Distress as a mediator for pain and activities of daily living in older adults with fibromyalgia.

Introduction: Pain, distress, and activities of daily living impact the lives of those with chronic pain. This study investigated distress (depressive symptoms, anxiety) on the relationship between pain (intensity and pain interference) and activities of daily living in individuals with fibromyalgia while controlling for age. Methods: The current cross-sectional investigation focused on data from 123 men and women with fibromyalgia. Pain intensity, pain interference and anxiety were measured on 0-10 Likert type scales from the National Fibromyalgia Assessment Questionnaire. Depressive symptoms were assessed using the Beck Depression Inventory II. Activities of daily living (basic, instrumental) were measured with the Physical Activity Inventory Scale. Results: It was hypothesized that the relationships between pain intensity and pain interference and activities of daily living in individuals with fibromyalgia would be mediated by the construct of distress while controlling for age. Mediation significantly occurred in both models as predicted. However, those who were older reported lower levels of pain intensity and distress than their younger counterparts, which may be related to time since diagnosis or other factors. Discussion: Results of this study suggest that individuals with chronic pain conditions would benefit from treatment options which address distress, specifically depressive symptoms and anxiety.

Bisphenol A Exposure Induces Sensory Processing Deficits in Larval Zebrafish during Neurodevelopment.

Because of their ex utero development, relatively simple nervous system, translucency, and availability of tools to investigate neural function, larval zebrafish are an exceptional model for understanding neurodevelopmental disorders and the consequences of environmental toxins. Furthermore, early in development, zebrafish larvae easily absorb chemicals from water, a significant advantage over methods required to expose developing organisms to chemical agents in utero Bisphenol A (BPA) and BPA analogs are ubiquitous environmental toxins with known molecular consequences. All humans have measurable quantities of BPA in their bodies. Most concerning, the level of BPA exposure is correlated with neurodevelopmental difficulties in people. Given the importance of understanding the health-related effects of this common toxin, we have exploited the experimental advantages of the larval zebrafish model system to investigate the behavioral and anatomic effects of BPA exposure. We discovered that BPA exposure early in development leads to deficits in the processing of sensory information, as indicated by BPA's effects on prepulse inhibition (PPI) and short-term habituation (STH) of the C-start reflex. We observed no changes in locomotion, thigmotaxis, and repetitive behaviors (circling). Despite changes in sensory processing, we detected no regional or whole-brain volume changes. Our results show that early BPA exposure can induce sensory processing deficits, as revealed by alterations in simple behaviors that are mediated by a well-defined neural circuit.

Dose-dependent effects of adenosine antagonists on tacrine-induced tremulous jaw movements.

The present study examines the effect of three adenosine receptor antagonists on tremulous jaw movements (TJMs), an animal model of tremor. Forty-five rats were pre-treated with one adenosine antagonist: caffeine (0.0, 5.0, or 10.0 mg/kg; non-selective adenosine receptor antagonist), 8-cyclopentyltheophylline (CPT; 0.0, 5.0, or 10.0 mg/kg; selective adenosine A1 receptor antagonist), or SCH 58261 (0.0 or 8.0 mg/kg; selective adenosine A2A receptor antagonist) followed by TJM induction with tacrine (0.0, 0.75, or 2.5 mg/kg; acetylcholinesterase inhibitor). CPT and SCH 58261 both significantly reduced TJMs while caffeine did not. Unexpectedly, both SCH 58261 and CPT reduced TJMs even in the absence of tacrine. Also, CPT showed a robust reduction of TJMs, achieved at both (5.0 mg/kg) and (10.0 mg/kg) doses and regardless of tacrine dose. In conclusion, this study shows adenosine receptor antagonism to generally suppress low-dose tacrine-induced TJMs. In concert with two prior studies, these results are suggestive of behavioral evidence for a biphasic effect of adenosine A2A receptor antagonists (caffeine and SCH 58261) that is modulated by tacrine, and a model of this effect is proposed.

Dopamine manipulation alters immediate-early gene response of striatal parvalbumin interneurons to cortical stimulation.

