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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.

Ten healthy males between 18 and 33 years received 10 mg morphine sulfate intravenously, or by lumbar epidural injection at two sessions 2-4 weeks apart, in random sequence. The following observations were made at intervals for 22 h. (1) Segmental hypalgesia to ice and pin scratch. (2) Cold pressor response test in hand and foot as an index of analgesia. (3) Time of onset and duration of side effects. (4) Serum concentrations of morphine. Few non-respiratory changes were seen after intravenous morphine. Cold pressor response was unchanged in hand and foot, no segmental hypalgesia or itching occurred, and only one subject complained of nausea. Marked changes occurred after epidural morphine. Cutaneous hypalgesia to ice and pin scratch appeared in the thoracolumbar region all subjects. In six subjects hypalgesia rose to the midthoracic region during the second or third hour and to the trigeminal distribution between the sixth and ninth hour in five subjects. Cold pressor response fell rapidly in the foot during the first 1.5 h after epidural morphine, and a little later cold pressor response also fell in the hand in all subjects, and remained depressed for the duration of the experimental period. Pruritus occurred at three hours in nine of the 10 subjects, nausea at about four hours in six of the subjects, and vomiting at about six hours in five of the subjects. Hypalgesia and side effects were not related to serum concentrations of morphine. These results suggest that lumbar epidural morphine travels cephalad in the cerebrospinal fluid to reach the brain stem and fourth ventricle by the sixth hour.

A new technique of epidural catheterization in rats is described. The pharmacologic characterizations of the model were established after epidural injection of bupivacaine, morphine, fentanyl, lofentanil, and D-Ala2-D-Leu5-enkephalin (DADL) on hot plate (HP) and tail flick (TF). In addition, rostral spread, motor function, behavior, and reproducibility of the effects over time were assessed. The time-response curves showed an almost immediate onset of action for bupivacaine, fentanyl, and lofentanil and a delayed onset for morphine and DADL. Morphine and lofentanil displayed a significantly longer duration of action than bupivacaine, fentanyl, and DADL. The dose-response curves were monotonic and the slopes were log-linear. Based on the ED50 values, the following rank order of potency was obtained 1 day after catheterization for both HP and TF: lofentanil much greater than fentanyl greater than morphine much greater than DADL greater than bupivacaine. Intraperitoneal (IP) administration of naloxone antagonizes the agonist effects of epidural morphine, fentanyl, and lofentanil. To assess the role in analgesia played by epidural vascular uptake after epidural administration of morphine, fentanyl, and lofentanil, the lowest maximally effective epidural dose of these agents was given intravenously. After iv fentanyl and lofentanil, the analgesic and behavioral effects were not different from the values obtained after epidural administration. By contrast, the effects were negligible after iv morphine when compared with the epidural route. Epidural vascular uptake is thought to be low for morphine and high for fentanyl and lofentanil. The reproducibility of the analgesic and behavioral effects over time was assessed by epidurally injecting the lowest maximally effective dose of bupivacaine, morphine, fentanyl, and lofentanil 1 day and 10 days after catheterization. After 10 days, a significant reduction of analgesic and behavioral effects was noted and was thought to be due to a complete fibrotic sheath surrounding the epidural catheter.

Ten healthy young male volunteers received in random sequence 10 mg of morphine sulfate intravenously and by lumbar epidural route during two 26-hour study sessions, in order to observe the appearance and resolution of the following side effects: (a) pruritus, (b) nausea, (c) vomiting, (d) urinary dysfunction. With the exception of one subject, who experienced transient (2 hours) nausea, none of the subjects experienced any adverse side effects after the intravenous morphine. However, all subjects experienced some degree of one or more complications, starting 3 hours after the epidural administration: generalized pruritus started at 3.0 +/- 0.3 hours (nine of 10 subjects, mean +/- SD) and lasted 5.3 +/- 4.0 hours. Nausea occurred in six subjects at 4.0 +/- 0.6 hours, and lasted 3.0 +/- 2.1 hours; vomiting occurred at 6.3 +/- 2.0 hours in five of the nauseated subjects. Urinary retention of varying intensity and duration appeared in nine subjects and required pharmacologic intervention in six subjects. Serum levels of unmodified morphine were measured at various times after administration during both sessions and did not correlate with the incidence or temporal appearance of side effects. Serial evaluation of dermatomal level of hypalgesia to ice and pin scratch demonstrated a progressive spread in the rostral direction after epidural morphine; trigeminal areas were affected by 9 hours in five of the 10 subjects. The stereotyped sequence of side effects after 10 mg of morphine by the epidural route can be interpreted to reflect widespread dispersion of morphine throughout the subarachnoid and ventricular cerebrospinal fluid.

