Prevention of precipitated withdrawal symptoms by activating central cholinergic systems during a dependence-producing schedule of morphine in rats

Previous studies in this and other laboratories have suggested an important role for central cholinergic neurons in the expression of morphine withdrawal symptoms. This study was designed to determine whether the symptoms of withdrawal could be mitigated by normalization of the effect of morphine on cholinergic neurons. Since this effect is generally inhibitory, we used centrally acting cholinergic agonists to augment central cholinergic tone during chronic morphine infusion. Rats were made dependent following the intra-arterial (i.a.) infusion of increasing concentrations (35-100 mg kg(-1) day(-1)) of morphine over 5 days. I.a. injection of 0.5 mg/kg of naloxone precipitated a profound withdrawal response that included a dramatic increase in mean arterial pressure (MAP) which was maintained over the 60-min observation period, a short duration increase in heart rate (HR), and characteristic opiate withdrawal symptoms. In separate groups of rats, non-toxic doses (50 and 250 microg/kg) of the acetylcholinesterase (AChE) inhibitor, diisopropylflurophosphate (DFP) were administered as single daily injections concomitant with the morphine infusion. DFP treated rats, exhibited significantly reduced expression of the naloxone-evoked pressor response. The apparent anti-withdrawal effect of DFP was not reproduced by the selective peripherally acting AChE inhibitor, echothiophate, although both compounds effectively reduced the expression of certain other withdrawal symptoms. The centrally acting muscarinic cholinergic receptor agonist, arecoline, resulted in an even more impressive suppression of withdrawal symptoms. While not all symptoms associated with morphine withdrawal are mediated via central cholinergic pathways, these results suggest that physical dependence on morphine can be suppressed to a significant degree by the augmentation of central cholinergic activity during morphine administration.     

The importance of brainstem cholinergic neurons in the pressor response to cocaine

After intracisternal injection, 140 nmol (48 microg) of cocaine (but not lidocaine or procaine) evoked an increase in mean arterial pressure (MAP) of 41 mm Hg. The increase in MAP began within 1 min after injection and lasted 10 to 15 min. The pressor response to intracisternal injection of cocaine was not mediated through central alpha-adrenergic receptors, but intracisternal pretreatment with D1 or D2 dopamine receptor antagonists shortened the duration of the response. Pretreatment with intracisternal injection of hemicholinium-3 to deplete medullary acetylcholine produced a dose-dependent inhibition of the pressor and tachycardic responses to intracisternal injection of cocaine. Central pretreatment with hemicholinium-3 also inhibited the pressor response to intravenous injection of 0.5 mg/kg cocaine. Atropine pretreatment was only partly effective in blocking the pressor and tachycardic responses to intracisternal injection of cocaine. However, a single intracisternal injection of the nicotinic ganglionic receptor blocker hexamethonium inhibited the pressor response to cocaine administered intracisternally 24 h later, and on each of the following 4 days. The blocking effect of hexamethonium was not mimicked by the alpha7 selective antagonist methyllycaconitine or by the alpha4beta2 subtype-preferring antagonist dihydro-beta-erythroidine. The data suggest that the pressor response to cocaine is mediated by medullary acetylcholine release on to nicotinic receptors of the ganglionic type, enhancing the output of bulbospinal sympathetic premotor neurons. Our results provide new evidence for the prolonged inactivation of relevant central nicotinic receptors by nicotinic receptor antagonists, and suggest that such compounds might be used safely for cocaine overdose, as well as for antiabuse issues without the concern for autonomic side effects.     

