Current and Future Issues in the Development of Spinal Agents for the Management of Pain
In an unanesthetized chronic rat model involving the placement of one catheter in the bladder for cystometrography and one catheter in the intrathecal (IT) space for drug injections, 10 micrograms morphine sulfate injected intrathecally (it) produced long-lasting inhibition of the volume-evoked micturition reflex. During inhibition of the micturition reflex, intravesical pressure rose with infusion until a continuous emission of urine (dribbling) was observed. Such a level of intravesical pressure (overflow pressure) was significantly greater than the premorphine bladder opening pressure (+56%). During dribbling, no periodic vesical contractions were observed, and the effects of a variety of agents on bladder tone were assessed. Significant (P less than 0.05) increases in vesical pressure over that produced by morphine were observed after intraperitoneal (ip) injection of carbachol (+86%), bethanechol (+55%), norepinephrine (+53%), methoxamine (+88%), and ST-91, an alpha 2-adrenergic agonist (+70%). The increased vesical pressure was not accompanied by an increase in the rate of urine expression. Intraperitoneal injection of serotonin produced no effects on intravesical pressure or urine expression. Significant decreases in the otherwise elevated intravesical pressure were observed after ip injection of isoproterenol (-30%) and phentolamine (-21%), with no change in the rate of urine expression. In contrast, ip injection of apomorphine (dopamine agonist) resulted in significant decreases in vesical pressure (-49%) and near maximal emptying of the bladder. Apomorphine produced no effects on it morphine-induced antinociception as assessed by the tail flick response. Regarding potential treatments of spinal morphine-induced urinary retention, the present study suggests that: 1) cholinomimetic and alpha-adrenergic agonist agents might be harmful; 2) beta-adrenergic agonist and alpha-adrenergic blocking agents might be useful; and 3) dopaminergic agonist agents might be the drugs of choice.