Central muscarinic receptor subtypes and carrageenin-induced paw oedema in rats

In an earlier report from this laboratory, it was demonstrated that the central cholinergic system exerted a modulatory pro-inflammatory effect on carrageenin-induced paw inflammation in rats. In this study, the role of the central muscarinic receptors in cholinergic modulation of peripheral inflammation was investigated by using several M1 and M2 receptor agonists and antagonists. The M1 receptor agonists aceclidine and arecholine and the nonspecific muscarinic receptor agonist oxotremorine augmented carrageenin oedema, an effect attenuated by the M1 receptor antagonist scopolamine. Physostigmine behaved like a M1 receptor agonist at all dose levels. However, the other M2 receptor agonist, carbachol, produced a dose-dependent dual effect, with lower doses attenuating the oedema and higher doses augmenting the inflammation. While the former action appeared to be due to M2 receptor stimulation, because it was blocked by AF-DX 116--a M2 receptor antagonist, the latter action appeared to be induced by M1 receptor stimulation, because it was inhibited by scopolamine. The pro-inflammatory effect of the M2 receptor antagonists AF-DX 116 and gallamine appeared to be induced by enhanced neuronal release of acetylcholine, because the effects were not evident following pretreatment with hemicholinium, which attenuates synthesis of the amine. Muscarinic receptor binding studies with (3H)-QNB indicated that the corpus striatum has substantially higher population of M1 receptors compared with the cerebellum. In the corpus striatum, (3H)-QNB binding indicated initial up-regulation followed by down-regulation of M1 receptors during peak inflammation, which appeared to persist even after a decrease in the inflammation. In contrast, the M1 receptors in the cerebellum appeared to be down-regulated very transiently during the early phase of the inflammation. While these receptor alterations may be due to the inflammation, it is equally possible that they represent changes induced by the stress of pain and inflammation induced by carrageenin.