Biphasic Activation of Extracellular Signal-regulated Kinase in Anterior Cingulate Cortex Distinctly Regulates the Development of Pain-related Anxiety and Mechanical Hypersensitivity in Rats after Incision

Dai, Renke; Li, Chang-Qi; Zhang, Jianwei; Li, Fang; Shi, Xudan; Zhang, Jianyi; Zhou, Xin‐Fu

doi:10.1097/aln.0b013e3182242045

Cited by 47 publications

(40 citation statements)

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“…The second experiment explored the CBD effects on pain relief, which is fundamentally rewarding and it is achieved by termination of an aversive event. Our data also confirmed that a hind paw incision provokes an aversive stimulus that persist for at least 2 days post-injury (Dai et al, 2011). This can provide a discriminative learning and fit easily within a reinforcement learning framework by aversive stimulus (King et al, 2009).…”

Section: Discussionsupporting

confidence: 85%

Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats

et al. 2017

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Background: Pain involves different brain regions and is critically determined by emotional processing. Among other areas, the rostral anterior cingulate cortex (rACC) is implicated in the processing of affective pain. Drugs that interfere with the endocannabinoid system are alternatives for the management of clinical pain. Cannabidiol (CBD), a phytocannabinoid found in Cannabis sativa, has been utilized in preclinical and clinical studies for the treatment of pain. Herein, we evaluate the effects of CBD, injected either systemically or locally into the rACC, on mechanical allodynia in a postoperative pain model and on the negative reinforcement produced by relief of spontaneous incision pain. Additionally, we explored whether CBD underlies the reward of pain relief after systemic or rACC injection.Methods and Results: Male Wistar rats were submitted to a model of incision pain. All rats had mechanical allodynia, which was less intense after intraperitoneal CBD (3 and 10 mg/kg). Conditioned place preference (CPP) paradigm was used to assess negative reinforcement. Intraperitoneal CBD (1 and 3 mg/kg) inverted the CPP produced by peripheral nerve block even at doses that do not change mechanical allodynia. CBD (10 to 40 nmol/0.25 μL) injected into the rACC reduced mechanical allodynia in a dose-dependent manner. CBD (5 nmol/0.25 μL) did not change mechanical allodynia, but reduced peripheral nerve block-induced CPP, and the higher doses inverted the CPP. Additionally, CBD injected systemically or into the rACC at doses that did not change the incision pain evoked by mechanical stimulation significantly produced CPP by itself. Therefore, a non-rewarding dose of CBD in sham-incised rats becomes rewarding in incised rats, presumably because of pain relief or reduction of pain aversiveness.Conclusion: The study provides evidence that CBD influences different dimensions of the response of rats to a surgical incision, and the results establish the rACC as a brain area from which CBD evokes antinociceptive effects in a manner similar to the systemic administration of CBD. In addition, the study gives further support to the notion that the sensorial and affective dimensions of pain may be differentially modulated by CBD.

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Section: Discussionsupporting

confidence: 85%

Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats

et al. 2017

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“…It is widely accepted that pain-related negative factors influence the perception pain and the anxiety-decreased pain threshold [26]. In a recent study, we demonstrated that pain-related anxiety is dissociated from pain perception following surgery [6]. The clinical features of visceral pain, the most common form of pathological pain, differ from those of somatic pain—a difference likely due to differences in the underlying neurobiology [4, 11].…”

Section: Introductionmentioning

confidence: 99%

Activation of Anterior Cingulate Cortex Extracellular Signal-Regulated Kinase-1 and -2 (ERK1/2) Regulates Acetic Acid-Induced, Pain-Related Anxiety in Adult Female Mice

Zhong

Rong

Zhou

et al. 2012

Acta Histochem. Cytochem.

