Reversal of tolerance to the antitransit effects of morphine during acute intestinal inflammation in mice

Abstract

1 The aim of investigation was to establish and compare the reversibility of tolerance to the antitransit e ects of morphine by three di erent procedures: (a) acute in¯ammation of the gut, (b) lorglumide a cholecystokinin A (CCK A ) receptor antagonist, or (c) MK-801, an N-methyl-D-aspartate (NMDA) receptor ion channel blocker. The type of interaction between morphine and lorglumide or MK-801 on the inhibition of gastrointestinal transit (GIT) in naive animals was also evaluated. 2 Male Swiss CD-1 mice were implanted with 75 mg of morphine base or placebo pellets. Gastrointestinal transit was assessed with a charcoal meal and results expressed as % inhibition of GIT. In¯ammation was induced by the intragastric (p.o.) administration of croton oil (CO), while controls received castor oil (CA) or saline (SS). Morphine was administered by subcutaneous (s.c.) or intracerebroventricular (i.c.v.) injection, to naive and tolerant animals treated with CO, CA or SS. Doseresponse curves for s.c. morphine were also perforrmed in naive and tolerant mice receiving 5.2 or 7.4 nmol (s.c.) lorglumide or MK-801, respectively. 3 The ED 50 values for inhibition of GIT by s.c. morphine were: 45.9+2.7 and 250.1+3.1 nmol in naive and tolerant animals, respectively, demonstrating a ®ve fold decrease in the potency of morphine. In naive animals, in¯ammation (CO) decreased the ED 50 of morphine three times (14.4+2.2 nmol). However, no tolerance to s.c. morphine (ED 50 16.4+2.6 nmol) was manifested during intestinal in¯ammation. After i.c.v. administration, a similar degree of tolerance to morphine was observed (4.8 fold decrease in potency). Intestinal in¯ammation had no e ect on the ED 50 values of i.c.v. morphine in naive and tolerant animals, showing that reversal of tolerance is related to local mechanism/s. Mean values for intestinal pH were 6.9+0.04 and 6.2+0.04 in SS and CO treated mice, respectively. In addition, morphine was 74 times more potent by the i.c.v. than by the s.c. route (naive-SS). 4 Morphine and lorglumide interacted synergistically in naive animals; in addition, the administration of lorglumide reversed tolerance to s.c. morphine. No interaction (additivity) was observed in naive animals when morphine and MK-801 were administered in combination. However, the drug completely reversed tolerance to the antitransit e ects of morphine. 5 The present investigation shows that acute in¯ammation of the gut reverses tolerance to the antitransit e ects of s.c. morphine by a peripheral mechanism. Qualitatively similar results were obtained after the administration of lorglumide or MK-801. Our results suggest that a local decrease in pH could play an important role during in¯ammation, while antagonism of endogenous compensatory systems would explain the reversal of tolerance induced by lorglumide or MK-801.

Antinociceptive and nociceptive actions of opioids

“…However, the apparent reversal of tolerance may be related to the observations that conditions of inflammation are associated with reduced availability of CCK and enhanced activity of morphine (Stanfa et al, 1994;Ossipov et al, 1995a;Vanderah et al, 1996a). This interpretation is consistent with the fact that CCK antagonists reversed tolerance to morphine-induced inhibition of GI motility (Pol and Puig, 1997).…”

“…Nevertheless, the analgesic effect of intraarticular morphine in this population, leading to the assertion that opioid peptides expressed in inflamed tissue do not produce tolerance to peripheral morphine (Stein et al, 1996). In a study of gastrointestinal (GI) transit in mice, it was found that intestinal inflammation reversed tolerance to morphine-induced inhibition of GI motility (Pol and Puig, 1997). However, the apparent reversal of tolerance may be related to the observations that conditions of inflammation are associated with reduced availability of CCK and enhanced activity of morphine (Stanfa et al, 1994;Ossipov et al, 1995a;Vanderah et al, 1996a).…”

Tolerance to the Antinociceptive and Antiexudative Effects of Morphine in a Murine Model of Peripheral Inflammation

“…For the induction of tolerance, a 75-mg morphine pellet was implanted subcutaneously (Pol and Puig, 1997) that induced steady morphine plasma levels without the intermittent periods of abstinence or changes in nociceptive behavior observed when a daily injection protocol is used (Li and Clark, 2002). This method of morphine administration closely reproduces the clinical situation where patients are exposed to therapeutic plasma levels of opioids (e.g., slowrelease formulations and transdermal patches) capable of controlling pain in a continuous manner.…”

“…Morphine tolerance was induced by the s.c. implantation of a 75-mg morphine pellet (Pol and Puig, 1997;Bohn et al, 2002), whereas control animals received a placebo pellet. Under halothane anesthesia, a small skin pocket was dissected in the back of the animal, where a single pellet was inserted, and the skin was closed with surgical sutures.…”

“…After naloxone, animals were observed (30 min) for increased spontaneous activity, tremors, jumping, or rotating movements, which were considered signs of withdrawal (Pol and Puig, 1997).…”