Low Stress-induced Analgesia Research Articles

Mechanisms Underlining Inflammatory Pain Sensitivity in Mice Selected for High and Low Stress-Induced Analgesia-The Role of Endocannabinoids and Microglia.

In this work we strived to determine whether endocannabinoid system activity could account for the differences in acute inflammatory pain sensitivity in mouse lines selected for high (HA) and low (LA) swim-stress-induced analgesia (SSIA). Mice received intraplantar injections of 5% formalin and the intensity of nocifensive behaviours was scored. To assess the contribution of the endocannabinoid system, mice were intraperitoneally (i.p.) injected with rimonabant (0.3–3 mg/kg) prior to formalin. Minocycline (45 and 100 mg/kg, i.p.) was administered to investigate microglial activation. The possible involvement of the endogenous opioid system was investigated with naloxone (1 mg/kg, i.p.). Cannabinoid receptor types 1 and 2 (Cnr1, Cnr2) and opioid receptor subtype (Oprm1, Oprd1, Oprk1) mRNA levels were quantified by qPCR in the structures of the central nociceptive circuit. Levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by liquid chromatography coupled with the mass spectrometry method (LC-MS/MS). In the interphase, higher pain thresholds in the HA mice correlated with increased spinal anandamide and 2-AG release and higher Cnr1 transcription. Downregulation of Oprd1 and Oprm1 mRNA was noted in HA and LA mice, respectively, however no differences in naloxone sensitivity were observed in either line. As opposed to the LA mice, inflammatory pain sensitivity in the HA mice in the tonic phase was attributed to enhanced microglial activation, as evidenced by enhanced Aif1 and Il-1β mRNA levels. To conclude, Cnr1 inhibitory signaling is one mechanism responsible for decreased pain sensitivity in HA mice in the interphase, while increased microglial activation corresponds to decreased pain thresholds in the tonic inflammatory phase.

Divergent Response to Cannabinoid Receptor Stimulation in High and Low Stress-Induced Analgesia Mouse Lines Is Associated with Differential G-Protein Activation

Bidirectional selection of mice for high (HA) and low (LA) swim stress-induced analgesia (SSIA) is associated with a divergent response to opioids. In the current study, we investigated whether the genetic divergence in opioid system activity between HA and LA mice also affects cannabinoid sensitivity. Additionally, we also investigated whether the endocannabinoid system mediates SSIA in these lines. Numerous reports support the existence of pharmacological and molecular interactions between the opioid and cannabinoid systems along the pain pathways, as both systems utilize the same G-protein subtype for signal transduction. Mice from both lines were treated with a non-selective CB1/CB2 agonist, WIN55,212–2 and their behavior was evaluated according to the tetrad paradigm assessing antinociception, catalepsy, hypothermia and locomotor activity. Surprisingly, the engagement of CB1 receptors in SSIA was not confirmed. G-protein activation was studied in different brain regions and the spinal cord in the [35S]GTPγS assay. It was shown that WIN55,212–2 produced more potent antinociception in HA than in LA mice. Also, HA mice displayed stronger cannabinoid-induced catalepsy in the bar test. However, LA mice were more sensitive to the hypothermic effect of WIN55,212–2. The intensity of behavioral responses to WIN55,212–2 was correlated with increased G-protein activation in the periaqueductal gray matter, frontal cortex, striatum and thalamus in HA mice. A weak response to WIN55,212–2 in LA mice could depend on impaired CB2 receptor signaling. In conclusion, differences in both opioid and cannabinoid sensitivity between HA and LA mice could stem from alterations in intracellular second messenger mechanisms involving G-protein activation.

