Local administration of mu or kappa opioid agonists attenuates capsaicin-induced thermal hyperalgesia via peripheral opioid receptors in rats.

RATIONALE: By acting on peripheral opioid receptors, opioid agonists can attenuate nociceptive responses induced by a variety of agents. OBJECTIVES: This study was conducted to characterize capsaicin-induced thermal hyperalgesia in rats and to evaluate the hypothesis that local administration of either mu or kappa opioid agonists (fentanyl and U50,488, respectively) can attenuate capsaicin-induced nociception. METHODS: Capsaicin was administered s. c. in the tail of rats to evoke a nociceptive response, which was measured by the warm-water tail-withdrawal procedure. Either fentanyl or U50,488 was co-administered with capsaicin in the tail to evaluate local antinociceptive effects. In addition, the local antagonism study was performed to confirm the site of action of both opioid agonists. RESULTS: Capsaicin (0.3-10 microg) dose dependently produced thermal hyperalgesia manifested as reduced tail-withdrawal latencies in 45 degrees C water. Co-administration of either fentanyl (0.32-3.2 microg) or U50,488 (10-100 microg) with capsaicin (3 microg) attenuated capsaicin-induced hyperalgesia in a dose-dependent manner. Furthermore, this local antinociception was antagonized by small doses (10-100 microg) of an opioid antagonist, quadazocine, applied s.c. in the tail. However, the locally effective doses of quadazocine, when applied s.c. in the back (i.e., around the scapular region), did not antagonize either fentanyl or U50,488. CONCLUSIONS: In this experimental pain model, activation of peripheral mu or kappa opioid receptors can attenuate capsaicin-induced thermal hyperalgesia in rats. It supports the notion that peripheral antinociception can be achieved by local administration of analgesics into the injured tissue without producing central side effects.

Cardiac defects and renal failure in mice with targeted mutations in Pkd2.

PKD2, mutations in which cause autosomal dominant polycystic kidney disease (ADPKD), encodes an integral membrane glycoprotein with similarity to calcium channel subunits. We induced two mutations in the mouse homologue Pkd2 (ref.4): an unstable allele (WS25; hereafter denoted Pkd2WS25) that can undergo homologous-recombination-based somatic rearrangement to form a null allele; and a true null mutation (WS183; hereafter denoted Pkd2-). We examined these mutations to understand the function of polycystin-2, the protein product of Pkd2, and to provide evidence that kidney and liver cyst formation associated with Pkd2 deficiency occurs by a two-hit mechanism. Pkd2-/- mice die in utero between embryonic day (E) 13.5 and parturition. They have structural defects in cardiac septation and cyst formation in maturing nephrons and pancreatic ducts. Pancreatic ductal cysts also occur in adult Pkd2WS25/- mice, suggesting that this clinical manifestation of ADPKD also occurs by a two-hit mechanism. As in human ADPKD, formation of kidney cysts in adult Pkd2WS25/- mice is associated with renal failure and early death (median survival, 65 weeks versus 94 weeks for controls). Adult Pkd2+/- mice have intermediate survival in the absence of cystic disease or renal failure, providing the first indication of a deleterious effect of haploinsufficiency at Pkd2on long-term survival. Our studies advance our understanding of the function of polycystin-2 in development and our mouse models recapitulate the complex human ADPKD phenotype.

Synthesis of messenger RNA and chromosome structure in the cellular slime mold.

This paper summarizes our knowledge of the structure and biosynthesis of messenger RNA in the slime mold Dictyostelium discoideum, the arrangement of DNA sequences in the Dictyostelium chromosome, and the changes in the pattern of predominant polypeptides synthesized during Dictyostelium development.