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.
Highlights
Neuropathic pain is a complex chronic pain state caused by a lesion or dysfunction of the somatosensory nervous system[1,2]
The amygdala is a structure located in the medial temporal lobe that is formed by a heterogeneous group of nuclei, each of which has a different pattern of cytoarchitecture, neurochemistry, connectivity and functionality[22,23,24,25] have proposed the following classification for the amygdala nuclei: (1) the basolateral nucleus (BLA) is subdivided into anterior (BLAa) and posterior (BLP) portions, (2) the lateral nucleus (LA) has dorsolateral (LAdl) and ventrolateral (LAvl) subdivisions, and (3) the central nucleus (CeA) is formed by medial (CeAm), lateral (CeAl) and central (CeAc) portions
Newman-Keuls post hoc test showed that peripheral neuropathy (CCI) induced a significant decrease in the nociceptive threshold, inducing mechanical hyperalgesia (F(5,20) = 9.55, p = 0.0001; Fig. 1A) and mechanical allodynia (F(5,20) = 7.67, p = 0.0004; Fig. 1B) in the right hind paw in comparison with the baseline measurements
Summary
Neuropathic pain is a complex chronic pain state caused by a lesion or dysfunction of the somatosensory nervous system[1,2]. Neuropathic pain consists of a multidimensional and multifactorial experience that reflects the functional integration and modification of structures of the limbic and cortical systems responsible for the perception of pain and the responses, including their sensory, cognitive and affective aspects, generated as a result of the injury[4]. The amygdala is responsible for modulating emotional responses, such as fear, sadness, depression and anxiety, and has emerged as a structure critical to pain chronicity that contributes to the affective-motivational and cognitive aspects of pain[15,16,21]. We use an experimental model of peripheral neuropathy in which we focus on the amygdala to improve our understanding of the neurocircuitry involved in the modulation of neuropathic pain and how it controls the affective-motivational aspects of pain
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