Inhibition by lithium of opioid withdrawal-like syndrome and physical dependency in a model of acute cholestasis in mice

Abstract

Because of the claim that chronic cholestatic liver disease is associated with increased opioidergic tone and that lithium (Li ) inhibits physical dependency in morphine-dependent mice, the eects of chronic Li treatment on naloxoneprecipitated withdrawal-like syndrome and antinociception were evaluated in an animal model of cholestasis. For this purpose, acute cholestasis was induced by bile duct ligation in mice. The treated group of mice was given lithium chloride (300 mg/l) as drinking¯uid for 10±12 days before surgery and 5 days after surgery. Physical dependency was observed by precipitating an abstinence syndrome with naloxone (4 mg/kg, s.c.) 5 days after induction of cholestasis. Antinociception was assessed by tail-¯ick latency test in control and treated groups before administration of naloxone. Results of the present study revealed that chronic Li administration signi®cantly reduced the withdrawallike signs, whereas the antinociception assessed by tail-¯ick test was not observed in the control group of cholestatic mice. Serum Li level in this study was much lower than the commonly accepted therapeutic range. Lithium and opioid agonist ligands have diverse eects on transmembrane signal control systems. So the interaction of Li and opioid agonists observed in this study might also be through these systems. #

Lithium Inhibits the Development of Physical Dependence to Clonidine in Mice

“…Serum lithium levels were measured according to the method as previously described (Dehpour et al 1994(Dehpour et al , 1995(Dehpour et al , 1998(Dehpour et al & 2000. One hr after the 90 min.…”

Elevation of pentylenetetrazole‐induced seizure threshold in cholestatic mice: Interaction between opioid and cannabinoid systems

“…Several findings in human beings and experimental animals strongly suggest that cholestasis is associated with increased opioidergic tone including: (i) the opiate withdrawal–like syndrome that can be precipitated in patients with chronic cholestatic liver disease by opiate antagonists; 1,5–7 (ii) the state of antinociception that is stereoselectively reversed by the opiate antagonist naloxone displayed by rats with cholestasis secondary to bile duct resection; 10 (iii) in a rat model of acute cholestasis, total plasma opioid activity is increased, and in the model and in patients with chronic cholestasis, plasma concentrations of individual endogenous opioid agonists (methionine and leucine enkephalins) are elevated; 1–4 (iv) in a rat model of acute cholestasis, μ‐opioid receptors in the brain are down‐regulated; 8,9 (v) plasma extracts from patients with cholestatic pruritus, but not from non‐pruritic patients, induce naloxone‐reversible facial scratching activity when injected into the medullary dorsal horn of monkeys, 39 suggesting that plasma of patients with cholestatic pruritus contains one or more substances that induce central opioid‐receptor‐mediated scratching activity; (vi) the granulocyte and monocyte subpopulations of leukocytes from rats with acute cholestasis have a significant increase in specific opioid‐receptor labeling compared with same subpopulations; 40 and (vii) opioid system blockade by naltrexone improves the degree of liver injury in a rat model of cholestasis 41 . Endogenous opioid peptides exert both anticonvulsant 26,42,43 and proconvulsant 23,24 effects depending on the seizure model, animal species, site of action and type of the opioid receptor involved 24,25 .…”

Obstructive cholestasis alters intestinal transit in mice: role of opioid system

“…Elevated plasma levels of endogenous opioid peptides, mainly methionin enkephalin, are described in cholestatic patients and animal subjects Losowsky, 1988a,b, 1989a,b;Swain et al, 1992;Bergasa et al, 1992;Ghafourifar et al, 1997;Dehpour et al, 1998). Many important pathophysiologic changes during cholestasis are attributed to this increased opioidergic tone and have been shown to be blocked by administration of opioid receptor antagonists.…”

“…Many important pathophysiologic changes during cholestasis are attributed to this increased opioidergic tone and have been shown to be blocked by administration of opioid receptor antagonists. Precipitation of an opioid withdrawal-like syndrome in patients with cholestasis (Thornton and Losowsky, 1988a) as well as in bile duct-ligated cholestatic mice (Ghafourifar et al, 1997;Dehpour et al, 1998) following injection of an opioid antagonist, alleviation of cholestasis-associated pruritus by administration of naloxone (Bergasa et al, 1995) or naltrexone (Wolfhagen et al, 2000), inhibition by naloxone of cholestasisinduced antinociception in rats (Bergasa et al, 1994), reversal of decreased susceptibility to pentylenetetrazole-induced clonic seizure in mice by naltrexone administration and the naloxone-reversible increase in susceptibility to NSAID-induced gastric ulcer (Dehpour et al, 1999) are among the compatible observations. Accordingly, a global down regulation of Aopioid receptors in the brain of bile duct-ligated rats has been attributed to the increased availability of opioid-agonist ligands at opioid receptors .…”