Mu-opiate binding and morphine antagonism by octapeptide analogs of somatostatin.

A series of cyclic conformationally restrained octapeptide analogs of somatostatin were examined for their ability to inhibit the binding of tritiated mu, kappa, and delta opiate receptor ligands. Several of these substances were found to have high affinity for mu opiate receptors while having very low affinity for both kappa and delta receptors. Previous suggestions that somatostatin analogs exhibit opiate antagonist activity led to a study of the ability of the two most potent compounds to inhibit morphine analgesia in rats after intracerebroventricular injection. One of the compounds significantly antagonized morphine analgesia although the other displayed severe toxicity. These two compounds differed in that the very toxic compound had previously been found to possess significant somatostatin activity. It thus appears that the structural requirements for toxicity and somatostatin activity can be differentiated from those for opiate activity.

Sigma binding parameters in developing rats predict behavioral efficacy of a sigma ligand.

The relationship between sigma binding and the behavioral efficacy of a selective sigma ligand was examined in rats of varying ages (30, 45, 60, 75, 90, and 150 days old). Scatchard analyses of the binding of the sigma radioligand [3H]1,3-di-o-tolylguanidine ([3H]DTG) to brain membranes revealed significant age-related differences in binding to both crude synaptosomal and microsomal fractions. The functional significance of these developmental changes in sigma ligand binding was studied by determining the postural effects of rubral microinjections of DTG in age-matched littermates of rats used in the binding studies. The degree of dystonia produced by a single dose of DTG was significantly correlated with the amount of [3H]DTG bound to rat brain synaptosomal membranes at low but not at high concentrations. No significant correlation between binding to the microsomal fraction and drug efficacy was observed. These experimental results were in good agreement with predicted amounts bound as estimated from a Scatchard analysis of the data. The results suggest that sigma binding sites found in brain synaptosomal membranes are functional receptors involved in the control of movement and posture.

Effects of 1,3-di-o-tolylguanidine (DTG), a sigma ligand, on local cerebral glucose utilization in rat brain.

The 2-deoxy-D-[1-14C]glucose ([14C]DG) method was used to examine the effects of the relatively selective sigma ligand 1,3-di-o-tolylguanidine (DTG) on cerebral metabolism in freely moving rats. Each animal received an i.p. injection of DTG (0.2, 1, or 5 mg/kg) or normal saline 20 min prior to the infusion of [14C]DG. DTG induced dose-dependent changes in local cerebral glucose utilization (LCGU) in several motor and limbic structures. Most structures showed increases in LCGU, with a maximum effect at 1 mg/kg. The most profound increases in LCGU were observed in brain regions that are rich in sigma receptors. These included cerebellar and related nuclei (interpositus, lateral and medial cerebellar n., vestibular n., olivary n.), ambiguus n., superior colliculus (superior layers), hippocampus (CA2, CA3, DG), n. basalis of Meynert interpeduncular n., and the substantia nigra pars compacta and pars reticulata. No significant decreases in glucose utilization were observed at any dose. Although the areas affected by DTG are similar to those previously reported for other sigma ligands, future studies employing a range of doses for additional selective sigma ligands must be carried out in order to confirm whether these changes in LCGU were sigma-mediated.

Drug specificity of pharmacological dystonia.

Three (+)-benzomorphans that bind to sigma receptors produced dystonia in a dose-related manner when microinjected into the red nucleus of rats. Two lines of evidence suggest that these effects were related to the sigma-binding properties of the compounds. First, the behavioral potency of the (+)-benzomorphans and other active sigma compounds correlated highly with their affinities for [3H]1,3-di-o-tolylguanidine-labelled sigma receptors in the rat brain (r = .94). Second, similar intrarubral injections of non-sigma ligands were without effect: various vehicles, a structurally related (+)-opiate with no affinity for sigma receptors, and selective dopaminergic and serotonergic compounds failed to significantly alter the normal posture of rats. The only ligand in this study that binds with high affinity to sigma receptors, but failed to elicit torsional head movements was (+)-[3-(3-hydroxyphenyl)-N-(1-propyl)piperidine] [(+)-3PPP], a ligand with mixed activity at sigma and dopamine receptors. Since (+)-3PPP failed to produce an effect on its own and also failed to attenuate the dystonia produced by another sigma ligand (DTG), it may interact with a non-sigma mechanism or with a different sigma receptor type from the other compounds.

Reversible posterior leukoencephalopathy following organ transplantation. Description of two cases.

Although neurologic changes after organ transplantation are often secondary to opportunistic infections or vascular insults, new pathological entities are emerging. We have recently encountered two patients who, a few days after liver and heart transplant, respectively, developed neurological signs and symptoms. Head computerized tomography (CT) scan showed nonenhancing areas of low attenuation, and magnetic resonance imaging (MRI) demonstrated multiple areas of increased signal intensity in the subcortical white matter on T2-weighted images. Stereotactic biopsy of the intracranial lesions was performed in one case. Light microscopic examination demonstrated only mildly edematous white matter. No infectious organisms were observed on light or electron microscopy. In one patient, follow-up MRI 3 months later showed almost complete resolution of the signal abnormalities. Both patients' clinical condition progressively improved. The neuroradiological abnormalities described are consistent with the 'reversible posterior leukoencephalopathy' syndrome associated with cyclosporine toxicity. The pathophysiology of these lesions is unclear; however, it has been suggested that cyclosporine causes an acute ischemic insult secondary to vascular spasm with resultant axonal swelling. This hypothesis is supported by the hypoattenuation seen on CT, the prolonged T2 relaxation seen on MRI, and the absence of contrast enhancement. Concomitant factors (such as hypocholesterolemia or associated therapy with high dose steroids) are important in the development of these lesions as in both of our patients cyclosporine levels were in the normal range. Fortunately, these lesions and the associated manifestations are most often reversible and regress with adjustments of cyclosporine dosage and/or correction of concomitant facilitating factors.