Type 1 and type 3 ryanodine receptors are selectively involved in muscarinic antinociception in mice: An antisense study

Abstract

Abstract-The importance of an intracellular calcium content increase to obtain cholinergic antinociception was demonstrated. The physiological and pathological role of ryanodine receptors (RyRs), receptors involved in the mobilization of intracellular calcium stores, at the CNS level is poorly understood. The aim of the present study was, therefore, to investigate the role of supraspinal endoplasmic type 1, 2 and 3 RyR subtypes in muscarinic antinociception in conditions of acute thermal (hotplate test) and inflammatory (abdominal constriction test) pain. In the absence of isoform selective RyR antagonists, types 1, 2 and 3 RyR knockdown mice were obtained. Western blotting experiments were performed to quantify the RyR isoform protein levels in knockdown mice demonstrating a selective protein level reduction in knockdown animals. I.c.v. pretreatment with an antisense oligonucleotide (aODN) against type 1 or type 3 RyR prevented cholinergic antinociception in the hotplate test shifting to the right of the physostigmine dose-response curve. This antagonistic effect disappeared 7 days after the end of the aODN administration. Conversely, the physostigmine analgesia remained unmodified in type 2 RyR knockdown mice. Similar results were obtained in the abdominal constriction test. Mice undergoing aODN treatments showed neither alteration of animals' gross behavior nor locomotor impairment (rota-rod and hole board tests). These results elucidate the intracellular mechanism underlying muscarinic antinociception. A selective involvement of RyR1 and RyR3 in supraspinal muscarinic analgesia was demonstrated whereas RyR2 appears not to play an essential role in acute thermal and inflammatory pain.

Lack of Adrenomedullin in the Central Nervous System Results in Apparently Paradoxical Alterations on Pain Sensitivity

“…The degree of nociception on each mouse was quantified using two methods: 1) the tail-flick latency test (8), and 2) the hotplate latency test (9). For the first one, the tail of the mouse was immersed in a water bath kept at 45 Ϯ 0.5 C, and the latency from the time of immersion until the mouse flicked the tail was recorded as the nociceptive value.…”

Alpha-7 Nicotinic Receptor-Targeted Cinobufagin Induces Antinociception and Inhibits NF-κB Signaling Pathway in DRG Neurons

“…to the mouse 15 min after oral CBG administration. The total number of abdominal constrictions was recorded from 5 to 20 min after acetic acid injection . All the injections and the following observations were completed within 1.5 h after the CBG administration.…”

“…The total number of abdominal constrictions was recorded from 5 to 20 min after acetic acid injection. 30 All the injections and the following observations were completed within 1.5 h after the CBG administration. The percentage of inhibition was expressed by following formula: inhibition (%) = Formalin Test.…”

Roles of ryanodine receptors in the central nervous system

“…Farelerde intraserebroventriküler ryanodin enjeksiyonu doza bağimli bir şekilde ağri eşiğini düşürmektedir [16]. Bununla beraber, RyR3'ün, RyR1'e kiyasla muskarinik analjezide büyük öneme sahip olduğu gösterilmiştir [17]. Ayrica, yapilan bir çalişmada asetik asit ile indüklenen viseral ağri modelinde intratalamokortikal ryanodin ve dantrolen hiperaljeziye neden olmuş, buna karşilik kafein uygulanmasi analjezik etki göstermiştir [18].…”