Glutamate receptors are implicated in the genesis of opioid tolerance and dependence. Factors governing release of amino acids in systems chronically exposed to opiates, however, remain undefined. Using rats, each prepared with a spinal loop dialysis catheter and with a chronic lumbar intrathecal infusion catheter connected to a subcutaneous minipump, the release of amino acids before and during antagonist-precipitated withdrawal in unanesthetized rats was examined. Spinal infusion of morphine (20 nmol/micro l/hr) for 4 d had little effect on resting release of amino acids. In morphine-infused, but not saline-infused, rats naloxone (2 mg/kg, i.p.) evoked an immediate increase in the release of L-glutamate (299 +/- 143%) and taurine (306 +/- 113%) but not other amino acids. The magnitude and time course of the release of these amino acids significantly correlated with behavioral indices of withdrawal intensity. Acute intrathecal pretreatment immediately before naloxone with clonidine (20 microg; alpha2 agonist), MK-801 (3 microg; noncompetitive NMDA antagonist), or aminophosphonopentanoic acid (AP-5; 3 microg; competitive NMDA antagonist) suppressed naloxone-induced increases in spinal L-glutamate and taurine release and behavioral signs of withdrawal in spinal morphine-infused rats. Results point to a correlated increase in spinal L-glutamate release, which contributes to genesis of the opioid withdrawal syndrome. Agents such as clonidine that suppress opioid withdrawal may owe their action to an inhibition of excitatory amino acid release. The effects of MK-801 and AP-5 suggest a glutamate-evoked glutamate release.
The acute intrathecal (i.t.) administration of 10, 25, 50, and 100 microgram morphine and 7.5, 10, 15, and 30 microgram (-)norepinephrine (NE) to the rat produced dose-dependent, long-lasting analgesia as assessed by the tail-flick and hot-plate tests. For i.t. morphine, maximum analgesia was observed 30-60 min after drug administration. The duration of analgesia in the tail-flick test ranged from 30 to 150 min; the duration of analgesia in the hot-plate test ranged from 60 to 120 min. For i.t. NE, maximum analgesia was observed 15-60 min after drug infusion. The duration of NE-induced analgesia in the hot-plate test ranged from 45 to 120 min and was 120 min in the tail-flick test. The effects of acute i.t. and intravenous (i.v.) infusions of morphine (10 microgram) and NE (15 microgram) on heart rate, blood pressure, arterial pH, partial pressure of oxygen (Po2), partial pressure of carbon dioxide (Pco2), and standard bicarbonate were determined over 45 min in rats anesthetized with alpha-chloralose (70 mg/kg). Morphine significantly decreased Po2 throughout the experiment but did not affect blood pressure, heart rate, pH, Pco2 and standard bicarbonate. A significant increase in blood pressure (137% of control) was observed 2.5 min after i.t. administration of NE. Intravenous NE produced a marked increase in blood pressure (246% of control) followed by a compensatory decrease in heart rate. There were no significant changes in blood gases with i.t. and i.v. NE. The data suggest that i.t. morphine and NE can produce effective analgesia with minimal effects on cardiovascular and respiratory function.
Both methionine- and leucine-enkephalin caused the isolated rat ileum to relax in a concentration-dependent manner; the EC50 values were in the order of 10−8 to 10−7 M. This isolated preparation was generally not sensitive to morphine. The enkephalin-induced inhibitions were not blocked by the classical narcotic antagonist, naloxone.
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