An examination of neurogenic mechanisms involved in mustard oil-induced inflammation in the mouse.

The mechanisms by which topical mustard oil causes vasodilatation in the mouse were investigated using the tachykinin NK1 receptor antagonist SR140333 and the calcitonin gene-related peptide (CGRP) antagonist BIBN4096BS, alongside alphaCGRP or NK1 receptor knockout mice. Blood flow was assessed by laser Doppler flowmetry and plasma extravasation by 125I-albumin accumulation. Mustard oil produced significant plasma extravasation and vasodilatation in wild type mice, although the plasma extravasation was less than that seen with capsaicin whilst the vasodilatation was greater. The plasma extravasation was abolished in tachykinin NK1 knockout mice, whilst the vasodilatation was enhanced. BIBN4096BS was unable to inhibit the vasodilatation in wild type mice but abolished it in the NK1 knockout mice. In alphaCGRP knockout mice, mustard oil also caused plasma extravasation and vasodilatation, which were both inhibited by treatment with SR140333. These data suggest that both a tachykinin NK1 receptor agonist and a CGRP agonist are active as vasodilators, producing redundancy, requiring blockade of both mediators to prevent vasodilatation.

Analysis of the cellular expression pattern of beta-CGRP in alpha-CGRP-deficient mice.

In this study we compared the alpha-calcitonin gene-related peptide (alphaCGRP) and betaCGRP expression patterns in wild-type and knockout mice by using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. In dorsal root ganglia and spinal cord of wild-type animals, alphaCGRP mRNA was about two times more abundant than betaCGRP mRNA. The betaCGRP mRNA was the only isoform expressed in the intestine. In alphaCGRP knockout mice, we found no change in betaCGRP mRNA levels in dorsal root ganglia and spinal cord compared with wild-type controls, but a twofold decrease in the intestine. CGRP immunoreactivity (IR) was detected in many small and some large neurons in the dorsal root ganglia, was found in sensory fibers and motor neurons in the spinal cord, and labeled neuromuscular junctions in wild-type mice. In the dorsal root ganglia of alphaCGRP knockout mice, punctate betaCGRP-IR again was predominantly found in small neurons. In the spinal cord, betaCGRP-IR fibers were localized to the outermost layer of the dorsal horn. IR was found in the cell bodies of motor neurons, but it was undetectable in neuromuscular junctions. In the intestine, CGRP-IR was localized to neurons of the myenteric plexus and to fibers in the mucosal folds, with similar staining intensity in both wild-type and knockout mice. Finally, CGRP-IR was undetectable in preganglionic fibers and postganglionic sympathetic neurons in mice from both genotypes. Our results indicate that alphaCGRP and betaCGRP are variably coexpressed in different functional aspects of the mouse nervous system. This pattern suggests distinct roles for betaCGRP in pain, neuromuscular, and gastrointestinal systems.

Reduction of withdrawal signs after chronic nicotine exposure of alpha-calcitonin gene-related peptide knock-out mice.

Nicotine, the main substance responsible for the addictive behavior of smokers, binds to a variety of nicotinic acetylcholine receptors (nAChRs) diversely distributed in the brain, notably in areas involved in motivation and reward mechanisms. The alpha-calcitonin gene-related peptide (alphaCGRP) has been previously shown to modulate the functions of nAChRs and is released in brain areas implicated in motivation, such as the amygdala or the ventral tegmental area. Interestingly, alphaCGRP -/- mice display a decrease in morphine withdrawal symptoms. In this context, we investigate the tolerance and withdrawal symptoms in alphaCGRP -/- mice exposed to acute and chronic nicotine. We report that these animals develop a normal tolerance to the antinociceptive effects of nicotine, but display an attenuation of somatic withdrawal symptoms.