Sensitization of neurons in the central nucleus of the amygdala via the decreased GABAergic inhibition contributes to the development of neuropathic pain-related anxiety-like behaviors in rats

Abstract

BackgroundDespite high prevalence of anxiety accompanying with chronic pain, the mechanisms underlying pain-related anxiety are largely unknown. With its well-documented role in pain and emotion processing, the amygdala may act as a key player in pathogenesis of neuropathic pain-related anxiety. Pain-related plasticity and sensitization of CeA (central nucleus of the amygdala) neurons have been shown in several models of chronic pain. In addition, firing pattern of neurons with spike output can powerfully affect functional output of the brain nucleus, and GABAergic neurons are crucial in the modulation of neuronal excitability. In this study, we first investigated whether pain-related plasticity (e.g. alteration of neuronal firing patterns) and sensitization of CeA neurons contribute to nerve injury-evoked anxiety in neuropathic rats. Furthermore, we explored whether GABAergic disinhibition is responsible for regulating firing patterns and intrinsic excitabilities of CeA neurons as well as for pain-related anxiety in neuropathic rats.ResultsWe discovered that spinal nerve ligation (SNL) produced neuropathic pain-related anxiety-like behaviors in rats, which could be specifically inhibited by intra-CeA administration of anti-anxiety drug diazepam. Moreover, we found potentiated plasticity and sensitization of CeA neurons in SNL-induced anxiety rats, of which including: 1) increased burst firing pattern and early-adapting firing pattern; 2) increased spike frequency and intrinsic excitability; 3) increased amplitude of both after-depolarized-potential (ADP) and sub-threshold membrane potential oscillation. In addition, we observed a remarkable reduction of GABAergic inhibition in CeA neurons in SNL-induced anxiety rats, which was proved to be important for altered firing patterns and hyperexcitability of CeA neurons, thereby greatly contributing to the development of neuropathic pain-related anxiety. Accordantly, activation of GABAergic inhibition by intra-CeA administration of muscimol, a selective GABAA receptors agonist, could inhibit SNL-induced anxiety-like behaviors in neuropathic rats. By contrast, suppression of GABAergic inhibition by intra-CeA administration of bicuculline, a selective GABAA receptors antagonist, produced anxiety-like behavior in normal rats.ConclusionsThis study suggests that reduction of GABAergic inhibition may be responsible for potentiated plasticity and sensitization of CeA neurons, which likely underlie the enhanced output of amygdala and neuropathic pain-related anxiety in SNL rats.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-014-0072-z) contains supplementary material, which is available to authorized users.

Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

“…Analysis of innate anxiety in the behavioural tests used previously revealed that icv R3(B1-22)R (4 nmol; a dose shown to reduce motivated food seeking in mice [44]) increased anxiety-like behaviour in the EPM ( Table 2 In regard to the latter, RXFP3 mRNA is abundantly expressed in several brain areas associated with control of anxiety-like behaviours, including the well characterised extended amygdala [6,[50][51][52]. Relaxin-3 is primarily expressed in GABA neurons, as reflected by the co-expression of relaxin-3 and glutamate decarboxylase immunoreactivity in the rat nucleus incertus [18], which suggests RXFP3 activation may act to reinforce inhibitory signalling on target neurons.…”

GABAA Receptors in the Central Nucleus of the Amygdala Are Involved in Pain- and Itch-Related Responses

“…6,16 Evidence accumulated from recent studies has suggested that GABA A receptors in the CeA are involved in pain modulation. For example, intra-CeA administration of muscimol hydrochloride (Mus), a selective GABA A receptors agonist, could inhibit mechanical allodynia, 11,25 whereas intra-CeA application of bicuculline (Bic), a selective GABA A receptor antagonist, showed no influence on mechanical allodynia 25 or induced mechanical hyperalgesia. 11 Nonetheless, several recent studies report contradictory results that indicated that microinjection of Bic and Mus into the CeA increased and decreased antinociceptive response, respectively.…”

Multimodal Care in the Management of a Patient With Chronic Tendinopathy of the Biceps Femoris: A Case Report

“…GABAergic inhibition has been observed in chronic pain conditions as well. 24 Evidence suggests that treatment with medications for anxiety and insomnia can help alleviate chronic pain. 23,24 Data from this case do not adequately explain the impact of auricular acupuncture on chronic tendinopathy.…”

“…24 Evidence suggests that treatment with medications for anxiety and insomnia can help alleviate chronic pain. 23,24 Data from this case do not adequately explain the impact of auricular acupuncture on chronic tendinopathy. The alleviation of pain as a result of exercise and dry needling may have accounted for the reduction in psychosomatic symptoms.…”