mechanism could help design preferable bifunctional opioid compounds.

Lack of independent relationship between the MMP-12 gene polymorphism and carotid plaque susceptibility in the Chinese Han population.

The purpose of this study was to investigate whether a polymorphism in the matrix metalloproteinase-12 gene (MMP-12 -82A/G) is correlated with serum protein levels or with the susceptibility for carotid plaques in the Chinese Han population. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed on the -82A/G polymorphism in the MMP-12 gene for 1314 patients with acute cerebral infarctions; 710 of these cases were diagnosed with stable plaques, 340 cases were diagnosed with vulnerable plaques and 264 cases had no plaques. At the same time, serum MMP-12 levels were measured using the enzyme-linked immunosorbent assay (ELISA). Compared to the AA genotype, the frequency of the AG+GG genotypes was not significantly different between the three groups (χ(2) = 1.242, p = 0.537), and the frequency of the G allele of the MMP-12 gene was not different within the three subgroups (χ(2) = 1.218, p = 0.544). There were no significant differences in MMP-12 protein levels among the three groups (F = 0.675, p = 0.510); similarly, there was no difference in MMP-12 protein levels between the stable plaque group and the vulnerable plaque group (p = 0.755). There was also no difference between the vulnerable plaque group and the no plaque group (p = 0.420). The current data suggest that the inter-individual variability in the MMP-12 gene variation may not be a risk factor for vulnerable plaques in the Chinese Han population.