Michelle Roche

Stress-induced hyperalgesia

The importance of the modulation of pain by emotion is now widely recognised. In particular, stress and anxiety, depending on their nature, duration and intensity, can exert potent, but complex, modulatory influences typified by either a reduction or exacerbation of the pain state. Exposure to either acute or chronic stress can increase pain responding under experimental conditions and exacerbate clinical pain disorders. There is evidence that exposure to chronic or repeated stress can produce maladaptive neurobiological changes in pathways associated with pain processing, resulting in stress-induced hyperalgesia (SIH). Preclinical studies of SIH are essential for our understanding of the mechanisms underpinning stress-related pain syndromes and for the identification of neural pathways and substrates, and the development of novel therapeutic agents for their clinical management. In this review, we describe clinical and pre-clinical models used to study SIH and discuss the neural substrates, neurotransmitters and neuromodulatory systems involved in this phenomenon.

The effect of CB1 receptor antagonism in the right basolateral amygdala on conditioned fear and associated analgesia in rats

The endocannabinoid system mediates analgesia expressed following exposure to conditioned or unconditioned aversive stimuli, and controls the extinction of conditioned aversive behaviour. The present study investigated the effects of administration of the cannabinoid1 (CB1) receptor antagonist SR141716A into the right basolateral amygdala (BLA) on expression of conditioned fear, formalin‐evoked nociceptive behaviour, fear‐conditioned analgesia and associated alterations in monoamine levels in discrete rat brain areas. Re‐exposure to a context previously paired with footshock significantly reduced formalin‐evoked nociceptive behaviour. Intra‐BLA administration of SR141716A did not attenuate fear‐conditioned analgesia, but reduced formalin‐evoked nociceptive behaviour and attenuated the formalin‐induced decrease in freezing and 22‐kHz ultrasonic vocalizations in the early part of the trial. Furthermore, intra‐BLA SR141716A significantly prolonged the duration of these fear‐related behaviours in fear‐conditioned rats not receiving formalin. Fear‐conditioned analgesia was accompanied by increased homovanillic acid (HVA) : dopamine (DA) ratio and reduced serotonin (5‐HT) in the cerebellum, an effect not altered by SR141716A. SR141716A‐induced analgesia was accompanied by reduced DA, increased HVA : DA ratio and reduced 5‐HT levels in the cerebellum, increased hippocampal HVA levels and increased 5‐hydroxyindole‐3‐acetic acid (5‐HIAA) in the amygdaloid cortex. The SR141716A‐induced prolongation of contextually induced aversive behaviour was accompanied by reduced DA and 3,4‐dihyroxyphenylacetic acid (DOPAC), levels in the hippocampus, and increased DA and 5‐HIAA in the periaqueductal grey. These data suggest an important role for CB1 receptors in the right BLA in mediating short‐term extinction of conditioned aversive behaviour but not fear‐conditioned analgesia. The results also enhance our understanding of endocannabinoid–monoamine interactions of relevance to conditioned fear and associated analgesia.

Olfactory bulbectomy in mice induces alterations in exploratory behavior.

The olfactory bulbectomy syndrome is thought to represent a rodent model for psychomotor agitated depression. While this model has been extensively characterized in rats, fewer studies have been conducted with mice. Therefore, the present study aimed at extending the characterization of the OBX-induced behavioral syndrome in mice, using tests like open field, novel object exploration, novel cage and T-maze learning. OBX mice exhibited hyperactivity in a brightly illuminated open field, and also in a novel home cage as well as in the T-maze. Furthermore, OBX mice demonstrated increased exploratory behavior in the novel object test and in the T-maze. The complex alterations described here with respect to locomotion and exploration are robust and can be achieved by relatively simple test procedures. The extended behavioral characterization of the murine OBX model may contribute in particular to the increasing need to test transgenic mice for the presence of depression-like behaviors.

