Physiological Research. (In Press)
Involvement of the periaqueductal gray in the descending antinociceptive effect induced by the central nucleus of amygdala
Nora BOURBIA, Antti PERTOVAARA.
Here we studied whether descending control of mechanical nociception by glutamate in the central nucleus of the amygdala (CeA) of healthy control animals is induced by amygdaloid NMDA receptors and relayed through the midbrain periaqueductal gray (PAG). Mechanical nociception in the hind paws was assessed in rats with chronic guide cannulae for glutamate administration in the right CeA and for inducing local anesthesia in the PAG. In a separate electrophysiological study, ON-like PAG neurons giving an excitatory response to noxious pinch of the tail were recorded in anesthetized rats following glutamate administration into the CeA. A high dose of glutamate (100 μg) in the CeA induced mechanical antinociception in the contra- but not ipsilateral hind limb. Antinociception was prevented by an NMDA receptor antagonist in the CeA or local anesthesia of the PAG. Discharge rate of ON-like PAG neurons was increased by a high dose of glutamate (100 μg) in the CeA and this increase was prevented by an NMDA receptor antagonist in the CeA. The results indicate that amygdaloid NMDA receptors in the CeA may induce contralaterally mechanical antinociception through a circuitry relaying in the PAG. Activation of ON-like PAG neurons is associated with the descending antinociceptive effect. Mechanisms and causality of this association still remain to be studied.
Link and pubmed
Behav Brain Res. 2014 Dec 31
Bidirectional amygdaloid control of neuropathic hypersensitivity mediated by descending serotonergic pathways acting on spinal 5-HT3 and 5-HT1A receptors
Sagalajev B, Bourbia N (shared the first-authorship), Beloushko E, Wei H, Pertovaara A.
Amygdala is involved in processing of primary emotions and particularly its central nucleus (CeA) also in pain control. Here we studied mechanisms mediating the descending control of mechanical hypersensitivity by the CeA in rats with a peripheral neuropathy in the left hind limb. For drug administrations, the animals had a guide cannula in the right CeA and an intrathecal catheter or another guide cannula in the medullary raphe. Hypersensitivity was tested with monofilaments. Glutamate administration in the CeA produced a bidirectional effect on hypersensitivity that varied from an increase at a low-dose (9μg) to a reduction at high doses (30-100μg). The increase but not the reduction of hypersensitivity was prevented by blocking the amygdaloid NMDA receptor with a dose of MK-801 that alone had no effects. The glutamate-induced increase in hypersensitivity was reversed by blocking the spinal 5-HT3 receptor with ondansetron, whereas the reduction in hypersensitivity was reversed by blocking the spinal 5-HT1A receptor with WAY-100635. Both the increase and decrease of hypersensitivity induced by amygdaloid glutamate treatment were reversed by medullary administration of a 5-HT1A agonist, 8-OH-DPAT, that presumably produced autoinhibition of serotonergic cell bodies in the medullary raphe. The results indicate that depending on the dose, glutamate in the CeA has a descending facilitatory or inhibitory effect on neuropathic pain hypersensitivity. Serotoninergic raphe neurons are involved in mediating both of these effects. Spinally, the 5-HT3 receptor contributes to the increase and the 5-HT1A receptor to the decrease of neuropathic hypersensitivity induced by amygdaloid glutamate.
Neurosci Lett. 2014 Jun 6;570:26-31
Descending effect on spinal nociception by amygdaloid glutamate varies with the submodality of noxious test stimulation
Nora Bourbia, Boriss Sagalajev, Antti Pertovaara
Amygdala has an important role in the processing of primary emotions, such as fear. Additionally, amygdala is involved in processing and modulation of pain. While the amygdala, particularly its central nucleus (CeA), has been shown to contribute to pain control, the descending pain regulation by the CeA is still only partly characterized. Here heat and mechanical nociception was tested in both hind limbs of healthy rats with a chronic guide cannula for microinjection of glutamate into the CeA of the left or right hemisphere. The aim was to assess whether the descending pain regulatory effect by glutamate in the amygdala varies with the submodality or the body side of nociceptive testing, brain hemisphere or the amygdaloid glutamate receptor. Motor performance was assessed with the Rotarod test. Amygdaloid glutamate, independent of the treated hemisphere, produced a dose-related heat and mechanical antinociception that varied with the submodality of testing. Heat antinociception was short lasting (minutes), bilateral and not reversed by blocking the amygdaloid NMDA receptor with MK-801. In contrast, mechanical antinociception lasted longer (>20 min), was predominantly contralateral and reversed by blocking the amygdaloid NMDA receptor. At an antinociceptive dose, amygdaloid glutamate failed to influence motor performance. The results indicate that independent of the brain hemisphere, the spatial extent and duration of the descending antinociceptive effect induced by amygdaloid glutamate varies with the amygdaloid glutamate receptor and the submodality of pain.
