Development and characterization of a novel, anatomically relevant rat model of acute postoperative pain.

UNLABELLED: Acute postoperative pain remains a significant health care issue. Development of anatomically relevant animal models of postoperative pain, with improved predictive validity, would advance understanding of postoperative pain mechanisms and improve treatment outcomes. This study aimed to develop, characterize, and validate a rat model of acute postoperative pain associated with inguinal hernia repair based on the Lichtenstein inguinal hernia repair procedure (without hernia induction). We hypothesized that the surgery would result in reduced spontaneous locomotor activity, which would represent a pain-related phenotype. Postsurgical characterization involved extensive monitoring of home cage and open field locomotor activity, as well as mechanical hypersensitivity and assessment of c-Fos expression in the dorsal horn of the spinal cord. In pharmacologic validation studies, rats received morphine, carprofen, or paracetamol 1 hour before, and/or immediately after, surgery. Rats that underwent hernia repair surgery exhibited significantly lower horizontal and vertical activities in the home cage and open field in the early postsurgical period, compared with sham rats or rats that underwent skin incision only. Morphine, carprofen, and paracetamol attenuated the surgery-induced reductions in locomotor activity, to varying degrees. Surgery was associated with significantly increased c-Fos expression in the ipsilateral dorsal horn of the spinal cord, an effect attenuated by carprofen treatment. These results support the development and characterization of a novel, anatomically relevant animal model of acute postoperative pain that may facilitate development of improved treatment regimens. PERSPECTIVE: Acute pain following inguinal hernia repair can be difficult to treat. Here we report, for the first time, the development of a novel, anatomically relevant rat model to facilitate improved understanding and treatment of acute postoperative pain following inguinal hernia repair.

Chronic stress-induced alterations in mouse colonic 5-HT and defecation responses are strain dependent.

Mood disorders and chronic stress are frequently associated with gastrointestinal (GI) symptoms including diarrhoea or constipation. Locally produced serotonin [5-hydroxytryptamine (5-HT)] regulates GI motility and is a key factor in the pathophysiology of stress-associated GI disorders. We aimed to establish whether chronic stress can differentially affect faecal output and colon 5-HT concentration in two inbred mouse strains: BALB/c and C57BL/6 which differ in their ability to cope with stress. Adult male BALB/c and C57BL/6 mice were restrained for 2 h daily for 10 days. Defecation was monitored during each stress session. Twenty-four hours after the last session of stress, plasma corticosterone concentration was higher than control in both strains, indicative of a physiological effect of chronic stress; however, stress-induced diarrhoea was more persistent in C57BL/6 mice. Basal concentration of colon 5-HT was higher in C57BL/6 mice, and stress elicited an increase in colon 5-HT only in this strain. Finally, naïve BALB/c mice had a higher sensitivity (incidence of diarrhoea) to 5-HT (0.33 mg/kg, i.p.) than C57BL/6 mice. Our results suggest that differential defecation responses to stress may be associated with colon 5-HT concentration, which may in turn reflect the individual sensitivity to 5-HT. In addition, C57BL/6 mice emerge as a relevant model for studying GI alterations induced by chronic stress.

Strain differences in the neurochemical response to chronic restraint stress in the rat: relevance to depression.

The neurochemical basis of depression focuses on alterations in the monoaminergic and amino acid neurotransmitter systems. Moreover, decreases in serum levels of the neurotrophin brain-derived neurotrophic factor (BDNF) have led to the more recent neurotrophic hypothesis of depression. Chronic stress is one of the major predisposing factors to developing the disorder and thus we investigated the impact of chronic restraint stress on the levels of several neurotransmitters and their metabolites in a genetic animal model of depression, the Wistar Kyoto (WKY) rat. Behavioural analysis of WKY rats indicated both a depressive and anxiety-like phenotype compared to their Sprague Dawley (SD) controls. WKY animals showed similar stress-induced decreases in hippocampal GABA, noradrenaline and dopamine as their SD counterparts while exhibiting a divergent decrease in 5-HT, 5-HIAA and DOPAC. WKY rats also showed a stress-dependent increase in GABA concentrations in the amygdala compared to the SD animals. Moreover, WKY but not SD rats had a chronic stress-induced decrease in serum BDNF levels. Together these data show that there are specific strain-dependent changes in neurotransmitter and neurotrophin levels in response to chronic stress which may predispose WKY animals to a depressive-like phenotype.

Comparison of hippocampal metabotropic glutamate receptor 7 (mGlu7) mRNA levels in two animal models of depression.

There is increasing evidence to suggest that metabotropic glutamate (mGlu) receptors including mGlu(7) receptor are important in the pathophysiology of stress-related psychiatric disorders such as anxiety and major depression. mGlu(7) receptor is highly expressed in the hippocampus, a key region involved in the modulation of depression-related behaviour. Moreover, mice deficient in mGlu(7) receptor have an antidepressant-like behaviour and altered stress response. To our knowledge there is little information as to whether stressful phenotypes can influence hippocampal mGlu(7) receptor levels. To this end, we examined hippocampal mGlu(7) receptor mRNA expression in two models of depression, the stress-sensitive Wistar Kyoto (WKY) and the maternally separated model of early-life stress. In situ hybridization analysis revealed that the WKY, but not the maternally separated (MS) rats displayed selective increases in mGlu(7) receptor mRNA expression in subregions of the hippocampus compared to relevant controls. These data suggest that higher levels of this receptor could affect the behaviour in response to stressful conditions and may play a role in WKY animal's susceptibility to stress-related disorders. However, the data in maternally separated animals confirm that whilst hippocampal mGlu(7) receptors maybe involved in certain aspects of stress biology, an increased expression is not necessary for the manifestation of depression-related phenotype per se.

Restraint stress-induced brain activation patterns in two strains of mice differing in their anxiety behaviour.

Genetically identical inbred mouse strains are one of the most useful tools in dissecting the genetic basis of complex disorders. C57BL/6 and BALB/c mice differ markedly in emotionality. In particular, BALB/c mice are more stress-sensitive and have been proposed to be a model of pathological anxiety. There is a paucity of studies investigating whether brain activation in response to a stressor is different in these two strains. To this end, having confirmed that the strains differ in anxiety responses in a light-dark box test, we then examined if restraint stress induced increases in c-Fos protein expression in selective regions of the mouse brain. The areas of interest analysed were the paraventricular nucleus (PVN) of the hypothalamus, prefrontal cortex (PFC), the paraventricular thalamic nucleus (PV) and the hippocampus. These areas were chosen due to their known involvement in stress response. Our data demonstrate that BALB/c showed a similar cellular activation pattern to stress, with respect to c-Fos expression, in the PVN, PV and in the hippocampus. On the other hand, BALB/c showed markedly blunted stress-induced brain activation compared with stressed C57BL/6 mice in both the CG1 and CG2 regions of the PFC. The lower levels of stress-induced activity in high anxiety BALB/c mice, possibly indicate a circuit dysregulation at the cortico-limbic level in response to stress.