OREXIN 1 AND 2 RECEPTOR INVOLVEMENT IN CO₂-INDUCED PANIC-ASSOCIATED BEHAVIOR AND AUTONOMIC RESPONSES

Abstract

Background The neuropeptides orexin A and B play a role in reward and feeding and are critical for arousal. However, it was not initially appreciated that most prepro-orexin synthesizing neurons are almost exclusively concentrated in the perifornical hypothalamus, which when stimulated elicits panic-associated behavior and cardiovascular responses in rodents and self-reported “panic attacks” and “fear of dying” in humans. More recent studies support a role for the orexin system in coordinating an integrative stress response. For instance, orexin neurons are highly reactive to anxiogenic stimuli, are hyperactive in anxiety pathology, and have strong projections to anxiety and panic-associated circuitry. Although the two cognate orexin receptors are colocalized in many brain regions, the orexin 2 receptor (OX2R) most robustly maps to the histaminergic wake-promoting region, while the orexin 1 receptor (OX1R) distribution is more exclusive and dense in anxiety and panic circuitry regions, such as the locus ceruleus. Overall, this suggests that OX1Rs play a critical role in mobilizing anxiety and panic responses. Methods Here, we used a CO2-panic provocation model to screen a dual OX1/2R antagonist (DORA-12) to globally inhibit orexin activity, then a highly selective OX1R antagonist (SORA1, Compound 56) or OX2R antagonist (SORA2, JnJ10397049) to assess OX1R and OX2R involvement. Results All compounds except the SORA2 attenuated CO2-induced anxiety-like behaviors, and all but the SORA2 and DORA attenuated CO2-induced cardiovascular responses. Conclusions SORA1s may represent a novel method of treating anxiety disorders, with no apparent sedative effects that were present with a benzodiazepine.

Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential

“…A difference in time spent in inner zone was reduced over time (F (2,6) =8.0, p=0.020) for TNI rats. While the reason for this was not investigated further, this is commonly observed when rodents are re-exposed to same arena and it ceases to be novel [40]. …”

Hypothalamic orexin’s role in exacerbated cutaneous vasodilation responses to an anxiogenic stimulus in a surgical menopause model

“…The sleep-promoting properties of DORAs are primarily through antagonism of OX2Rs which are exclusive to histaminergic neurons in the tuberomammillary nucleus, which is a brain region that plays a critical role in wake promotion (Huang et al, 2001; Marcus et al, 2001), but also plays a role in regulating thermogenic activity (Yasuda et al, 2004) which could partially explain the ability of the OX2R antagonist to attenuate TST responses. The anxiolytic effects of DORAs may be preferentially through antagonism of OX1Rs (Bonaventure et al, 2015; Johnson et al, 2012a, 2015a, 2010), but also potentially OX2Rs (Li et al, 2010). Anatomically, OX1Rs appear to be more selectively expressed in panic and anxiety-associated neural circuits such as the bed nucleus of the stria terminalis, amygdala, cingulate cortex and exclusively in noradrenergic neurons in the locus ceruleus [(Marcus et al, 2001), see review (Johnson et al, 2012b)], which also play a role in sympathetic mobilization.…”

“…This dramatic increase in OX activity during menopause is likely contributing to disrupted sleep since OX’s most prominent role is to promote wakefulness (Sakurai, 2007), and higher OXA concentrations in cerebrospinal fluid have been demonstrated in individuals with poor sleep quality (Allen et al, 2002). But there is also emerging evidence that a hyperactive OX system contributes to anxiety states and panic-associated sympathetic activity in rodents (Johnson et al, 2012a, 2015, 2010), and that central OX levels are elevated in patients with increased anxiety symptoms (Johnson et al, 2010). These findings, combined with the building evidence that anxiety and stress are strongly associated with more severe and persistent hot flashes in large cohort studies (Avis et al, 2015), and that stressful stimuli can increase objective hot flashes (Swartzman et al, 1990) led to our current hypothesis that “the OX system plays a critical role in menopause-related symptoms such as hot flashes, anxiety, and sleep disruption”.…”

Narcolepsia: o despertar para uma realidade subestimada

“…O sistema hipocretinérgico desempenha papel crítico na coordenação de sistemas neurais relacionados a ansiedade, pânico e estresse [31][32][33][34] . Os antagonistas seletivos do receptor de hipocretina-1 (selective orexin1 receptor antagonist -SORA1) estão sendo estudados como ansiolíticos, não apresentando a sedação que se vê com os benzodiazepínicos 35 . reti rada abrupta do medicamento anti depressivo venlafaxina gerou uma síndrome transitória assemelhada à narcolepsia, com ataques de cataplexia 36 .…”