Anxiety-induced Hyperalgesia Research Articles

Anxiety-induced hyperalgesia in female rats is mediated by cholecystokinin 2 receptor in rostral ventromedial medulla and spinal 5-hydroxytryptamine 2B receptor.

BackgroundPreoperative anxiety is associated with postoperative hyperalgesia; however, few studies have investigated the mechanism underlying this association in female surgical patients. Research has suggested that ON cells in the rostral ventromedial medulla (RVM) receive nerve impulses via cholecystokinin 2 (CCK2) receptors, facilitating hyperalgesia. Additionally, the downstream serotonergic projection system from the RVM to the spinal cord has a dual regulating effect on pain responses, and the 5-hydoxytryptophan 2B (5-HT2B) receptor in spinal dorsal horn neurons is critically involved in mechanical allodynia.MethodsOvariectomized rats were treated with estrogen replacement, single prolonged stress (SPS), and plantar incision. Various receptor agonists and antagonists were then administered into the RVM and spinal cord to study the mechanism underlying postoperative hyperalgesia caused by preoperative anxiety in female rats.ResultsBehavioral testing revealed that preoperative SPS induced postoperative hyperalgesia, as well as the expression of the CCK2 receptor in the RVM and the expression of the 5-HT2B receptor, protein kinase Cγ (PKCγ), and phosphorylation of the N-methyl-d-aspartate receptor1 (p-NR1) in the spinal cord increased confirmed by Western blot. RVM microinjection of the CCK2 receptor agonist CCK-8 and intrathecal injection of the 5-HT2B receptor agonist BW723C86 both produced hyperalgesia in female rats after plantar incision, whereas the CCK2 receptor antagonist YM022, the 5-HT2B receptor antagonist RS127445, and the PKCγ inhibitor C37H65N9O13 decreased the rats’ sensitivity to the same stimulus. Additionally, electrophysiological analysis suggested that activation of the 5-HT2B receptor increased the whole-cell current (IBa) in superficial dorsal horn neurons through the PKCγ pathway.ConclusionOur study demonstrated that preoperative anxiety-induced postoperative hyperalgesia in female rats is associated with descending pain pathways. The CCK2 receptor in the RVM and spinal 5-HT2B receptor may play a role in this hyperalgesic effect.

The effect of glucocorticoids on anxiety-induced mechanical hyperalgesia in rats

Objective To investigate the role of glucocorticoids(GCs) in anxiety-induced mechanical hyperalgesia in rats. Methods Seventy-two rats were divided into two part of experiments. ① Behavioral test. 24 rats were randomly divided into 3 groups(n=8): control group(C group), single prolonged stress(SPS) group(A group), SPS+ metyrapone group(M group). A group and M group were exposed to SPS. Intraperitoneal injection of metyrapone(25 mg/kg) was performed 1 h before SPS procedure. Elevated plus-maze test was tested on the first day after the SPS exposure. Paw withdrawal mechanical threshold (PWMT) was test on day 1 before SPS(T0) and days 1(T1), 4(T2), 7(T3), 14(T4) after SPS. ②Western blot. 48 rats were used, glucocorticoid receptor(GR) protein expression of A group was tested by Western blot in T0, T1, T3, T4, 3 rats in each time point. GR protein expression of every group was tested by Western blot in T1, T2, T3, T4, 3 rats in each group. Results In the elevated plus-maze test, the number of entries and the percentage of time spent in open-arms of A group [(4.6±1.5), (12.0±1.9)%]was significantly decreased compared with C group [(12.3±1.8), (17.8±2.5)%]and M group [(9.9± 1.5), (16.4±3.3)% ](P<0.05). The PWMT of A group was significantly decreased on 1, 4, 7, 14 d after SPS compared with C group(P< 0.05), the PWMT of M group was significantly increased on 1, 4, 7, 14 d compared with A group(P<0.05). The expression levels of glucocorticoid receptor(GR) in the spinal cord were increased significantly after SPS exposure, and it lasted 14 days(P<0.05). The expression levels of GR of M group were significantly increased compared with A group(P<0.05). Conclusions GCs are involved in anxiety-induced hyperalgesia in rats exposed to SPS. Metyrapone can significantly inhibit anxiety-induced mechanical hyperalgesia. Key words: Glucocorticoids; Single prolonged stress; Anxiety; Hyperalgesia; Metyrapone; Rat

Modulation of nociceptive-like behavior in zebrafish (Danio rerio) by environmental stressors.

