Segmental effects on motor function following different intrathecal receptor agonists and antagonists in rabbits.

BACKGROUND: The occurrence of motor impairment after intrathecal drug administration is infrequently reported in the literature and the methods of determining motor function vary. METHODS: Motor function was examined in rabbits after a wide dose range of a variety of intrathecally administered opioid agonists, alpha-adrenergic agonists, non-competitive NMDA antagonists, a benzodiazepine agonist, a sigma agonist, paracetamol, isotonic and acidified saline. The opioids, sigma agonist and NMDA antagonists were additionally examined following pretreatment with naloxone. The opioid antagonists naltrindole and MR2266 (delta- and kappa-opioid receptor antagonists, respectively) were administered before the delta agonist and the kappa agonist. The alpha 2-adrenergic antagonist yohimbine was given before administration of dexmedetomidine and xylazine. Motor function was evaluated by a five-point scale of motor impairment ranging from normal function to total paralysis of the hindlegs. RESULTS: DPDPE (delta agonist), paracetamol, naloxone, naltrindole, yohimbine, isotonic and acidified saline did not affect motor function. MR2266 produced minor motor impairment. The alpha-adrenergic agonist dexmedetomidine reduced motor function slightly and dose independently. The remaining compounds affected motor function in a dose-dependent fashion. High doses of morphine produced hypersensitivity and myoclonus. An irreversible paralysis of the hindlegs was observed following intrathecal administration of the sigma agonist SKF10047 in high doses. Naloxone and MR2266 attenuated the effects of U50488H (kappa agonist). CONCLUSION: The present results reveal a dose-dependent reduction in motor function after intrathecal administration of some of the investigated compounds. The mechanisms behind these effects appear to be multifactorial.

Tonic endogenous opioid inhibition of visceral noxious information in rabbits.

BACKGROUND & AIMS: A tonic intrinsic spinal inhibitory system on spinal motor reflexes in rabbits has been shown earlier. The aim of this study was to examine the effects of different opioid antagonists against visceral noxious stimulation in awake rabbits. METHODS: The opioid receptor antagonists examined were naloxone (nonselective), MR2266 (kappa), and naltrindole (delta). The effects on the visceromotor response thresholds induced by colorectal distention in rabbits were determined after intrathecal and intramuscular administration of the antagonists. RESULTS: Intrathecal naloxone resulted in a dose-dependent decrease of visceromotor response thresholds. The selective antagonists MR2266 and naltrindole had no significant effects. In the presence of MR2266, intrathecal naloxone reduced thresholds to the same degree as when given alone. Analysis of the data from all rabbits showed a statistically significant reduction in visceromotor response thresholds after intrathecal naloxone compared with intramuscular administration. CONCLUSIONS: In rabbits, tonic active intrinsic spinal and supraspinal endogenous opioids modulate visceral noxious information. This inhibition is exerted at the mu opioid receptor.

The effect of intrathecal opioid-receptor agonists on visceral noxious stimulation in rabbits.

BACKGROUND & AIMS: Conflicting results have been published concerning the effects of different opioid-receptor agonists against visceral noxious stimulation. The introduction of colorectal distention facilitates research in this field. The aim of this study was to examine intrathecally administered opioid agonists against colorectal distention in conscious rabbits. METHODS: Rabbits were equipped with a subcutaneous intrathecal injection system. Colorectal distention was induced by inflation of a balloon inserted into the descending colon. The test parameter was the pressure eliciting a characteristic visceromotor response. Examinations were performed before and after administration of the following drugs: morphine, U50488H, [D-Pen2, D-Pen5]enkephalin (DPDPE), naloxone, MR2266, naltrindole, saline, and acidified saline. RESULTS: The visceromotor response to colorectal distention was inhibited in a dose-dependent fashion by intrathecal opioids acting as agonists at all three types of opioid receptors. Morphine was antagonized more effectively by intrathecal than intramuscular naloxone. U50488H and DPDPE were equally antagonized by the specific antagonists MR2266 and naltrindole. Electrical thresholds in the lumbar region were increased, although they remained unaltered in the cervical region after administration of all three agonists. CONCLUSIONS: Intrathecal administration of different opioid agonists produces a dose-dependent spinal effect. The rank order of potencies in this model is DPDPE > U50488H > morphine > saline = 0.

Histopathology after repeated intrathecal injections of preservative-free ketamine in the rabbit: a light and electron microscopic examination.

Epidural and spinal administration of ketamine has been used in humans. Single-dose studies have shown that preservative-free ketamine lacks neurotoxic effects, but there are no studies after repeated administrations. The aim of this study was to examine the effects of daily administration of preservative-free ketamine. Fourteen New Zealand albino rabbits were assigned to two groups receiving either intrathecal preservative-free ketamine 5 mg, 0.5 mL 1% solution (eight rabbits) or saline 0.5 mL (six rabbits) once a day for 14 consecutive days. The rabbits had a total subcutaneous implanted intrathecal catheter, which was introduced during general anesthesia. On Day 15 the rabbits were anesthetized and in vivo fixated by transcardial perfusion with Tyrode's solution followed by a mixture of 2% glutaraldehyde and 1% formaldehyde in a 0.1 mol/L phosphate buffer. A segment 5 cm on each side of the catheter tip was removed and kept in a cold solution of the fixative. Light microscopic, electron microscopic, and morphometric examinations showed no differences between the spinal cords from the rabbits injected with ketamine versus saline. Intrathecal ketamine produced motor impairment for a period of 15 min. We conclude that repeated intrathecal administration of preservative-free ketamine confirms the lack of neurotoxicity from single-dose studies.

Direct spinal effect of intrathecal acetaminophen on visceral noxious stimulation in rabbits.

The aim of this study was to investigate the effect of intrathecal acetaminophen on visceral and somatic noxious stimulation in the intact, non-anesthetized rabbit. Sixteen rabbits had intrathecal catheters implanted surgically. Visceral noxious stimulation was induced by intestinal distension of the distal colon and somatic stimulation with increasing electrical current through skin electrodes placed in either the cervical or the lumbar area. The effect on visceral noxious stimulation was assessed following intrathecal injection of 0.5, 2.5 and 5 mg of acetaminophen and following 10 and 50 mg acetaminophen intravenously. Naloxone 0.2 mg and yohimbine 0.1 mg were administered intrathecally prior to intrathecal injection of acetaminophen 5 mg. A dose-dependent effect of intrathecal acetaminophen against the visceromotor reflex produced by intestinal distension was shown. No effects on thresholds to lumbar or cervical electrical stimulation or intestinal distension were observed following i.v. administration. Thresholds to noxious electrical stimulation were only significantly elevated at the lumbar level following i.t. injection of 5 mg acetaminophen. Naloxone failed to antagonize the effect of intrathecal acetaminophen, whereas intrathecal yohimbine attenuated the effect of intrathecal acetaminophen in both tests. In conclusion, a spinal, dose-dependent, naloxone-irreversible, and yohimbine-reversible effect of intrathecal acetaminophen on electrical and visceral noxious stimulation was demonstrated.