Substantial evidence indicates an association between clinical depression and altered immune function. Systemic administration of bacterial lipopolysaccharide (LPS) is commonly used to study ...inflammation-associated behavioral changes in rodents. In these experiments, we tested the hypothesis that peripheral immune activation leads to neuroinflammation and depressive-like behavior in mice. We report that systemic administration of LPS induced astrocyte activation in transgenic GFAP-luc mice and increased immunoreactivity against the microglial marker ionized calcium-binding adapter molecule 1 in the dentate gyrus of wild-type mice. Furthermore, LPS treatment caused a strong but transient increase in cytokine levels in the serum and brain. In addition to studying LPS-induced neuroinflammation, we tested whether sickness could be separated from depressive-like behavior by evaluating LPS-treated mice in a panel of behavioral paradigms. Our behavioral data indicate that systemic LPS administration caused sickness and mild depressive-like behavior. However, due to the overlapping time course and mild effects on depression-related behavior per se, it was not possible to separate sickness from depressive-like behavior in the present rodent model.
Described here is a comparison of five peripheral sciatic nerve injury models in rats which all result in various degrees of neuropathic pain symptoms. They are the chronic constriction injury (CCI), ...the spinal nerve ligation (SNL), the partial sciatic ligation (PSL), the tibial and sural transection (TST), and the complete sciatic transection (CST) model. Behavioral testing was performed on these models over a 56-day period under strict experimental conditions to minimise variability between the surgical models and to allow for an accurate evaluation of the sensory deficits produced by each model. Overall, all five models of neuropathic pain produced signs of allodynia and hyperalgesia to various stimuli. However, the duration and magnitude of the evoked responses varied considerably between the different models.
Inflammatory processes may cause depression in subsets of vulnerable individuals. Inflammation-associated behavioral changes are commonly modelled in rodents by administration of bacterial ...lipopolysaccharide (LPS). However, the time frame in which immune activation and depressive-like behavior occur is not very clear. In this study, we showed that systemic administration of LPS robustly increased circulating levels of corticosterone, leptin, pro- and anti-inflammatory cytokines, and chemokines. Serum concentrations of most analytes peaked within the first 6 h after LPS injection and returned to baseline values by 24 h. Chemokine levels, however, remained elevated for up to 96 h. Using an optimized sucrose preference test (SPT) we showed that sickness behavior was present from 2 to 24 h. LPS-induced anhedonia, as measured by decreased sucrose preference, lasted up to 96 h. To mimic the human situation, where depression develops after chronic inflammation, rats were preexposed to repeated LPS administration or subchronic restraint stress and subsequently challenged with LPS. While these procedures did not increase the duration of anhedonia, our results do indicate that inflammation may cause depressive symptoms such as anhedonia. Using our SPT protocol, more elaborate rodent models can be developed to study the mechanisms underlying inflammation-associated depression in humans.
Reduced side-effect liability of opioids may enhance the patients quality of life and decrease the incidence of opioid-insensitive pain. Literature offers few comparative data between different ...opioids at equianalgesic doses. Therefore morphine, fentanyl, buprenorphine, codeine, hydrocodone and oxycodone were compared for analgesic properties and side-effect profiles in rats. Analgesic efficacy was analysed using a tail withdrawal test for acute thermal nociception, a formalin test for chemically induced inflammatory pain and a von Frey test for mechanical hypersensitivity. For side-effect profiling inhibition of gastrointestinal activity was evaluated in a charcoal and ricinus oil test, arterial PCO
2 was determined for measuring respiratory depression, the discriminative stimulus properties linked to the narcotic cue were assessed using a drug discrimination learning test, and motor coordination was tested through rotarod performance.
ED
50's for the occurrence of side-effects were compared to ED
50's in behavioural pain tests. Fentanyl had a strong analgesic potency and, compared to other opioids, an acceptable side-effect profiling at analgesic ED
50's. Also consistent was the ceiling effect of buprenorphine implying an increased safety margin for side-effects, but a decreased analgesic efficacy. Differences between opioids as observed in this study can have important indications for their use in acute as well as in the onset of chronic treatments.
Clinical observations indicate that activation of the TNF-α system may contribute to the development of inflammation-associated depression. Here, we tested the hypothesis that systemic upregulation ...of TNF-α induces neuroinflammation and behavioral changes relevant to depression. We report that a single intraperitoneal injection of TNF-α in mice increased serum and brain levels of the proinflammatory mediators TNF-α, IL-6, and MCP-1, in a dose- and time-dependent manner, but not IL-1β. Protein levels of the anti-inflammatory cytokine IL-10 increased in serum but not in the brain. The transient release of immune molecules was followed by glial cell activation as indicated by increased astrocyte activation in bioluminescent Gfap-luc mice and elevated immunoreactivity against the microglial marker Iba1 in the dentate gyrus of TNF-α-challenged mice. Additionally, TNF-α-injected mice were evaluated in a panel of behavioral tests commonly used to study sickness and depressive-like behavior in rodents. Our behavioral data imply that systemic administration of TNF-α induces a strong sickness response characterized by reduced locomotor activity, decreased fluid intake, and body weight loss. Depressive-like behavior could not be separated from sickness at any of the time points studied. Together, these results demonstrate that peripheral TNF-α affects the central nervous system at a neuroimmune and behavioral level.
That IL-6 is an interesting target in the study of pain is underscored by its biomolecular properties, its localization after experimental pain, and its modulating effect on pain after administration.