Zebrafish have been demonstrated to react consistently to noxious chemical stimuli and present reliable phenotypes of stress, fear, and anxiety. In this article, we describe the modulation of nociceptive-like responses of zebrafish to fear-, stress-, and anxiety-eliciting situations. Animals were exposed to an alarm substance, confinement stress, or a novel environment before being injected with 1% acetic acid in the tail. The alarm substance and confinement stress reduced the display of erratic movements and tail-beating behavior elicited by acetic acid. The novelty of the environment, in contrast, increased the frequency of tail-beating behavior. The results suggest that descending modulatory control of nociception exists in zebrafish, with apparent fear- and stress-induced analgesia and anxiety-induced hyperalgesia.

Chronic stress induces transient spinal neuroinflammation, triggering sensory hypersensitivity and long-lasting anxiety-induced hyperalgesia

Chronic stressful events induce biochemical, physiological and psychological changes, resulting in stress-related neuropsychiatric disorders, such as anxiety or depression. Using repeated social defeat as a stressful event model, we show that this preclinical paradigm induces a transient increase in the expression of the genes encoding the pro-inflammatory molecules iNOS and COX-2. We provide the first demonstration that chronic stress affects spinal plasticity through a mechanism involving local neuroinflammation. The functional consequences of such neuroinflammation are associated with a transient decrease in the mechanical nociceptive threshold. Administration of the cholecystokinin(CCK)-2 receptor antagonist, CI-988, directly into the Rostral Ventromedial Medulla reverses the chronic stress-induced decrease in the nociceptive threshold. These data strongly suggest that chronic stress induces a spinal neuroinflammation associated with transient sensory hypersensitivity involving the activation of CCK-dependent nociceptive descending facilitatory pathways. Pharmacological data show that chronic social stress-induced long-lasting state of anxiety is not responsible for maintaining the spinal neuroinflammation and, therefore, for the associated sensory hypersensitivity. Conversely, an evaluation of pain-related behavior in the formalin model indicates that anxiety is directly related to prolonged hyperalgesia prevented by systemic benzodiazepine or CCK-2 receptor antagonist treatments. The present study highlights the adverse effects of chronic stress on spinal neuroinflammation triggering sensory hypersensitivity. Exploration of this phenomenon points out the divergence between pain sensitivity and anxiety-induced hyperalgesia, which is in agreement with clinical observations. Altogether, these data open up new perspectives for clinical research devoted to the evaluation and treatment of pain in anxio-depressive patients.

Nocebo hyperalgesia: how anxiety is turned into pain

Nocebo hyperalgesia is a phenomenon that is opposite to placebo analgesia and whereby expectation of pain increase plays a crucial role. In recent times, both the neuroanatomical and the neurochemical bases of the nocebo effect and of nocebo-related effects have begun to be explored. Here, we highlight recent advances in our understanding of the neurobiology of the nocebo hyperalgesic effect. A typical nocebo hyperalgesic response occurs following the administration of an inert substance which the subject believes to be a hyperalgesic agent (negative placebo or nocebo). It has been shown that the subject's negative expectations of pain worsening induce anticipatory anxiety about the impending pain increase and this triggers the activation of cholecystokinin that, in turn, facilitates pain transmission. Accordingly, cholecystokinin antagonists have been found to prevent this anxiety-induced hyperalgesia. Brain-imaging studies have shown that the perceived intensity of a painful stimulus following negative expectations of pain increase is higher than in the absence of negative expectations and this is associated with changes in activation of specific brain regions. Since pain appears to be amplified by anxiety through the activation of cholecystokininergic systems, new therapeutic strategies, such as new cholecystokinin antagonists, can be envisaged whenever pain has an important anxiety component.

The Biochemical and Neuroendocrine Bases of the Hyperalgesic Nocebo Effect

Despite the increasing research on placebos in recent times, little is known about the nocebo effect, a phenomenon that is opposite to the placebo effect and whereby expectations of symptom worsening play a crucial role. By studying experimental ischemic arm pain in healthy volunteers and by using a neuropharmacological approach, we found that verbally induced nocebo hyperalgesia was associated to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of adrenocorticotropic hormone and cortisol plasma concentrations. Both nocebo hyperalgesia and HPA hyperactivity were antagonized by the benzodiazepine diazepam, suggesting that anxiety played a major role in these effects. The administration of the mixed cholecystokinin (CCK) type-A/B receptor antagonist proglumide blocked nocebo hyperalgesia completely but had no effect on HPA hyperactivity, which suggests a specific involvement of CCK in the hyperalgesic but not in the anxiety component of the nocebo effect. Importantly, both diazepam and proglumide did not show analgesic properties on basal pain, because they acted only on the nocebo-induced pain increase. These data indicate a close relationship between anxiety and nocebo hyperalgesia, in which the CCKergic systems play a key role in anxiety-induced hyperalgesia. These results, together with previous findings showing that placebo analgesia is mediated by endogenous opioids, suggest that the analgesic placebo/hyperalgesic nocebo phenomenon may involve the opposite activation of endogenous opioidergic and CCKergic systems.