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Double stranded, short interfering RNAs (siRNA) of 21-22 nt length initiate a sequence-specific, post-trancriptional gene silencing in animals and plants known as RNA interference (RNAi). Here we show that RNAi can block a pathophysiological pain response and provide relief from neuropathic pain in a rat disease model by down regulating an endogenous, neuronally expressed gene. Rats, intrathecally infused with a 21 nt siRNA perfectly complementary to the pain-related cation-channel P2X3, showed diminished pain responses compared to missense (MS) siRNA-treated and untreated controls in models of both agonist-evoked pain and chronic neuropathic pain. This form of delivery caused no adverse effects in any of the animals receiving P2X3 siRNA, MS siRNA or vehicle. Molecular analysis of tissues revealed that P2X3 mRNA expressed in dorsal root ganglia, and P2X3 protein translocated into the dorsal horn of the spinal cord, were significantly diminished. These observations open a path toward use of siRNA as a genetic tool for drug target validation in the mammalian central nervous system, as well as for proof of concept studies and as therapeutic agents in man.

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Abstract. This paper reports on the spectroscopic investigation of 12 Cepheids which are situated in the crucial region of galactocentric distances from 9 kpc to 12 kpc, where according to our previous results (Andrievsky et al. 2002c;Luck et al. 2003) the radial metallicity distribution experiences an obvious change. In particular, the wriggle in the iron abundance distribution is found to fall approximately at galactocentric distances 10-11 kpc (assuming galactocentric distance of the Sun R G, = 7.9 kpc). Within the transition zone from 10 to 11 kpc the relative-to-solar iron abundance decreases approximately to -0.2 dex. The new sample of stars, analyzed in present paper, gives results supporting the previous conclusion about the multimodal character of the metallicity distribution in galactic disc. Using a quite simple consideration of galactic chemical evolution we show that the observed distribution can be explained in the framework of a model which includes the spiral arms. In particular, the wriggle feature associated with R G ≈ 11 kpc can be interpreted as a change of metallicity level in the vicinity of the galactic corotation resonance.