Cortical projections provide the major excitatory inputs to the striatum. In addition to innervating medium spiny cells, these axons contact striatal interneurons that are parvalbumin-immunoreactive (PV-ir). PV-ir interneurons make synaptic connections with many medium spiny cells, and thus can modulate striatal output. The striatum also receives dopaminergic projections from the substantia nigra, but it has been challenging to study the impact of dopamine (DA) cell injury on corticostriatal activity in vivo due to limitations in the methods used to induce cortical activity. Using epidural application of the GABA(A) antagonist picrotoxin, which produces a topographically restricted region of striatal immediate-early gene expression, we have investigated the effect of DA cell injury or DA receptor antagonism on immediate-early gene (IEG) expression in striatal medium spiny cells and PV-ir interneurons. Epidural application of picrotoxin to the rat's M1 motor cortex induced Fos in ipsilateral dorsolateral striatum. Animals previously given 6-hydroxydopamine (6-OHDA) injections into the ascending DA pathways had greater total numbers of cortical stimulation-induced striatal Fos-ir cells but fewer Fos-ir/PV-ir cells, compared to sham-operates. In a separate experiment, rats given cortical stimulation and treated with the DA D2-class antagonist eticlopride (0.10 mg/kg) exhibited fewer Fos-ir/PV-ir cells than did vehicle-treated rats. Taken together, these results indicate that DA may importantly control striatal output via influences on PV-ir interneurons. Possible mechanisms for these influences are discussed.

The GABA uptake inhibitor beta-alanine reduces pilocarpine-induced tremor and increases extracellular GABA in substantia nigra pars reticulata as measured by microdialysis.

Substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia that receives GABAergic projections from neostriatum and globus pallidus. Previous research has shown that local pharmacological manipulations of GABA in SNr can influence tremulous jaw movements in rats. Tremulous jaw movements are defined as rapid vertical deflections of the lower jaw that resemble chewing but are not directed at a particular stimulus, and evidence indicates that these movements share many characteristics with parkinsonian tremor in humans. In order to investigate the role of GABA in motor functions related to tremor, the present study tested the GABA uptake blocker beta-alanine for its ability to reduce pilocarpine-induced tremulous jaw movements. In a parallel experiment, the effect of an active dose of beta-alanine on dialysate levels of GABA in SNr was assessed using microdialysis methods. GABA levels in dialysis samples were measured using high performance liquid chromatography with electrochemical detection. beta-Alanine (250-500 mg/kg) significantly reduced tremulous jaw movements induced by pilocarpine (4.0 mg/kg). Moreover, systemic administration of beta-alanine at a dose that reduced tremulous jaw movements (500 mg/kg) resulted in a substantial increase in extracellular levels of GABA in SNr compared to the pre-injection baseline. Thus, the present results are consistent with the hypothesis that GABAergic tone in SNr plays a role in the regulation of tremulous jaw movements. This research may lead to a better understanding of how parkinsonian symptoms are modulated by SNr GABA mechanisms.

Adenosine antagonists reverse the cataleptic effects of haloperidol: implications for the treatment of Parkinson's disease.

The effects of adenosine antagonists were compared in two rodent models of Parkinsonian symptoms. In the first experiment the dopamine D2 antagonist, haloperidol, was used to induce catalepsy. It was found that treatment with the non-selective adenosine antagonist caffeine significantly reduced catalepsy at each dose. Treatment with the selective A1 antagonist CPT also produced a significant reduction in catalepsy, as did treatment with the selective A2A antagonist SCH58261. In the second experiment haloperidol was used to suppress locomotor activity in an open field test. Treatment with caffeine significantly increased locomotion reduced by haloperidol, but not at all doses tested. Treatment with CPT also increased haloperidol-suppressed locomotor activity in dose-dependent manner. Surprisingly, treatment with SCH58261 did not significantly increase locomotor activity in animals treated with haloperidol at any dose tested. While some of these results were unexpected, the overall pattern suggests that adenosine antagonists would be useful as therapies for Parkinsonian patients as they appear to increase movement. The results also suggest that in acute timelines A1 antagonists may be more beneficial than previously supposed.