The antinociceptive and sedative effects of carbachol and oxycodone administered into brainstem pontine reticular formation and spinal subarachnoid space in rats.
To clarify the supraspinal and spinal actions of a cholinergic agonist, carbachol, and an opioid, oxycodone, we studied their antinociceptive and behavioral effects when administered into brainstem medial pontine reticular formation (mPRF) or spinal subarachnoid space with or without pretreatment of muscarinic receptor subtype antagonist. Sprague-Dawley rats were implanted with a 24-gauge stainless steel guide cannula into the mPRF and chronically implanted with a lumbar intrathecal catheter. Antinociception was tested using tail flick latency, motor coordination was evaluated by the rotarod test, and overt sedation was assessed using a behavioral checklist. Carbachol (0.5-4.0 microg) administered into the mPRF produced significant dose- and time-dependent antinociception, sedation, and motor dysfunction. These were completely blocked by pretreatment with atropine and the M(2) muscarinic antagonist, methoctramine, and partially blocked by pretreatment with M(1) pirenzepine but not with M(3) p-fHHSID: Oxycodone administered into the mPRF did not produce such effects. Spinal carbachol and oxycodone produced antinociception without any behavioral effects; their antinociceptive effects were completely blocked by pretreatment with atropine and M(2) antagonist. These results suggest that the antinociceptive action of carbachol is mediated by muscarinic cholinergic receptor activation, especially by M(2) receptor subtype in mPRF and spinal cord, and that although oxycodone seems unlikely to affect the cholinergic transmission of mPRF, spinal oxycodone-induced analgesia is at least partly mediated via the activation of M(2) receptor subtype at the spinal cord.


CONCLUSIONS
Carbachol-induced antinociception and sedation is mediated with the activation of M(2) muscarinic receptors. Oxycodone administered into brainstem medial pontine reticular formation did not cause any antinociceptive or behavioral effects, but its spinal administration produced a significant antinociception via M(2) muscarinic receptor activation
Ma
H C
HC
Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Tsukasamachi-40, Gifu City, Gifu 500-8705, Japan.
Dohi
S
S
Wang
Y F
YF
Ishizawa
Y
Y
Yanagidate
F
F
D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage*; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D001285:Atropine / Q000008:administration & dosage; D001522:Behavior, Animal / Q000187:drug effects; D002217:Carbachol / Q000008:administration & dosage*; D018679:Cholinergic Agonists / Q000008:administration & dosage*; D016292:Procedural Sedation; D003959:Diamines / Q000008:administration & dosage; D007278:Injections, Spinal; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000008:administration & dosage; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D012154:Reticular Formation; D013346:Subarachnoid Space
D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D018679:Cholinergic Agonists; D003959:Diamines; D018727:Muscarinic Antagonists; D010880:Piperidines; D011976:Receptors, Muscarinic; C058297:4-fluorohexahydrosiladifenidol; D001285:Atropine; D002217:Carbachol; C054938:methoctramine