Bidirectional selection for high and low stress-induced analgesia affects G-protein activity

Mice selected for high (HA) and low (LA) swim stress-induced analgesia (SSIA) are a unique model for studying the genetic background of this phenomenon. HA and LA miceshow substantial differences in the magnitude of the antinociceptive response to stress and when treated with exogenous opioids. However, the direct cause underplaying this distinctive feature has not yet been identified. The current study was designed to investigate the possibility that disturbances in G-protein signaling could explain the divergent response to opioid agonists. Supraspinal and spinal opioid sensitivity was assessed in vivo with intraperitoneal morphine and subsequent thermal stimulus exposure. The level of opioid receptor-mediated G-protein activation was investigated by means of DAMGO and morphine-stimulated [35S]GTPγS assay in the brain and spinal cord homogenates from HA and LA mice. Morphine (3–249 μmol/kg, i.p) was over 6 - and 3 - times more potent in HA than LA mice in the hot plate and tail-flick assays, respectively. Additionally, HA mice showed elevated β - endorphin levels in the brain. Enhanced efficacy of agonist-stimulated [35S]GTPγS binding was detected in opioid receptor-rich limbic regions of HA mice like the hypothalamus and hippocampus. Increased G-protein activity also emerged in the thalamus, periaqueductal gray matter and prefrontal cortex. In conclusion, the magnitude of the antinociceptive response to opioids in HA and LA mice is correlated with alterations in G-protein activation in brain regions responsible for integration and descending modulation of nociceptive information as well as at sites governing the emotional response to stressful stimuli.

Przegląd badań nad uzależnieniem od alkoholu w modelu myszy selekcjonowanych w kierunku wysokiej i niskiej analgezji postresowej

Przegląd badań nad uzależnieniem od alkoholu w modelu myszy selekcjonowanych w kierunku wysokiej i niskiej analgezji postresowej

Chronic mild stress facilitates melanoma tumor growth in mouse lines selected for high and low stress-induced analgesia

Both chronic stress conditions and hyperergic reaction to environmental stress are known to enhance cancer susceptibility. We described two mouse lines that displayed high (HA) and low (LA) swim stress-induced analgesia (SSIA) to investigate the relationship between inherited differences in sensitivity to stress and proneness to an increased growth rate of subcutaneously inoculated melanoma. These lines display several genetic and physiological differences, among which distinct sensitivity to mutagens and susceptibility to cancer are especially noticeable. High analgesic mice display high proneness both to stress and a rapid local spread of B16F0 melanoma. However, stress-resistant LA mice do not develop melanoma tumors after inoculation, or if so, tumors regress spontaneously. We found that the chronic mild stress (CMS) procedure leads to enhanced interlinear differences in melanoma susceptibility. Tumors developed faster in stress conditions in both lines. However, LA mice still displayed a tendency for spontaneous regression, and 50% of LA mice did not develop a tumor, even under stressed conditions. Moreover, we showed that chronic stress, but not tumor progression, induces depressive behavior, which may be an important clue in cancer therapy. Our results clearly indicate how the interaction between genetic susceptibility to stress and environmental stress determine the risk and progression of melanoma. To our knowledge, HA/LA mouse lines are the first animal models of distinct melanoma progression mediated by inherited differences in stress reactivity.

Effect of chronic mild stress on hippocampal transcriptome in mice selected for high and low stress-induced analgesia and displaying different emotional behaviors

There is increasing evidence that mood disorders may derive from the impact of environmental pressure on genetically susceptible individuals. Stress-induced hippocampal plasticity has been implicated in depression. We studied hippocampal transcriptomes in strains of mice that display high (HA) and low (LA) swim stress-induced analgesia and that differ in emotional behaviors and responses to different classes of antidepressants. Chronic mild stress (CMS) affected expression of a number of genes common for both strains. CMS also produced strain specific changes in expression suggesting that hippocampal responses to stress depend on genotype. Considerably larger number of genes, biological processes, molecular functions, biochemical pathways, and gene networks were affected by CMS in LA than in HA mice. The results suggest that potential drug targets against detrimental effects of stress include glutamate transporters, and cholinergic, cholecystokinin (CCK), glucocorticoids, and thyroid hormones receptors. Furthermore, some biological processes evoked by stress and different between the strains, such as apoptosis, neurogenesis and chromatin modifications, may be responsible for the long-term, irreversible effects of stress and suggest a role for epigenetic regulation of mood related stress responses.

