Tolerance to intrathecal oxymetazoline-induced analgesia, with paradigm-dependent cross-tolerance to intrathecal morphine.
Male, Sprague-Dawley rats, implanted with intrathecal (i.t.) catheters, were given repeated i.t. injections of morphine (40 nmol), oxymetazoline (100 nmol) or saline (10 microliter) at 12-h intervals for 3 days. Antinociception was determined 1 or 1.5 hr after each injection using the tail-flick and paw-pressure tests. Complete tolerance to i.t. morphine and oxymetazoline developed within 72 and 24 hr, respectively. Antinociception after i.t. oxymetazoline (100 nmol) in morphine-tolerant rats, and after i.t. morphine (20 nmol) in oxymetazoline-tolerant rats, was not significantly different from their respective effects in saline-pretreated rats. These data suggest an absence of cross-tolerance between morphine and oxymetazoline in the rat spinal cord. In a separate group of rats, the continuous i.t. infusion of morphine (26 nmol/hr) produced significant antinociception; tolerance to morphine developed within 36 hr. The antinociceptive effect of i.t. oxymetazoline (100 nmol) was significantly attenuated in rats pretreated with continuous i.t. morphine as compared to saline-pretreated rats. In rats pretreated with continuous i.t. oxymetazoline, cross-tolerance to morphine could not be determined due to severe adverse effects during oxymetazoline infusion. The results of this study suggest that functional cross-tolerance between morphine and alpha adrenoceptor agonists in the spinal cord cannot be excluded on the basis of repeated i.t. injection experiments alone.
Sherman
S E
SE
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Loomis
C W
CW
Milne
B
B
Cervenko
F W
FW
D000698:Analgesia; D000818:Animals; D001835:Body Weight; D004347:Drug Interactions; D004361:Drug Tolerance; D007093:Imidazoles / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010109:Oxymetazoline / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D007093:Imidazoles; D009020:Morphine; D010109:Oxymetazoline