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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.

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.

The streptozotocin (STZ)-induced diabetes model is widely used for the induction of neuropathy in the rat. In this model, diabetic animals often display chronic illness, which raises objections not only on ethical but also on scientific grounds. In this study, the investigators set out to determine the impact of bodyweight and body condition (BC) on behavioral testing in the rat. Animals were allocated to four different groups as a function of their bodyweight, in particular one control group and three experimental groups with different starting weights (low bodyweight [LBW], medium bodyweight [MBW] and high bodyweight [HBW]), the groups having been rendered diabetic with an intraperitoneal injection of STZ (65mg/kg). Bodyweight, blood glucose, body condition and thresholds for mechanical hyperalgesia and tactile allodynia were measured or evaluated over a 68-day period. Animals with a LBW at the start of the experiment showed a gradual increase in BW with a decrease in mechanical nociceptive thresholds, while MBW and HBW animals presented a decrease in both thresholds and BW. The body condition score (BCS) decreased in all STZ-treated groups over time. Since correlations between mechanical thresholds and BW were similar between the control group and the HBW and MBW groups, the loss in BW clearly contributed to the decrease in thresholds. In the LBW group, thresholds and BW correlated negatively, so that the decrease in thresholds was mainly caused by the development of a painful neuropathy. From an ethical and a scientific point of view, in the STZ-induced diabetic neuropathy model, animals should be chosen on the basis of bodyweight and it must also be ensured that STZ is correctly dosed.

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 mu-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 present study was conducted to evaluate the pain development and bone destruction during bone cancer growth in a murine model of bone cancer pain and to evaluate the analgesic efficacy of fentanyl, sufentanil, and morphine in this model. C3H/HeNCrl mice were inoculated into the intramedullary space of the femur with osteolytic NCTC 2472 fibrosarcoma cells, and followed during a 3-week period to assess pain behaviors (spontaneous lifting and limb-use during forced ambulation on rotarod) and bone destruction (parameters indicative of bone lesions determined by microCT-scans of the tumor-bearing bones) during bone cancer growth. The results showed that in this murine model of cancer-induced bone pain, behavioural manifestations of pain emerge in parallel with the progression of bone destruction. The subcutaneous administration of fentanyl (0.025-0.64 mg/kg), sufentanil (0.005-0.04 mg/kg), and morphine (2.5-40 mg/kg) on the test days 15 and 22 post-inoculation reduced pain-related behaviors in a dose dependent manner. A complete relief from pain-related behaviors was achieved with the following doses: > or =0.16 mg/kg fentanyl, 0.02 mg/kg sufentanil, and 20 mg/kg morphine. In conclusion, the results showed a clear link between tumor growth-induced bone destruction and behavioral pain manifestations, the latter was effectively controlled by the opioids fentanyl, sufentanil, and morphine.

Mu-, kappa- and delta-opioid receptor agonists are reported to attenuate the acetic-acid-induced abdominal constriction response in mice. NK-1, -2 and -3 receptor antagonists also display activity in several visceral pain models. As the gerbil NK-1 receptor is comparable to the human receptor, we evaluated the efficacy of NK-1, -2 and -3 receptor antagonists and opioids (both alone and in combination) in the writhing test in this species. The effects of a selective L-type calcium (Ca2+) channel antagonist on the writhing response were also assessed to determine the contribution of Ca2+ channel antagonism to the antinociceptive effects of the NK-1 antagonists. Gerbils received subcutaneous injections of either the mu-opioids morphine or fentanyl, the kappa-opioid U50,488-H, the delta-opioid SNC80, NK-1 antagonists R116301, CP-96,345 or GR203040, the NK-2 antagonist SR-48968, the NK-3 antagonist SR-142801 or the Ca2+ channel antagonist nimodipine. Writhing was evoked 1 h after treatment by intraperitoneal injection of 0.2 ml 1% acetic acid solution and the frequency was recorded. Morphine, fentanyl and U50,488-H attenuated the writhing response dose dependently with complete inhibition occurring at the highest doses. SNC80 did not significantly attenuate the writhing response even at a dose of 40 mg/kg. The tachykinin NK-1 antagonists CP-96,345 and GR203040, the NK-2 antagonist SR-48968 and the NK-3 antagonist SR-142801 reduced the writhing frequency although without complete inhibition. The NK-1 antagonist R116301 displayed limited activity at doses up to 40 mg/kg. Nimodipine did not exhibit any antinociceptive efficacy in this assay. Adding the NK-1, -2 or -3 antagonists to the opioids did not improve the efficacy of the opioids. Selective NK antagonists may therefore be effective in a visceral nociception assay in gerbils but do not modulate opioid action.

Stressful stimuli can activate the hypothalamo-pituitary-adrenal-axis and the endogenous opioid system. In addition, corticosterone and opioid release might cause analgesia. This rat study used adrenalectomy for corticosterone withdrawal and naloxone administration for opioid antagonism in order to study pain behavior and hypophyseal hormone release in the plasma after a formalin test. Twelve days before the formalin testing, male Sprague Dawley rats underwent adrenalectomy or sham-adrenalectomy, and non-operated rats were used as reference. The number of flinches and the duration of licking or biting behavior were measured during the early and late phase. In reference and sham-operated rats, injection of formalin 5% resulted in a marked pain behavior in the early and late phase with significant increases in ACTH and corticosterone plasma levels. In adrenalectomized rats, pain behavior was decreased during both phases. Naloxone, administered before the late phase, did not alter pain behavior in sham or reference rats, whereas in adrenalectomized rats pain reactivity returned to those levels observed in reference rats. Beta-endorphin plasma levels above the detection limit were more frequently found in adrenalectomized rats. Thyrotropin and prolactin levels were not different between studied groups. We speculate that the observed reduced pain behavior in adrenalectomized rats after formalin, is the result of an increased production of pro-opiomelanocortin, the pro-drug of both adrenocorticotrophic hormone and beta-endorphin.

The effects of meta-chlorophenylpiperazine (mCPP) were studied on exploratory behaviour in the open field test, using a procedure designed to evaluate the emergence of rats into a novel environment. mCPP reduced the exploratory activity in a dose-related manner after subcutaneous (s.c.), intraperitoneal (i.p.) and intravenous (i.v.) administration. The inhibition was manifest in all the parameters used to quantify the exploration of the open field area. Additional neuroendocrine experiments in a parallel group of rats revealed a dose-related increase in plasma prolactin and ACTH levels after i.v. mCPP, pointing to a general state of arousal in these mCPP-treated animals. A number of 5-HT antagonists were tested for their ability to prevent or reverse the behavioural inhibition induced by an i.v. injection of 1.0 g/kg mCPP given 15 min before testing in the open field. The antagonists were injected s.c. or given orally at various time intervals before mCPP, or they were injected i.v. 10 min after mCPP. The lowest active doses for the attentuation of the mCPP-induced behavioural inhibition after s.c., oral and i.v. administration, respectively, were 0.04, 40 and 10 mg/kg for pizotifen; 0.16, 0.16 and 0.16 mg/kg for mianserin; 0.63, 0.16 and 0.16 mg/kg for methysergide, and 0.16, 2.5 and 2.5 mg/kg for ritanserin. The lowest active doses of mirtazapine after s.c. and i.v. treatment were 0.01 and 0.16 mg/kg. These data indicate that mixed 5-HT1/5-HT2 receptor antagonists such as pizotifen and methysergide, and mixed 5-HT and catecholamine antagonists such as mianserin and mirtazapine are more potent antagonists of mCPP-induced behavioural inhibition in rats than the more selective 5-HT2A/5-HT2C antagonist ritanserin.