Deficits in spatial learning and nicotinic-acetylcholine receptors in older, spontaneously hypertensive rats

Spontaneously hypertensive rats are often used as models of attention deficit hyperactivity disorder and to investigate the effects of hypertension on cognitive function. Along with the wide variety of cardiovascular anomalies, these animals as young adults also exhibit deficits in memory and attention and central nicotinic-acetylcholine receptor sites. These findings may have particular significance since nicotinic receptors appear to be involved in the regulation of cerebral circulation and mnemonic function. Furthermore, a lack of high affinity nicotinic receptors (in knockout mice) has also been shown to accelerate both the structural and cognitive degeneration associated with age, findings that may be especially relevant to age-related memory disorders such as Alzheimer's Disease where large deficits in nicotinic receptors are observed. Since spontaneously hypertensive rats appear to be both memory-impaired and deficient in nicotinic receptors at a young age (compared to the non-hypertensive phenotype, Wistar-Kyoto rats), we were interested to learn if these conditions were exacerbated in older animals with particular interest in specific nicotinic receptor subtypes in memory areas of the brain.Spatial learning was assessed in 15-month-old subjects of each phenotype (i.e. hypertensive and non-hypertensive) using a two-phase water maze paradigm, and nicotinic receptors were measured via autoradiography with [125I]-alpha-bungarotoxin and [3H]-epibatidine. In the water maze, both groups learned to locate a hidden platform as indicated by progressively shorter latencies across training days, however, Wistar-Kyoto rats were more efficient in both phases. While the number of both bungarotoxin and epibatidine binding sites was lower in the hypertensive rats across several brain regions, in the case of epibatidine binding, the magnitude of the difference and the number of areas affected was generally greater and included areas important for spatial learning (e.g. frontal and entorhinal cortex). In a direct comparison between 3-month-old and 15-month-old rats of each phenotype, epibatidine sites were markedly reduced by age (i.e. by greater than 50% in some cases) across multiple brain regions in both groups, although Wistar-Kyoto rats appeared to be more substantially affected by age.These data further support the use of the spontaneously hypertensive rat as model for studying learning-impairment and reduced central nicotinic receptors and also indicate that these characteristics persist and (in the case of high affinity nicotinic receptor cites) worsen with age.     

Pigment epithelium-derived factor regulates early pancreatic fibrotic responses and suppresses the profibrotic cytokine thrombospondin-1

Pigment epithelium-derived factor (PEDF) is important for maintaining the normal extracellular matrix. We hypothesized that the initiation of pancreatic fibrosis is dependent on the loss of PEDF. Pancreatic PEDF expression was assessed in wild-type mice fed either a control or ethanol diet using an intragastric feeding model. Pancreatitis responses were elicited with either a single episode or a repetitive cerulein-induced (50 μg/kg, 6 hourly i.p. injections) protocol in wild-type and PEDF-null mice. Quantitative real-time PCR and immunoblotting were performed to assess fibrogenic responses. In wild-type animals, PEDF expression increased with pancreatitis and was more pronounced in mice fed ethanol. Compared with wild-type mice, α-smooth muscle actin staining and expression levels of fibrogenic markers (eg, transforming growth factor-β1, platelet-derived growth factor, collagen I, and thrombospondin-1) were higher in PEDF-null mice at baseline. Sirius red staining revealed more fibrosis in PEDF-null versus wild-type pancreas 1 week after pancreatitis. Differences in tissue fibrosis resolved with longer recovery periods. PEDF overexpression suppressed thrombospondin-1 levels in vitro. Ethanol feeding and experimental pancreatitis increased PEDF expression in wild-type mice. PEDF-null mice, however, demonstrated enhanced early fibrotic responses compared with wild-type mice with pancreatitis. These findings indicate that PEDF acts as a compensatory antifibrotic cytokine in pancreatitis.     

A rare case of non-Hodgkins B-cell lymphoma in a psoriatic patient: a case report and literature review

Cyclosporine has been shown to increase the risk of lymphoma when used in organ transplant patients; however, studies have failed to demonstrate an increased risk of lymphoma when used at lower dermatologic doses for psoriasis. The authors present a case of solid B-cell lymphoma occurring in a psoriasis patient with a history of intermittent exposure to high-dose methotrexate, followed by low-dose cyclosporine for two years and subsequently transitioned to treatment with adalimumab. Methotrexate, cyclosporine and adalimumab are each effective treatments for psoriasis. However, when faced with an interplay of several factors, closer surveillance for malignancy is warranted than that which is currently considered for monotherapy.