ly-297802 and Pain

This study compared the subjective, physiological and psychomotor effects of a novel muscarinic analgesic (LY297802) and oral morphine in healthy volunteers. Nine, non-dependent, occasional drug users participated in nine experimental sessions in which they received the following conditions: placebo, 0.1, 0.3, 0.56 and 1 mg of oral LY297802 and 10, 30, 56 and 100 mg of oral morphine. Subjective drug effects were assessed using the Visual Analog Scale (VAS), the Addiction Research Center Inventory (ARCI) and subjective and objective agonist and antagonist scales of the Adjective Rating Scale (ARS). These measures were collected 30 min before and every 30 min post drug administration for a 4-h period. Psychomotor performance was evaluated using the Digit Symbol Substitution Test (DSST) at these same time intervals. Physiological measures were collected continuously throughout the sessions. Oral morphine produced significant increases in some subjective effects scales, including elevations on the VAS, ARCI and ARS. In contrast, LY297802 did not engender changes different from placebo on any of these indices. Morphine produced significant dose-dependent effects in DSST performance, heart rate, blood oxygen saturation and pupil diameter. LY297802 significantly and dose dependently increased heart rate, mean arterial pressure and diastolic blood pressure. These results suggest that LY297802 does not induce subjective effects similar to morphine, but that it has some significant physiological effects.

Topics: Adult; Affect; Analgesics; Analgesics, Opioid; Analysis of Variance; Area Under Curve; Behavior, Addictive; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Humans; Male; Morphine; Muscarinic Agonists; Narcotics; Pain; Psychomotor Performance; Risk Assessment; Substance-Related Disorders; Thiadiazoles

Previous studies indicate cholinergic systems suppress somatic nociception. The present studies determined if cholinergic muscarinic systems suppress visceral nociception, specifically, chemical irritation of the lower urinary tract. Bladders of urethane-anesthetized rats were cannulated through the dome for continuous-infusion cystometrogram recordings. EMG electrodes recorded anal sphincter activity. Infusion of 0.5% acetic acid into the bladder to produce irritation increased bladder activity and anal sphincter activity (i.e. activation of a nociceptive vesicoanal reflex). Oxotremorine (a muscarinic agonist) and (-)butylthio[2.2.2] (a mixed muscarinic agonist/antagonist) dose-dependently inhibited vesicoanal reflex activity. This inhibition was antagonized by atropine (a centrally active muscarinic antagonist) but not by scopolamine methylbromide (a peripherally restricted muscarinic antagonist). Physostigmine (a centrally active cholinesterase inhibitor) also dose-dependently inhibited vesicoanal reflex activity in an atropine-sensitive manner, while neostigmine (a peripherally restricted cholinesterase inhibitor) did not. Atropine alone (i.e. administered without prior administration of muscarinic agonist or cholinesterase inhibitor) produced robust but transient (15 min) increases in vesicoanal activity and bladder activity under conditions of acetic acid infusion into the bladder. Under conditions of saline infusion into the bladder, atropine had the opposite effect on bladder activity (i.e. inhibition). These studies indicate that an endogenous cholinergic muscarinic system can be activated by lower urinary tract irritation to suppress visceral nociception through central nervous system mechanisms.

Topics: Acetylcholine; Action Potentials; Animals; Atropine; Cholinergic Agents; Cholinesterase Inhibitors; Electromyography; Female; Muscarinic Agonists; Muscarinic Antagonists; Muscle, Smooth; Neostigmine; Nociceptors; Oxotremorine; Pain; Physostigmine; Rats; Rats, Sprague-Dawley; Reflex; Thiadiazoles; Urinary Bladder; Vasodilator Agents