Beta cells occur naturally in extrahepatic bile ducts of mice.

Insulin-secreting beta cells were thought to reside only in the pancreas. Here, we show that beta cells are also present in the extra-hepatic bile ducts of mice. They are characterised by insulin and C-peptide content, the presence of secretory granules that are immunoreactive for insulin, and the ducts exhibit glucose-stimulated insulin secretion. Genetic lineage labelling shows that these beta cells arise from the liver domain rather than the pancreas and, by histological study, they appear to be formed directly from the bile duct epithelium in late embryogenesis. Other endocrine cell types (producing somatostatin and pancreatic polypeptide) are also found in close association with the bile-duct-derived beta cells, but exocrine pancreatic tissue is not present. This discovery of beta cells outside the mammalian pancreas has implications for regenerative medicine, indicating that biliary epithelium might offer a new source of beta cells for the treatment of diabetes. The finding also has evolutionary significance, because it is known that certain basal vertebrates usually form all of their beta cells from the bile ducts. The mammalian bile-duct-derived beta cells might therefore represent an extant trace of the evolutionary origin of the vertebrate beta cell.

Sex differences in inflammation and inflammatory pain in cyclooxygenase-deficient mice.

There are two cyclooxygenase (COX) genes encoding characterized enzymes, COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs are commonly used as analgesics in inflammatory arthritis, and these often inhibit both cyclooxygenases. Recently, inhibitors of COX-2 have been used in the treatment of inflammatory arthritis, as this isoform is thought to be critical in inflammation and pain. The objective of this study was to determine the effect of COX-1 or COX-2 gene disruption on the development of chronic Freund's adjuvant-induced arthritis and inflammatory pain in male and female mice. The effect of COX-1 or COX-2 gene disruption on inflammatory hyperalgesia, allodynia, inflammatory edema, and arthritic joint destruction was studied. COX-2 knockout mice (COX-2-/-) showed reduced edema and joint destruction in female, but not male, animals. In addition, neither male nor female COX-2-/- mice developed thermal hyperalgesia or mechanical allodynia, either ipsilateral or contralateral to the inflammation. COX-1 gene disruption also reduced inflammatory edema and joint destruction in female, but not male mice, although females of both COX-/- lines did show some bony destruction. There was no difference in ipsilateral allodynia between COX-1 knockout and wild-type animals, but female COX-1-/- mice showed reduced contralateral allodynia compared with male COX-1-/- or wild-type mice. These data show that the gene products of both COX genes contribute to pain and local inflammation in inflammatory arthritis. There are sex differences in some of these effects, and this suggests that the effects of COX inhibitors may be sex dependent.

Inflammation alters cation chloride cotransporter expression in sensory neurons.

Cation chloride cotransporters have been proposed to play a role in the modulation of neuronal responses to gamma-aminobutyric acid (GABA). In conditions of neuronal damage, where neuronal excitability is increased, the expression of the KCC2 transporter is decreased. This is also seen in spinal cord in models of neuropathic pain. We have investigated the expression of the Na-K-Cl, and K-Cl cotransporters NKCC1 and KCC2, in dorsal root ganglion (DRG) and spinal sensory neurons during arthritis, a condition in which neuronal excitability is also increased. NKCC1 was expressed in control DRG neurons, and its expression was decreased in arthritis. Both NKCC1 and KCC2 were expressed in sensory neurons in the spinal cord. In acute arthritis, both NKCC1 and KCC2 mRNA increased in superficial but not deep dorsal horn, and this was accompanied by an increase in protein expression. In chronic arthritis, NKCC1 expression remained raised, but KCC2 mRNA and protein expression returned to control levels. Altered KCC2 and NKCC1 expression in arthritis may contribute to the control of spinal cord excitability and may represent novel therapeutic targets in the treatment of inflammatory pain.

Characterisation of a Freund's complete adjuvant-induced model of chronic arthritis in mice.

Freund's complete adjuvant (FCA)-induced arthritis is a commonly used model in the rat. Use of FCA to induce arthritis in mice has been only occasionally reported, and most attempts to use this model have met with little success. Subdermal injection of FCA at multiple sites around the tibiotarsal joint of male C57Bl6 mice caused a localised inflammatory reaction to develop in 24 h. Significant swelling occurred around the injected tibiotarsal joint within 24 h (P<0.001), with joint circumferences increasing from 10.9 +/- 0.1 to 21 +/- 0.3 mm. This swelling showed no signs of resolution over 20 days. Unilateral joint swelling was accompanied by significant unilateral mechanical allodynia (P<0.001) and thermal hyperalgesia (P<0.001). At no point were changes in nociceptive thresholds observed in the contralateral paw. Although mice exhibited profound inflammation and showed significant alteration in nociceptive thresholds, the mobility of the mice remained generally unchanged. Histologically the tibiotarsal joints showed changes indicative of arthritis, including pannus formation. Subdermal injection of FCA around the tibiotarsal joint of the mouse provides a useful model to investigate inflammatory-induced nociceptive behaviours, which can be used in genetically manipulated mouse lines that use C57Bl6 as a background strain.