Chronic Fluoxetine Treatment Attenuates Stressor-Induced Changes in Temperature, Heart Rate, and Neuronal Activation in the Olfactory Bulbectomized Rat

The olfactory bulbectomized (OB) rat is a well-characterized animal model that exhibits a number of behavioral and neurochemical changes that have relevance to clinical depression. Hyperactivity in the open field is the most widely used parameter assessed in this model and is reversed following chronic, but not acute, antidepressant treatment. This study investigated OB-induced alterations in heart rate, body temperature, and neuronal activation following open-field exposure and the impact of chronic treatment with fluoxetine on these parameters. Upon placement in the open field, OB rats exhibited a characteristic hyperactivity response. Heart rate and body temperature were increased in sham-operated rats following open-field exposure, a predictable response to stress, which was significantly reduced in OB rats. Moreover bulbectomy reduced open field-induced cFOS expression in the basal nucleus of the stria terminalis while concurrently increasing expression in the hippocampus, amygdala, paraventricular nucleus of the thalamus, and dorsal raphe nucleus. Chronic fluoxetine treatment (10 mg/kg subcutaneous once daily for 5 weeks) attenuated all of these OB-associated changes. In conclusion, OB rats exhibit alterations in behavior, body temperature, heart rate, and neuronal activation in response to open-field exposure, which are reversed following chronic fluoxetine administration. These results identify stress-sensitive regions within the brain which are altered following bulbectomy and which may underlie the abnormal behavioral and physiological changes observed in this rodent model of depression.

Minocycline modulates neuropathic pain behaviour and cortical M1-M2 microglial gene expression in a rat model of depression

There is a paucity of data on the role of microglia and neuroinflammatory processes in the association between chronic pain and depression. The current study examined the effect of the microglial inhibitor minocycline on depressive-like behaviour, spinal nerve ligation (SNL)-induced mechanical and cold allodynia and associated changes in the expression of genes encoding microglial markers (M1 vs. M2 polarisation) and inflammatory mediators in the prefrontal cortex in the olfactory bulbectomised (OB) rat model of depression. Acute minocycline administration did not alter OB-induced depressive-like behaviour but prevented SNL-induced mechanical allodynia in both OB and sham rats. In comparison, chronic minocycline attenuated OB-induced depressive-like behaviour and prevented the development of SNL-induced mechanical allodynia in OB, but not sham, rats. Further analysis revealed that SNL-induced mechanical allodynia in OB rats was attenuated by chronic minocycline at almost all time-points over a 2week testing period, an effect observed only from day 10 post-SNL in sham rats. Chronic administration of minocycline reduced the expression of CD11b, a marker of microglial activation, and the M1 pro-inflammatory cytokine IL-1β, in the prefrontal cortex of sham-SNL animals. In comparison, the expression of the M2 microglia marker (MRC2) and anti-inflammatory cytokine IL-10 was increased, as were IL-1β, IL-6 and SOCS3, in the prefrontal cortex of OB-SNL animals following chronic minocycline. Thus, chronic minocycline attenuates neuropathic pain behaviour and modulates microglial activation and the central expression of inflammatory mediators in a manner dependent on the presence or absence of a depressive-like phenotype.

Supraspinal modulation of pain by cannabinoids: the role of GABA and glutamate

Recent physiological, pharmacological and anatomical studies provide evidence that one of the main roles of the endocannabinoid system in the brain is the regulation of γ‐aminobutyric acid (GABA) and glutamate release. This article aims to review this evidence in the context of its implications for pain. We first provide a brief overview of supraspinal regulation of nociception, followed by a review of the evidence that the brains endocannabinoid system modulates nociception. We look in detail at regulation of supraspinal GABAergic and glutamatergic neurons by the endocannabinoid system and by exogenously administered cannabinoids. Finally, we review the evidence that cannabinoid‐mediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions.

Alterations in the endocannabinoid system in the rat valproic acid model of autism

The endocannabinoid system plays a crucial role in regulating emotionality and social behaviour, however it is unknown whether this system plays a role in symptoms associated with autism spectrum disorders. The current study evaluated if alterations in the endocannabinoid system accompany behavioural changes in the valproic acid (VPA) rat model of autism. Adolescent rats prenatally exposed to VPA exhibited impaired social investigatory behaviour, hypoalgesia and reduced lococmotor activity on exposure to a novel aversive arena. Levels of the endocananbinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG) in the hippocampus, frontal cortex or cerebellum were not altered in VPA- versus saline-exposed animals. However, the expression of mRNA for diacylglycerol lipase α, the enzyme primarily responsible for the synthesis of 2-AG, was reduced in the cerebellum of VPA-exposed rats. Furthermore, while the expression of mRNA for the 2-AG-catabolising enzyme monoacylglycerol lipase was reduced, the activity of this enzyme was increased, in the hippocampus of VPA-exposed animals. CB1 or CB2 receptor expression was not altered in any of the regions examined, however VPA-exposed rats exhibited reduced PPARα and GPR55 expression in the frontal cortex and PPARγ and GPR55 expression in the hippocampus, additional receptor targets of the endocannabinoids. Furthermore, tissue levels of the fatty acid amide hydrolase substrates, AEA, oleoylethanolamide and palmitoylethanolamide, were higher in the hippocampus of VPA-exposed rats immediately following social exposure. These data indicate that prenatal VPA exposure is associated with alterations in the brains endocannabinoid system and support the hypothesis that endocannabinoid dysfunction may underlie behavioural abnormalities observed in autism spectrum disorders.