We describe procedures for catheterizing the epidural space, the azygos vein, and the thoracic lymph duct of dogs without using fluoroscopy. The success rates of the procedures were 100, 80, and 50%, respectively (n = 10). To assess the validity of the model, 3H-morphine and unlabeled morphine (2 mg) were injected epidurally in ten dogs. Lumbar cerebrospinal fluid (CSF), azygos venous blood, arterial blood, and lymph were sampled before and 5, 20, 60, 120, 180, 240, 300 and 360 min after injection. During the first 20 min, morphine levels in the azygos vein were about three and ten times greater than arterial and lymphatic levels, respectively (n = 3; P less than 0.01). Morphine levels were significantly greater in the azygos vein (n = 8) and the femoral artery (n = 10) during the first 20 and 60 min than they were later, respectively (P less than 0.05). In the lymph (n = 5), the levels of morphine at 60 min were statistically greater (P less than 0.05) than levels at 4, 5, and 6 hr. At no time were the concurrent arterial and lymph levels different from each other. In the lumbar CSF, the morphine peak concentration was reached 5-60 min after epidural injection and ranged between 5 and 93 micrograms/ml. In the CSF, the levels of morphine were significantly greater during the first 20 min than later (n = 7; P less than 0.05). The washout of the lumbar CSF curve for morphine appeared to be fitted by a two-compartment open model. The t1/2-alpha and t1/2-beta values were 14.7 +/- 7.2 min and 106 +/- 45 min, respectively (mean +/- SD). Cumulative percentages of the epidural dose of morphine passed into the azygos system within the first 5, 20, 60, and 120 min after injection were calculated to be 4.0 +/- 2.1, 23.5 +/- 14.6, 49.2 +/- 34.2, and 55.9 +/- 35.3, respectively (mean +/- SD; n = 8). Both 14C-inulin and 3H-morphine were injected epidurally in one dog and intrathecally in another dog. In the CSF, morphine appears to be cleared at a rate similar to that of inulin. The fraction of morphine and inulin crossing the dura after epidural injection was calculated to be 0.31% and 0.59%, respectively.

Ventilatory sensitivity to CO2 was measured at various times (0.5, 1, 3, 6, 10, 16, and 22 h) in 10 healthy young volunteers after 10 mg of morphine sulfate in 10 ml of saline injected intravenously (IVm) or by the epidural route (Em). The two randomized study sequences were completed 2-4 weeks apart. Ventilatory variables studied were resting end-tidal CO2 (PetCO2) measured before each rebreathing maneuver; slopes of the ventilatory response curve (sVE) and position of the curve, calculated as the ventilation sustained for a fixed stimulus of PetCO2 = 54 torr (VE54). Additionally, linear regressions were calculated for tidal volumes (VT) and respiratory rates (RR) during the rebreathing test, yielding sVT, VT54, sRR, and RR54. CO2-response curves were maximally depressed following IVm at the 0.5-h study period, while after Em, maximal respiratory depression was at the 6- and 10-h study period. Significantly greater depression after Em was demonstrated between 3 and 22 h by one or more of the following parameters: PetCO2, sVE, VE54, VT54, and sRR. The results indicate substantial differences in magnitude, duration, and characteristics of the depression of the CO2 chemosensitivity between the two modes of administration of morphine, quite separate from the differences observed for serum morphine levels in these volunteers.

A new technique of epidural catheterization in rats is described. The pharmacologic characterizations of the model were established after epidural injection of bupivacaine, morphine, fentanyl, lofentanil, and D-Ala2-D-Leu5-enkephalin (DADL) on hot plate (HP) and tail flick (TF). In addition, rostral spread, motor function, behavior, and reproducibility of the effects over time were assessed. The time-response curves showed an almost immediate onset of action for bupivacaine, fentanyl, and lofentanil and a delayed onset for morphine and DADL. Morphine and lofentanil displayed a significantly longer duration of action than bupivacaine, fentanyl, and DADL. The dose-response curves were monotonic and the slopes were log-linear. Based on the ED50 values, the following rank order of potency was obtained 1 day after catheterization for both HP and TF: lofentanil much greater than fentanyl greater than morphine much greater than DADL greater than bupivacaine. Intraperitoneal (IP) administration of naloxone antagonizes the agonist effects of epidural morphine, fentanyl, and lofentanil. To assess the role in analgesia played by epidural vascular uptake after epidural administration of morphine, fentanyl, and lofentanil, the lowest maximally effective epidural dose of these agents was given intravenously. After iv fentanyl and lofentanil, the analgesic and behavioral effects were not different from the values obtained after epidural administration. By contrast, the effects were negligible after iv morphine when compared with the epidural route. Epidural vascular uptake is thought to be low for morphine and high for fentanyl and lofentanil. The reproducibility of the analgesic and behavioral effects over time was assessed by epidurally injecting the lowest maximally effective dose of bupivacaine, morphine, fentanyl, and lofentanil 1 day and 10 days after catheterization. After 10 days, a significant reduction of analgesic and behavioral effects was noted and was thought to be due to a complete fibrotic sheath surrounding the epidural catheter.