Analgesic effects of Sazetidine-A, a new nicotinic cholinergic drug.
BACKGROUND
The use of nicotinic agonists for analgesia is limited by their unacceptable side effects. Sazetidine-A is a new partial agonist nicotinic ligand that has very high selectivity for beta2-containing nicotinic acetylcholine receptors. It potently and selectively desensitizes alpha4beta2 nicotinic acetylcholine receptors without measurable effects on alpha3beta4 receptors. The authors investigated the analgesic effects of Sazetidine-A using the formalin model of chronic inflammatory pain.


METHODS
The formalin test was conducted after rats received intraperitoneal saline, Sazetidine-A (0.125, 0.25, 0.5, 1, 2 mg/kg), or subcutaneous epibatidine (2.5-5-10 mug/kg). In other experiments, Sazetidine-A was preceded by naloxone (0.5 mg/kg) or mecamylamine (10 mg). Effects of Sazetidine-A and epibatidine on locomotor were tested in an open field, and seizure activity was measured using the Racine scale. Locus coeruleus neuron extracellular single-unit spontaneous discharge was recorded in anesthetized animals after Sazetidine-A and epibatidine.


RESULTS
Higher doses of Sazetidine-A (0.5, 1, or 2 mg/kg) induced analgesia, with pain scores significantly lower than those seen after saline, lower doses of Sazetidine-A, and epibatidine (P < 0.001). Naloxone did not antagonize the effects of Sazetidine-A, and mecamylamine had partial, dose-dependent antagonistic effects. Epibatidine excited locus coeruleus neurons, whereas Sazetidine-A had no effect on these neurons. Epibatidine and Sazetidine-A affected animals' locomotor activity for the initial 20 min. While analgesic doses of epibatidine caused seizures, no seizure activity or other neurologic complications were seen in animals that received as much as four times the minimum analgesic dose of Sazetidine-A.


CONCLUSIONS
Sazetidine-A seems to be a potent analgesic without causing neurologic side effects.
Cucchiaro
Giovanni
G
Department of Anesthesia and Critical Care Medicine, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA. cucchiaro@email.chop.edu
Xiao
Yingxian
Y
Gonzalez-Sulser
Alfredo
A
Kellar
Kenneth J
KJ
D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001384:Azetidines / Q000009:adverse effects / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage; D018678:Cholinergic Agents / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D008464:Mecamylamine / Q000008:administration & dosage; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D018722:Nicotinic Agonists / Q000008:administration & dosage; D018733:Nicotinic Antagonists / Q000008:administration & dosage; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012965:Sodium Chloride / Q000008:administration & dosage
D000700:Analgesics; D001384:Azetidines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018678:Cholinergic Agents; D009292:Narcotic Antagonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C514816:sazetidine-A; D009270:Naloxone; D012965:Sodium Chloride; D008464:Mecamylamine; C082748:epibatidine