The endocannabinoid system in the rat dorsolateral periaqueductal grey mediates fear-conditioned analgesia and controls fear expression in the presence of nociceptive tone

BACKGROUND AND PURPOSE Endocannabinoids in the midbrain periaqueductal grey (PAG) modulate nociception and unconditioned stress‐induced analgesia; however, their role in fear‐conditioned analgesia (FCA) has not been examined. The present study examined the role of the endocannabinoid system in the dorsolateral (dl) PAG in formalin‐evoked nociceptive behaviour, conditioned fear and FCA in rats.

Enhanced nociceptive responding in two rat models of depression is associated with alterations in monoamine levels in discrete brain regions

Altered pain responding in depression is a widely recognized but poorly understood phenomenon. The present study investigated nociceptive responding to acute (thermal and mechanical) and persistent (inflammatory) noxious stimuli in two animal models of depression, the olfactory bulbectomized (OB) and the Wistar-Kyoto (WKY) rat. In addition, this study examined if altered nociceptive behaviour was associated with changes in monoamine levels in discrete brain regions. OB rats exhibited mechanical allodynia (von Frey test) but not thermal hyperalgesia (hot plate and tail-flick tests) when compared to sham-operated counterparts. Formalin-induced nociceptive behaviour was both heightened and prolonged in OB versus sham-operated controls. An inverse correlation was observed between 5-hydroxyindoleacetic acid (5-HIAA) concentration in the hippocampus and amygdaloid cortex and nociceptive behaviour in the formalin test. In comparison, WKY rats exhibited thermal hyperalgesia in the hot plate test, while behaviour in the tail-flick and von Frey tests did not differ between WKY and Sprague-Dawley rats. Furthermore, WKY rats exhibited enhanced formalin-evoked nociceptive responding up to 40 min post administration, an effect inversely correlated with serotonin and 5-HIAA levels in the hypothalamus. In conclusion, these findings demonstrate that altered pain responding observed in clinically depressed patients can be modelled pre-clinically, providing a means of investigating the neurochemical basis of, and possible treatments for, this phenomenon.

Pharmacological inhibition of endocannabinoid degradation modulates the expression of inflammatory mediators in the hypothalamus following an immunological stressor

The endocannabinoid system is an important regulator of the nervous, neuroendocrine, and immune systems, thus representing a novel therapeutic target for stress-related neuroinflammatory and psychiatric disorders. However, there is a paucity of data relating to the effects of endocannabinoids on neuroinflammatory mediators following an immune stress/challenge in vivo. This study investigated the effects of URB597, a selective inhibitor of fatty acid amide hydrolyase (FAAH), the enzyme that preferentially metabolizes anandamide, on lipopolysaccharide (LPS)-induced increases in the expression of immune mediators in the hypothalamus. Systemic administration of URB597 increased the levels of anandamide and the related N-acylethanolamines, N-palmitoylethanolamide, and N-oleoylethanolamide, but not 2-arachidonoyl glycerol, in the hypothalamus and spleen. URB597 attenuated the LPS-induced increase in interleukin (IL)-1β expression while concurrently augmenting the LPS-induced increase in suppressor of cytokine signalling (SOCS)-3 expression. In addition, URB597 tended to enhance and reduce the LPS-induced increase in IL-6 and IL-10 mRNA expression, respectively. LPS-induced increases in peripheral cytokine levels or plasma corticosterone were not altered by URB597. The present study provides evidence for a role for FAAH in the regulation of LPS-induced expression of inflammatory mediators in the hypothalamus. Improved understanding of endocannabinoid-mediated regulation of neuroimmune function has fundamental physiological and potential therapeutic significance in the context of stress-related disorders.