α2-Noradrenergic antagonist administration into the central nucleus of the amygdala blocks stress-induced hypoalgesia in awake behaving rats

Abstract

Stress-induced hypoalgesia (SIH) is an adaptive behavioral phenomenon mediated in part by the amygdala. Acute stress increases amygdalar noradrenaline levels and focal application of α 2 -adrenoceptor agonists in the central nucleus of the amygdala (CeA) is antinociceptive. We hypothesized that α 2 -adrenoceptor antagonist administration into the CeA may block SIH.Bilateral microinjections of drug or saline via chronically implanted CeA cannulae were followed by either a period of restraint stress or rest. The nocifensive paw-withdrawal latency (PWL) to a focused beam of light was measured. PWLs were longer in restrained rats, constituting SIH. Microinjection of the α 2 -adrenoceptor antagonist idazoxan into the CeA prior to restraint blocked SIH. Idazoxan administration in unrestrained rats had no effect. Microinjection of the α 2 -adrenoceptor agonist clonidine in unrestrained rats caused dose dependent hypoalgesia, mimicking the effects of environmental stress. α 2 -Adrenoceptor function in the CeA is necessary for restraintinduced SIH. Keywords microinjection; α 2 -adrenoceptor; idazoxan; clonidine; restraint; nociception; stress-induced hypoalgesia Hypoalgesia resulting from exposure to an acute stressor, or "stress-induced hypoalgesia" (SIH), is a well-described phenomenon in both humans and experimental animals (Hayes et al., 1978, Amit and Galina, 1986, Bodnar, 1986, van der Kolk et al., 1989, Rushen and Ladewig, 1991. SIH can be evoked by a variety of acute stressors including footshock and restraint, as well as more biologically relevant threat stimuli such as exposure to a predator or to odors from stressed conspecifics (Watkins et al., 1982b, Fanselow, 1985, Lester and Fanselow, 1985, Kavaliers, 1988, Rushen and Ladewig, 1991.SIH may represent one component of a broader shift in attention towards salient environmental cues under stressful contingencies (Selden et al., 1990b, Berridge and Waterhouse, 2003, Morilak et al., 2005. This allows the organism to ignore distracting nociceptive stimuli, and Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Amit and Galina, 1988). NIH Public AccessOne neurotransmitter implicated in SIH is noradrenaline, and systemic treatment with the α 2 -adrenoceptor antagonists yohimbine or idazoxan blocks the expression of SIH in rodents (Coderre and Rollman, 1984, Oluyomi and Hart, 1990, Tokuyama et al., 1991. However, the site or sites of action of noradrenaline in evoking SIH are unknown.SIH can be blocked by lesions of the central nucleus of the amygdala (CeA) (Helmstetter and Bellgowan, 1993). The CeA is densely populate...

Role of Spinal Cord α2-Adrenoreceptors in Noradrenergic Inhibition of Nociceptive Transmission During Chemotherapy-Induced Peripheral Neuropathy

“…Intrathecal administration of α 2 -AR agonists induces antinociception in humans and animal models whereas the opposite occurs with α 2 -AR antagonists (Eisenach et al, 1996;Budai et al, 1998). However, NA may trigger pain facilitation after brain release (Bie et al, 2003;Ortiz et al, 2008;Martins et al, 2015). Further adding complexity to the studies of noradrenergic pain modulation, an effect of the pain model was reported.…”

A Peripheral Adrenoceptor-mediated Sympathetic Mechanism Can Transform Stress-induced Analgesia into Hyperalgesia

“…15 α-2 Receptors are also located in the spinal cord dorsal horn 16 and in brain regions associated with pain modulation including the hypothalamus and amygdala. 17–19 …”

Emotional regulation of pain: the role of noradrenaline in the amygdala

“…More specifically, microinjection of the  2 adrenergic receptor agonist in the CeA decreased the sensitizing effect of foot shocks on the amplitude of the acoustic startle response [73]. Furthermore, microinjection of the noradrenergic agonists clonidine in the CeA increased the tail-flick latency, again supporting a role for noradrenergic receptors in antinociception [74], whereas microinjections of an  2 receptor antagonist preceding the induction of stress by restraining, blocked the stress-induced hypoalgesia as measured as the paw-withdrawal latency [14]. Together, these data are consistent with the involvement of the amygdala in stress-induced analgesia and hypoalgesia, triggered by stress-induced release of noradrenaline in this region.…”

“…However, over recent years, a role for the amygdala in hypoalgesia and analgesia during emotionally heightened states such as fear has become of more interest. Much evidence has implicated release of noradrenaline, and activation of the α 2 receptors in the central amygdala in stress-induced analgesia [14]. The parabrachial afferents form large perisomatic excitatory synapses in the central amygdala, and carry nociceptive information into the nociceptive amygdala [43] are key targets for modulation by noradrenaline [71].…”

“…In contrast, stress-induced analgesia is a phenomenon in which fearful and often life-threatening situations (e.g., visual re-exposure of war veterans with posttraumatic stress disorder to war, exposure of mice to natural predators) suppresses the perception of pain, which may serve the purpose of fast defensive action, attention and/or flight from the dangerous situation [79]. Stressful situations increase the level of noradrenaline in the body [10,11], which acts besides many other neuromodulators, as an important modulator in the perception of pain at the spinal [12,13] and supra-spinal level [14,15].…”