The critical role of amygdala subnuclei in nociceptive and depressive-like behaviors in peripheral neuropathy

Abstract

The amygdala is an important component of the limbic system that participates in the control of the pain response and modulates the affective-motivational aspect of pain. Neuropathic pain is a serious public health problem and has a strong affective-motivational component that makes it difficult to treat. The central (CeA), basolateral (BLA) and lateral (LA) nuclei of the amygdala are involved in the processing and regulation of chronic pain. However, the roles of these nuclei in the maintenance of neuropathic pain, anxiety and depression remain unclear. Thus, the main objective of this study was to investigate the role of amygdala subnuclei in the modulation of neuropathic pain, including the affective-motivational axis, in an experimental model of peripheral neuropathy. The specific goals were as follows: (1) To evaluate the nociceptive responses and the patterns of activation of the CeA, BLA and LA in neuropathic rats; and (2) To evaluate the effect of inactivating the amygdala nuclei on the nociceptive response, anxiety and depressive behaviors, motor activity, and plasma stress hormones in animals with neuropathic pain. Thus, mechanical hyperalgesia and allodynia, and the pattern of c-Fos staining in the amygdala subnuclei were evaluated in rats with chronic constriction of the sciatic nerve, as well as sham-operated and naïve rats. Once the amygdala subnuclei involved in neuropathic pain response were defined, those subnuclei were pharmacological inactivated. The effect of muscimol inactivation on the nociceptive response (hyperalgesia and allodynia), anxiety (elevated plus-maze), depressive-like behavior (forced swim test), motor activity (open field), and plasma stress hormone levels (corticosterone and adrenocorticotropic hormone) were evaluated in sham-operated and neuropathic animals. The results showed that the anterior and posterior portions of the BLA and the central portion of the CeA are involved in controlling neuropathic pain. The inactivation of these nuclei reversed hyperalgesia, allodynia and depressive-like behavior in animals with peripheral neuropathy. Taken together, our findings improve our understanding of the neurocircuitry involved in persistent pain and the roles of specific amygdala subnuclei in the modulation of neuropathic pain, including the neurocircuitry that processes the affective-motivational component of pain.

Involvement of brain-derived neurotrophic factor (BDNF) in chronic intermittent stress-induced enhanced mechanical allodynia in a rat model of burn pain

“…We did not measure corticosterone levels in stressed rats with and without thermal injury. However, there are several studies showing stress-induced increased corticosterone levels in the plasma and brain tissue samples of stressed rodents [38–40]. In addition to CIS procedure-induced stress, pain behavioral tests might have influenced stress and corticosterone levels in rats.…”

The Mesolimbic Dopamine System in Chronic Pain and Associated Affective Comorbidities

“…Using a rat neuropathic pain model, a recent study demonstrated that inactivation of amygdala nuclei alleviates hyperalgesia/allodynia and depression-like behaviors (124). More recently, Corder et al combined circuit optogenetics with in vivo calcium imaging in mice to investigate the function of an amygdala-NAc circuit in pain-free and neuropathic pain states (125).…”

Neuroinflammation, Pain and Depression: An Overview of the Main Findings

“…Specifically, the PFC and amygdala have opposite responses to stress since synaptic plasticity is enhanced in the amygdala after depression and is decreased in the PFC (Marsden, 2013). Inhibition of the amygdala by local GABAergic agonists changes pain sensitivity and depressive-like behavior (Seno et al, 2018). Additionally, the volume of the amygdala has been suggested to be correlated with the severity of depression (Li et al, 2014), demonstrating the importance of its activation in the pathophysiology of depression.…”