Scandinavian Journal of Pain July 2011 (Vol. 2, Issue 3, Pages 137-138)
Is finding the common biological link(s) between pain and affect an infinity quest?
Nora Bourbia, Antti Pertovaara
Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland.
Clinical studies have demonstrated comorbidity between pain and depression or anxiety , . The prevalence of depression in patients with chronic pain reaches 5–100%, the prevalence of anxiety disorder reaches 11–60%, and the prevalence of pain in patients with depression disorder reaches 15–100% depending on the study and type of pain , . These comorbidities affect negatively the life of the patients. It is still not clear whether there is a causal relationship in the development of comorbidity between chronic pain and anxiety/depression or whether chronic pain and anxiety/depression have distinctly different mechanisms that coexist independent of each other. This question is not only of considerable academic interest but also of potential clinical importance when developing therapeutic interventions for the comorbid chronic pain and affective disorder.
J Pain. 2010 Dec;11(12):1461-71. doi: 10.1016/j.jpain.2010.05.004.
Corticotropin-releasing factor in the rat amygdala differentially influences sensory-discriminative and emotional-like pain response in peripheral neuropathy.
Bourbia N, Ansah OB, Pertovaara A.
Institute of Biomedicine/Physiology, University of Helsinki, Finland.
The central nucleus of the amygdala (CeA) is involved in processing and regulation of pain. We determined whether amygdaloid corticotropin-releasingfactor (CRF) contributes to pain modulation in the neuropathic rat. Emotional aspect of pain was assessed by an aversive place-conditioning test and sensory aspect of pain by determining monofilament-induced limb-withdrawal threshold. CRF₆₋₃₃ (an inhibitor of CRF-binding protein) or CRF₉₋₄₁, a nonselective CRF receptor antagonist, was microinjected to the left or right CeA or a control site in rats with spared nerve injury (SNI) or sham operation of the left hind limb. In SNI animals, CRF₆₋₃₃ in the left or right CeA, but not in a control site, attenuated emotional painlike behavior and increased sensory pain. In sham controls, CRF₆₋₃₃ in the right but not left CeA increased sensory aspect of pain, without influence on place-avoidance behavior. The effects induced by CRF₆₋₃₃ were reversed by CRF₉₋₄₁. The results indicate that endogenous CRF in the CeA, through action on CRF receptors, may differentially influence emotional and sensory aspects of pain in neuropathy. While the right CeA had a dominant role in modulation of pain-related responses in sham controls, left as well as right CeA contributed to pain modulation in neuropathic animals. PERSPECTIVE: An increase in free endogenous corticotropin-releasing factor in the central nucleus of the amygdala was accompanied by increased cutaneous hypersensitivity and decreased emotional painlike behavior in neuropathic animals. This finding indicates that CRF in the amygdala may have differential effects on sensory and emotional aspects of neuropathic pain.
Behav Brain Res. 2010 May 1;209(1):174-8. doi: 10.1016/j.bbr.2010.01.021.
Influence of amygdaloid glutamatergic receptors on sensory and emotional pain-related behavior in the neuropathic rat.
Ansah OB, Bourbia N, Gonçalves L, Almeida A, Pertovaara A.
Institute of Biomedicine/Physiology, University of Helsinki, Helsinki, Finland.
The role of amygdaloid glutamatergic receptors (GluRs) in maintenance of the sensory versus emotional component of neuropathic pain was studied by assessing monofilament-induced limb withdrawal response (sensory pain) and aversive place-conditioning behavior (emotional pain) followingamygdaloid administration of various glutamatergic compounds in nerve-injured animals. The results indicate that endogenous activation ofamygdaloid group I metabotropic GluRs, mGluR(1) and mGluR(5), and the NMDA-R contributes to maintenance of sensory and emotionalcomponents of neuropathic pain. The predominant effect by amygdaloid group I mGluRs was facilitation of emotional-like pain behavior.