The primary aim of the study was to describe and correlate pain behavior and changes in bone morphology in animal models of arthritis both in rats and guinea pigs. Either complete Freund's adjuvant ...(CFA) or mono-iodoacetate (MIA) solution was injected into the left knee joint to obtain a model for rheumatoid arthritis and osteoarthritis, respectively. Subsequently, animals were behaviorally tested during a period of 12 days after CFA injection and at least 19 days after MIA injection. During these observation periods increasing pain behavior was observed, characterized by decreased von Frey mechanical thresholds and weight bearing on the affected limb. In Hargreaves' paw flick test slightly increased thermal hypersensitivity was observed in some instances in guinea pigs. In rats there was also decreased limb-use during forced ambulation. To evaluate bone destruction μ-computed tomography scans of the arthritic knee were taken on the last experimental day. Different bone parameters indicative of osteolysis and decreased trabecular connectivity were significantly correlated with the observed pain behavior. Detailed description of morphological changes in arthritic joints better characterizes the different animal models and might add to the knowledge on the working mechanisms of analgesic compounds that have an influence on bone structures in arthritis.
The pathogenesis of diabetic neuropathy is multifactorial, but in general hyperglycemia through polyol and protein glycation pathways is considered to be a key etiological factor. Most likely insulin ...deficiency, in experimentally induced type I diabetes, contributes to the development of diabetes neuropathy. The aim of this study was to evaluate the
in vivo behavioral effect of low-dose insulin on diabetic neuropathy in rats through behavioral testing in hyperglycemic conditions. Mechanical sensitivity and allodynia were tested in streptozotocin (STZ)-induced diabetic rats. After diabetes and neuropathy induction, treatment with low-dose insulin normalized behavioral test results in 37 days, while severe hyperglycemia persisted. Although this study provided no evidence about the role of hypoinsulinemia in the etiology of diabetes neuropathy, the results confirmed that an insulin deficit with impaired insulin signaling and neurotrophic support, rather than hyperglycemia, plays an essential role in the pathophysiology of painful diabetic neuropathy.
: δ‐Opioid receptor agonists have been postulated to induce analgesia without the adverse effects commonly associated with μ‐opioids e.g. morphine. In the present study, we evaluated the occurrence ...of antinociceptive and opioid‐like side effects in rats (n=5–7) treated with a single dose of subcutaneous morphine (0.01 to 40 mg/kg) or SNC80 (0.63 to 80 mg/kg). The antinociceptive effects of morphine and SNC80 were compared using a range of nociceptive tests including the tail withdrawal test, the acetic acid‐induced abdominal constriction (writhing) assay, the automated formalin test and a model of inflammation‐induced thermal hyperalgesia. The adverse effects of both drugs were examined in animal models for gastrointestinal (GI) inhibition (charcoal test; ricinus oil test), respiratory depression (blood‐gas analysis), motor disturbances (automated rotarod model) and abuse liability (drug discrimination learning).
Morphine displayed significant antinociceptive and adverse effects in all the animal models employed. SNC80 exhibited a significant effect in the writhing test and limited efficacy in a model of inflammation‐induced thermal hypersensitivity. A delay in the occurrence of diarrhoea and some limited increases in PCO2 were observed with the higher doses of SNC80 (≥40 mg/kg). In conclusion, the δ‐opioid agonist SNC80 lacks both the analgesic efficacy and adverse effects of μ‐opioids. However, the activity of SNC80 in the inflammatory model suggests δ‐opioid agonists may be useful analgesics in the treatment of some forms of inflammatory pain.
Abstract The dose-limiting side effect of the anti-neoplastic agent, paclitaxel, is a chronic distal symmetrical peripheral neuropathy that produces sensory dysfunction (hypoesthesia and neuropathic ...pain) but little or no distal motor dysfunction. Similar peripheral neuropathies are seen with chemotherapeutics in the vinca alkaloid, platinum-complex, and proteasome inhibitor classes. Studies in rats suggest that the cause is a mitotoxic effect on axonal mitochondria. If so, then the absence of motor dysfunction may be due to mitotoxicity that affects sensory axons but spares motor axons. To investigate this, paclitaxel exposure levels in the dorsal root, ventral root, dorsal root ganglion, peripheral nerve, and spinal cord were measured, and the ultrastructure and the respiratory function of mitochondria in dorsal roots and ventral roots were compared. Sensory and motor axons in the roots and nerve had comparably low exposure to paclitaxel and exposure in the spinal cord was negligible. However, sensory neurons in the dorsal root ganglion had a very high and remarkably persistent (up to 10 days or more after the last injection) exposure to paclitaxel. Paclitaxel evoked a significant increase in the incidence of swollen and vacuolated mitochondria in the myelinated and unmyelinated sensory axons of the dorsal root (as seen previously in the peripheral nerve) but not in the motor axons of the ventral root. Stimulated mitochondrial respiration in the dorsal root was significantly depressed in paclitaxel-treated animals examined 2–4 weeks after the last injection, whereas respiration in the ventral root was normal. We conclude that the absence of motor dysfunction in paclitaxel-evoked peripheral neuropathy may be due to the absence of a mitotoxic effect in motor neuron axons, whereas the sensory dysfunction may be due to a mitotoxic effect resulting from the primary afferent neuron's cell body being exposed to high and persistent levels of paclitaxel.
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