P.2.b.019 Different modulation of transcription profiles in hypothalamus of mice bred for high and low stress-induced analgesia following chronic mild stress

P.2.b.019 Different modulation of transcription profiles in hypothalamus of mice bred for high and low stress-induced analgesia following chronic mild stress

Gender differences in opioid-mediated analgesia: animal and human studies.

Gender differences in opioid-mediated analgesia: animal and human studies.

Cross-tolerance between morphine and swim analgesia in mice selectivity bred for high and low stress-induced analgesia

Mice selectively bred for high (HA) and for low analgesia (LA) induced by 3-min swimming at 20°C and unselected controls (C) were injected three times daily for 3 days with 20 mg/kg morphine HCl. The analgesic effect of 10 mg/kg morphine in nontolerant mice differed between the lines in the rank order of HA > C > LA and significantly decreased after repeated treatment with morphine, as revealed by the hotplate test (56°C). The tolerance to morphine analgesia was more pronounced in HA than in C mice but did not develop at all in LA mice. Similarly, the magnitude of swim-induced analgesia in morphine tolerant mice decreased to a greater degree in the HA than the C line but did not change in LA mice. Naloxone HCl (1 and 10 mg/kg) attenuated swim analgesia more in nontolerant HA than C mice but had no effect in morphine-tolerant HA and C and in all LA mice. The differential degree of morphine tolerance and cross-tolerance with swim analgesia suggests that the strategy of selective breeding toward divergent magnitudes of stress-induced analgesia has differentiated opioid involvement in endogenous pain inhibition in the selected lines.

Tolerance and cross-tolerance with morphine in mice selectively bred for high and low stress-induced analgesia

Mice selectively bred for high (HA) and low (LA) swim-induced analgesia were exposed to two different stress paradigms; one consisting of a 3-min swim at 20°C daily for 14 days, and the other consisting of 3-min swims repeated at 2-h intervals for 48 h. Both forms of chronic stress resulted in the development of tolerance to swim-induced antinociception to a greater degree in the HA mice than in control (C) mice, but were both ineffective at inducing tolerance in LA mice. Swimming repeated at 2-h intervals for 48 h resulted in cross-tolerance with morphine in HA and C mice. Naloxone (1 and 10 mg/kg, IP) failed to antagonize swim-induced analgesia in mice that had experienced chronic swimming in the 2-h/48-h paradigm. The daily swimming paradigm failed to produce cross-tolerance with morphine analgesia in any line. Differential degree of tolerance in three lines supports a hypothesis that selective breeding for high and low stress-induced analgesia has modified the degree of opioid involvement in the endogenous analgesia mechanisms.

Genetic influences on brain stimulation-produced analgesia in mice. I. Correlation with stress-induced analgesia

The analgesic effect of electrical stimulation of the periaqueductal gray matter (PAG) was studied in mice selectively bred for high and low stress-induced analgesia (HA and LA lines, respectively). The current intensity required for stimulation-produced analgesia (SPA) in LA mice was 5 times that for HA mice. Naloxone produced a 4-fold increase of SPA threshold in HA mice, but was ineffective in LA mice. These findings suggest that the differential responsiveness of these two lines to the analgesic effect of stress reflects a more general genetic modification of the efficacy and mechanism of their pain-inhibitory systems.

Adrenalectomy and dexamethasone differentially affect postswim antinociception in mice selectively bred for high and low stress-induced analgesia

The effects of dexamethasone and naloxone on analgesia induced by swimming (3 min, 20°C) were studied in the 6th and 7th generations of adrenalectomized and intact mice selectively bred for high (HA) and low (LA) postswim analgesia. Swim-induced analgesia in intact HA animals was significantly reduced by naloxone and dexamethasone while in LA mice these two compounds were ineffective. Naloxone ability to reverse adrenalectomy-caused swim analgesia increase was much greater in HA than in LA mice. In both intact and adrenalectomized HA animals dexamethasone and naloxone decreased postswim analgesia to the level observed in LA mice. It is suggested that selective breeding for high and low swim analgesia modified the extent of pituitary-adrenal axis involvement in the generation of stress-induced analgesia.