Morphine‐tolerant longitudinal muscle strip from guinea‐pig ileum

1 Dose-response curves for normorphine in the absence and presence of naloxone have been obtained from myenteric plexus-longitudinal muscle strip preparations from normal and morphine pretreated guinea-pigs. In addition, the high affinity stereospecific binding of [3H1-etorphine has been measured in homogenates of the same tissue. 2 Higher concentrations of normorphine were required to produce 50% inhibition of the electrically stimulated contractions of strip preparations from morphine pretreated animals. There was also an increase in the slope of linearized dose-response curves in opiate-tolerant preparations. Maximum opiate effect was unchanged, and responses to exogenous acetylcholine were not affected by the pretreatment.3 There was a slight increase in the apparent equilibrium constant for naloxone after morphine pretreatment. 4 Tolerance to opiate effect was not accompanied by a change in the affinity or number of stereospecific binding sites for [3H1-etorphine. Hill plots of [3H1-etorphine binding in both control and morphine pretreated preparations gave slopes close to unity. 5Most of these results can be explained by the assumption that in tolerant preparations, a certain fractional opiate receptor occupation threshold must be exceeded before opiate effects become apparent. It is suggested that the tissue adapts toward a threshold equivalent to the mean receptor occupancy attained during the period of opiate drug pretreatment.

Section: Discussionmentioning

confidence: 68%

Section: Methods Pretreatment Ofguinea-pigsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Opiate Binding and Effect in Ileum Preparations From Normal and Morphine Pretreated Guinea‐pigs

Cox

Padhya

1977

“…Parotid secretion in morphine pretreated rats Goldstein & Schultz (1973), and Johnson, Westfall, Fleming & Howard (1977) found that tolerance in autonomic structures may not develop as rapidly as it does in the CNS. A summary of the effects of 5 and 25 mg/kg morphine on nerve-induced (2.5 Hz) flow rate in control and in morphine-pretreated ani- Figure 5 The effects of morphine (5 and 25 mg/kg) before (open columns) and after naloxone (40 mg/kg, hatched columns) on nerve-induced secretion by the parotid gland during stimulation at 2.5 Hz.…”

Section: Depression Of Nerve-induced Salivation By Morphinementioning

confidence: 99%

Morphine Depression and Tolerance of Nerve‐induced Parotid Secretion

Bowen

Carpenter

1979

1 The nerve-induced secretion produced by the rat parotid gland is proportional to the frequency of stimulation. Morphine decreased the flow rate during stimulation at 2.5 and 5 Hz, but not at 20 Hz. This frequency-dependent action of morphine was partially reversed by naloxone. 2 The secretion produced by the rat parotid gland during an intravenous infusion of acetylcholine was not diminished by morphine. Therefore, the action of morphine on nerve-induced secretion is most probably on the motor nerve terminals, which release acetylcholine. 3 Animals that had been implanted with morphine base pellets tolerated 4 times as much morphine as controls; after 6 days the minute ventilation was less depressed by graded doses of morphine than non-implanted controls. 4 Nerve-induced secretion in morphine-implanted animals was less depressed by morphine than control animals 6 and 24 h after the pellets were removed. The flow rates in the 6 h group treated with morphine were greater after naloxone than control (precipitated withdrawal) but at 24 h when withdrawal symptoms were no longer evident, naloxone produced only a slight reversal.

“…The isolated ileum of the guinea-pig displays many of the characteristics of the response of the central nervous system (CNS) to opiates and has been used successfully in the study not only of the acute effects of opiates but also the long term effects of tolerance and dependence (Paton, 1957;Goldstein & Schulz, 1973;Kosterlitz, Lord, & Watt, 1973;Kosterlitz & Waterfield, 1975;Schulz & Herz, 1976;Gintzler, 1979;1980). Previous studies have shown that there are at least two separate neuronal pathways that mediate naloxone-precipitated enteric withdrawal from opiates.…”

Section: Introductionmentioning

confidence: 99%

Effects of Opioids on Noncholinergic Excitatory Responses of the Guinea‐pig Isolated Ileum: Inhibition of Release of Enteric Substance P

Gintzler

Scalisi

1982

Experiments were carried out to determine whether opiates and opioid peptides could affect noncholinergic excitatory responses of the isolated guinea‐pig ileum. Transmural field stimulation (10–20 Hz) of an atropine pretreated, intact segment of gut produced a contracture that could be elicited repeatedly without significant variation in magnitude. This noncholinergic contracture was significantly reduced 75.3 ±8.3% (mean±s.e.mean) by tetrodotoxin (TTX; 1 μg/ml) and by desensitizing the preparation to substance P (76.3 ± 10.1%). Morphine (5 × 10−6 m) as well as the opioid peptides d‐Ala2, N‐Phe4, Met‐(0)‐01 (FK 33–824; 9 × 10−7 m), d‐Met2‐Pro5 enkephalin (3 × 10−7 m) and d‐Ala2‐d‐Leu5‐enkephalin (5 × 10−6 m) inhibited the magnitude of the noncholinergic contracture but did not alter contractile responses to exogenous substance P (4 × 10−11 m‐4 × 10−10 m). Pretreatment with the nicotinic receptor blocker, hexamethonium (10−5‐10−4 m) reduced by about 35% the magnitude of the atropine‐resistant contracture but did not affect inhibitory responses to morphine or opioid peptides. Thus the inhibition produced by morphine on the 20 Hz contracture does not involve a nicotinic cholinergic mechanism. Naloxone pretreatment (10−6 m) in the presence of hexamethonium (10−5‐10−4 m) enhanced the magnitude of the noncholinergic contracture without affecting responses to exogenous substance P (4 × 10−11‐4 × 10−10 m). These data suggest that substance P is the main, if not the sole, mediator of the atropine‐resistant 20 Hz contracture and indicate further that exogenous as well as endogenous opioids can modulate the release of this enteric peptide.