Dysfunction of Glutamate Delta-1 Receptor-Cerebellin 1 Trans-Synaptic Signaling in the Central Amygdala in Chronic Pain

Abstract

Chronic pain is a debilitating condition involving neuronal dysfunction, but the synaptic mechanisms underlying the persistence of pain are still poorly understood. We found that the synaptic organizer glutamate delta 1 receptor (GluD1) is expressed postsynaptically at parabrachio-central laterocapsular amygdala (PB-CeLC) glutamatergic synapses at axo-somatic and punctate locations on protein kinase C δ -positive (PKCδ+) neurons. Deletion of GluD1 impairs excitatory neurotransmission at the PB-CeLC synapses. In inflammatory and neuropathic pain models, GluD1 and its partner cerebellin 1 (Cbln1) are downregulated while AMPA receptor is upregulated. A single infusion of recombinant Cbln1 into the central amygdala led to sustained mitigation of behavioral pain parameters and normalized hyperexcitability of central amygdala neurons. Cbln2 was ineffective under these conditions and the effect of Cbln1 was antagonized by GluD1 ligand D-serine. The behavioral effect of Cbln1 was GluD1-dependent and showed lateralization to the right central amygdala. Selective ablation of GluD1 from the central amygdala or injection of Cbln1 into the central amygdala in normal animals led to changes in averse and fear-learning behaviors. Thus, GluD1-Cbln1 signaling in the central amygdala is a teaching signal for aversive behavior but its sustained dysregulation underlies persistence of pain. Significance statement: Chronic pain is a debilitating condition which involves synaptic dysfunction, but the underlying mechanisms are not fully understood. Our studies identify a novel mechanism involving structural synaptic changes in the amygdala caused by impaired GluD1-Cbln1 signaling in inflammatory and neuropathic pain behaviors. We also identify a novel means to mitigate pain in these conditions using protein therapeutics.

Adolescent ethanol drinking promotes hyperalgesia, neuroinflammation and serotonergic deficits in mice that persist into adulthood

“…The number of 5-HT neurons was reduced in the DRN and accompanied by a reduction in 5-HT expression in the thalamus, ACC and amygdala. These regions were selected because they mediate descending modulation of pain and receive 5-HT input from the DRN (Ab Aziz and Ahmad, 2006;Chao et al, 2021;Duan et al, 2021;Gandhi et al, 2021;Gilpin et al, 2021;Heijmans et al, n.d.;Juarez-Salinas et al, 2019;Li et al, 2019;Price, 2000;Zargarani et al, 2021).…”

Intravenous recombinant cerebellin 1 treatment restores signalling by spinal glutamate delta 1 receptors and mitigates chronic pain

“…While spinal-nerve ligation is a more commonly used method for inducing neuropathic pain, chemotherapeutic agentinduced peripheral neuropathy (CIPN) is also a well-characterized model of neuropathic pain. Importantly, we have already shown that recombinant Cbln1, given ICV, produces partial mitigation of pain behaviour in a model of CIPN (Gandhi et al, 2021). Thus, we examined whether IV Cbln1 is able to produce analgesic effects in the…”

“…Immunohistochemical analysis was carried out as previously described (Gandhi et al, 2021). Mice were transcardially perfused with 4% PFA in 0.1-M phosphate buffer (PB) pH 7.4, and lumbar spinal cord was collected and incubated overnight in the same fixative at 4 C. The tissues were then transferred successively into solutions of 10%, 20%, and 30% sucrose in 0.1-M PB and thereafter frozen at À30 C to À40 C using isopentane.…”

“…We have previously found that recombinant Cbln1 injection into the CeA mitigated nocifensive, averse, and affective behaviour in a spinal nerve ligation model of neuropathic pain (Gandhi et al, 2021). While spinal-nerve ligation is a more commonly used method for inducing neuropathic pain, chemotherapeutic agentinduced peripheral neuropathy (CIPN) is also a well-characterized model of neuropathic pain.…”

Fluoxetine attenuates pain-like and depression-related behaviors via reducing neuroinflammation and synaptic deficits in bone cancer mice

“…In addition, uoxetine also displays a critical role in synaptic remodeling of hippocampus in postpartum model of depression [9]. Although current researches suggest that neuroin ammation and remodeling of neuronal synapses or dendritic spine structures simultaneously engaged in the regulation of pain or depression, whether the antidepressant uoxetine is involved in the regulation of BCP through above mechanisms remain unclear [10,11]. Meanwhile, studies have shown that basolateral amygdala (BLA) is the transit station for pain and negative emotional processing [12,13],…”