Involvement of M3 muscarinic receptors of the spinal cord in formalin-induced nociception in mice.
Subcutaneous injection of formalin into a paw of mice caused two distinct phases of licking and biting, first phase (1-5 min) and the second phase (7-30 min) after the injection. The muscarinic antagonist atropine (0.1-10 ng, i.t.) and the M(3) receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) (0.1-20 ng, i.t.) inhibited the second phase of this response, whereas higher doses of atropine (20-100 ng, i.t.) did not cause inhibition. The M(1) muscarinic receptor antagonist pirenzepine (10-100 ng, i.t.) did not inhibit either the first or the second phase response, but a high dose of pirenzepine (1000 ng, i.t.) tended to inhibit the second phase response. On the other hand, the M(2) muscarinic receptor antagonist 11-¿(2-[(diethylamino)methyl]-1-piperidinyl¿acetyl)-5, 11-dihydro-6H-pyrido(2,3-b)(1,4)benzodiazepine-6-one (AF-DX116; 10-1000 ng, i.t.) had no effect on either the first or the second phase of response. The opioid receptor antagonist naloxone did not affect the 4-DAMP-induced anti-nociceptive response. The i.t. injection of the acetylcholinesterase inhibitor neostigmine (25 ng) significantly inhibited only the second phase. The acetylcholine (ACh) depletor hemicholinium-3 (HC-3) (1 microg, i.t.) completely abolished the 4-DAMP-induced anti-nociceptive response. The ACh content of the spinal cord was significantly increased 14 min after formalin injection. This significant increase in the ACh content was inhibited by pretreatment with 4-DAMP (10 ng, i.t.). These results suggest that endogenous ACh in the spinal cord acts as a transmitter anti-nociception, and that ACh release regulated by presynaptic M(3) muscarinic receptors in the spinal cord is involved in the second phase of nociception induced by formalin.
Honda
K
K
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan. khonda@fukuoka-u.ac.jp
Harada
A
A
Takano
Y
Y
Kamiya
H
H
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D018678:Cholinergic Agents / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D005557:Formaldehyde; D006426:Hemicholinium 3 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009388:Neostigmine / Q000494:pharmacology; D009619:Nociceptors / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced*; D010147:Pain Measurement; D010880:Piperidines / Q000494:pharmacology; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D009292:Narcotic Antagonists; D010880:Piperidines; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D005557:Formaldehyde; D006426:Hemicholinium 3; D009270:Naloxone; D009388:Neostigmine; D001285:Atropine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D000109:Acetylcholine