Direct inhibition of hypocretin/orexin neurons in the lateral hypothalamus by nociceptin/orphanin FQ blocks stress-induced analgesia in rats

Abstract

We recently demonstrated that hypocretin/orexin (Hcrt) and nociceptin/orphanin FQ (N/OFQ) systems coordinately regulate nociception in a mouse model of stress-induced analgesia (SIA). However, the site of N/OFQ action on modulation of SIA was elusive, since N/OFQ was administered via intracerebroventricular (i.c.v.) injection acting on widely distributed N/OFQ receptors (NOP) in the brain. In the present study, we tested the hypothesis that N/OFQ modulates the SIA directly via the inhibition of the Hcrt neurons in the lateral hypothalamus. Using both fluorescent and electron microscopy, we found that N/OFQ-containing neurons are located in the lateral hypothalamus and the N/OFQ-containing fibers make direct contacts with the Hcrt neurons. Paw thermal nociceptive test revealed that the immobilization restraint of the rat increased the thermal pain threshold by 20.5±7.6%. Bilateral microinjection of N/OFQ (9 µg/side) into the rat perifornical area of the lateral hypothalamus, the brain area in which the Hcrt neurons are exclusively located, abolished the SIA. Activity of Hcrt neurons in the same animals was assessed using Fos immunohistochemistry. Percentage of Fos+/Hcrt neurons was lower in rats injected with N/OFQ than rats injected with saline, with the difference between groups stronger in the Hcrt neurons located medially to the fornix than in Hcrt neurons located laterally to the fornix. These results suggest that N/OFQ modulation of SIA is mediated by direct inhibition of Hcrt neuronal activity in the perifornical area. The uncovered peptidergic interaction circuitry may have broad implication in coordinated modulation by Hcrt and N/OFQ on other stress adaptive responses.

Modification of anxiety‐like behaviors by nociceptin/orphanin FQ (N/OFQ) and time‐dependent changes in N/OFQ‐NOP gene expression following ethanol withdrawal

“…Hypocretins participate in regulating ethanol reward and re-establishment of ethanol seeking through actions in the LH and VTA (Dayas et al, 2008; Lawrence et al, 2006). It is plausible that withdrawal associated CRF activation in the LH elevates hypocretin release (Winsky-Sommerer et al, 2004) altering the activity of N/OFQ neurons that have recently been discovered to make synaptic contacts with hypocretin neurons in the LH (Gerashchenko et al, 2011). Indeed, in the LH, N/OFQ blocks stress-induced analgesia via direct inhibition of hypocretin neurons (Gerashchenko et al, 2011).…”

“…It is plausible that withdrawal associated CRF activation in the LH elevates hypocretin release (Winsky-Sommerer et al, 2004) altering the activity of N/OFQ neurons that have recently been discovered to make synaptic contacts with hypocretin neurons in the LH (Gerashchenko et al, 2011). Indeed, in the LH, N/OFQ blocks stress-induced analgesia via direct inhibition of hypocretin neurons (Gerashchenko et al, 2011). It is therefore reasonable to speculate that an analogous mechanism contribute to anxiety triggered by the ethanol abstinence and that the increased NOP gene expression in the LH may represent an up-regulation to counteract CRF-induced hyperactivity of hypocretin neurons during withdrawal.…”

Differences in carbachol dose, pain condition, and sex following lateral hypothalamic stimulation

“…Both electrical (Lopez and Cox,1992; Dafny et al,1996; Franco and Prado, 1996) and chemical stimulation with S -glutamate (Behbehani et al, 1988), morphine (Dafny et al, 1996; Franco and Prado, 1996), carbamylcholine (carbachol; Holden & Naleway, 2001; Holden et al, 2002; Holden et al, 2005; Holden and Pizzi, 2008; Holden et al, 2009; Safari et al, 2009), or nociception/orphanin FQ (Gerashchenko et al, 2011;) increase response latencies to acute (nociceptive) pain in rats. This nociceptive modulation was found in both male (Dafny et al, 1996; Franco and Prado, 1996; Behbehani et al, 1988; Safari et al, 2009; Gerashchenko et al, 2011) and female rats (Lopez and Cox, 1992; Holden and Naleway, 2001; Holden et al, 2002; Holden et al, 2005; Holden and Pizzi, 2008; Holden et al, 2009). The role of the LH in modulating neuropathic pain states is not known for either male or female rats.…”

Mitigation of Murine Focal Cerebral Ischemia by the Hypocretin/Orexin System is Associated With Reduced Inflammation

“…1,2 They project broadly throughout the brain and mediate many physiological functions, including wakefulness and sleep, energy homeostasis, glucose metabolism, autonomic function, 2-11 and stress-adaptive responses such as stress-induced analgesia. 12, 13 Loss of Hcrt neurons or dysfunction in the Hcrt system has been observed in several disorders, including narcolepsy 14, 15 and subarachnoid hemorrhage. 16 Recently, a few studies have indicated that the Hcrt system may be involved in cerebral ischemic injury.…”