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In visceral pain, anxiety and pain occur simultaneously, but the etiogenesis of this effect is not yet well-described. The anterior cingulate cortex (ACC) is known to be associated with the affective response to noxious stimuli. The aim of the current study is to define the role of ACC extracellular signal-regulated (ERK)-1 and-2 (ERK1/2) activity in the development of pain-related anxiety/depression and the nocifensive response in acetic acid (AA)-elicited visceral pain. The model of visceral pain was created by intraperitoneal (ip) injection of AA to female Kunming mice. We found that AA injection resulted in a dynamic, bilateral ERK1/2 activation pattern in the ACC. Inhibition of ERK1/2 activation 2 hr after AA injection by subcutaneous (sc) injection of the mitogen-activating extracellular kinase (MEK) inhibitor, SL327, had no effect on the nocifensive responses, but did attenuate anxiety-like behavior, as determined by elevated plus-maze and open-field testing results. These data suggest that AA-induced visceral pain activates expression of ACC ERK1/2, which regulates visceral pain-related anxiety, but not the nocifensive response.

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“…The method of intrainjection of lentivirus into the DG region of the bilateral hippocampus was described in our previous study with a slight modification (Dai et al, 2011). In brief, rats were anesthetized with an intraperitoneal injection of chloral hydrate (40 mg/kg), and securely placed into a stereotaxic device with bregma and lambda at a horizontal level.…”

Section: Bilateral Intra-dg Injectionmentioning

confidence: 99%

“…Immunohistochemistry IGF-2 immunohistochemistry was performed as described in our previous study (Dai et al, 2011). Briefly, transverse sections of the brain (30 mm) were cut with a cryostat and mounted on 3-aminopropyl triethoxy-silane-coated slides, and rabbit anti-IGF 2 antibodies (dilution 1:200; Abcam, Eugene, OR).…”

Section: Golgi Staining and Quantitative Analysis Of Dendrites And Spinementioning

confidence: 99%

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Development of Anxiety-Like Behavior via Hippocampal IGF-2 Signaling in the Offspring of Parental Morphine Exposure: Effect of Enriched Environment

Luo

Cui

et al. 2014

Neuropsychopharmacol

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Opioid addiction is a major social, economic, and medical problem worldwide. Long-term adverse consequences of chronic opiate exposure not only involve the individuals themselves but also their offspring. Adolescent maternal morphine exposure results in behavior and morphologic changes in the brain of their adult offspring. However, few studies investigate the effect of adult opiate exposure on their offspring. Furthermore, the underlying molecular signals regulating the intergenerational effects of morphine exposure are still elusive. We report here that morphine exposure of adult male and female rats resulted in anxiety-like behavior and dendritic retraction in the dentate gyrus (DG) region of the hippocampus in their adult offspring. The behavior and morphologic changes were concomitant with the downregulation of insulin-like growth factor (IGF)-2 signaling in the granular zone of DG. Overexpression of hippocampal IGF-2 by bilateral intra-DG injection of lentivirus encoding the IGF-2 gene prevented anxiety-like behaviors in the offspring. Furthermore, exposure to an enriched environment during adolescence corrected the reduction of hippocampal IGF-2 expression, normalized anxietylike behavior and reversed dendritic retraction in the adult offspring. Thus, parental morphine exposure can lead to the downregulation of hippocampal IGF-2, which contributed to the anxiety and hippocampal dendritic retraction in their offspring. An adolescent-enriched environment experience prevented the behavior and morphologic changes in their offspring through hippocampal IGF-2 signaling. IGF-2 and an enriched environment may be a potential intervention to prevention of anxiety and brain atrophy in the offspring of parental opioid exposure.

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Biphasic Activation of Extracellular Signal-regulated Kinase in Anterior Cingulate Cortex Distinctly Regulates the Development of Pain-related Anxiety and Mechanical Hypersensitivity in Rats after Incision

Cited by 47 publications

References 41 publications

Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats

Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats

Activation of Anterior Cingulate Cortex Extracellular Signal-Regulated Kinase-1 and -2 (ERK1/2) Regulates Acetic Acid-Induced, Pain-Related Anxiety in Adult Female Mice

Development of Anxiety-Like Behavior via Hippocampal IGF-2 Signaling in the Offspring of Parental Morphine Exposure: Effect of Enriched Environment

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