Effects of Interleukin-1β in Glycinergic Transmission at the Central Amygdala

Abstract

Interleukin-1β (IL-1β) is an important cytokine that modulates peripheral and central pain sensitization at the spinal level. Among its effects, it increases spinal cord excitability by reducing inhibitory Glycinergic and GABAergic neurotransmission. In the brain, IL-1β is released by glial cells in regions associated with pain processing during neuropathic pain. It also has important roles in neuroinflammation and in regulating NMDA receptor activity required for learning and memory. The modulation of glycine-mediated inhibitory activity via IL-1β may play a critical role in the perception of different levels of pain. The central nucleus of the amygdala (CeA) participates in receiving and processing pain information. Interestingly, this nucleus is enriched in the regulatory auxiliary glycine receptor (GlyR) β subunit (βGlyR); however, no studies have evaluated the effect of IL-1β on glycinergic neurotransmission in the brain. Hence, we hypothesized that IL-1β may modulate GlyR-mediated inhibitory activity via interactions with the βGlyR subunit. Our results show that the application of IL-1β (10 ng/ml) to CeA brain slices has a biphasic effect; transiently increases and then reduces sIPSC amplitude of CeA glycinergic currents. Additionally, we performed molecular docking, site-directed mutagenesis, and whole-cell voltage-clamp electrophysiological experiments in HEK cells transfected with GlyRs containing different GlyR subunits. These data indicate that IL-1β modulates GlyR activity by establishing hydrogen bonds with at least one key amino acid residue located in the back of the loop C at the ECD domain of the βGlyR subunit. The present results suggest that IL-1β in the CeA controls glycinergic neurotransmission, possibly via interactions with the βGlyR subunit. This effect could be relevant for understanding how IL-1β released by glia modulates central processing of pain, learning and memory, and is involved in neuroinflammation.

Neuropathic Pain Induces Interleukin-1β Sensitive Bimodal Glycinergic Activity in the Central Amygdala

“…In a previous study, we reported that in CeA neurons, IL-1β induces a short-lasting increment in glycinergic currents five minutes after the addition of IL-1β. However, fifteen minutes later, the whole range of amplitudes diminished, suggesting that IL-1β disaggregates the GlyR clusters and induces endocytosis [22]. Here, in slices from CCI animals, we observed that IL-1β reduces the whole range of current amplitudes, and the bimodality is almost lost, with a shift of the peak amplitudes from the bimodal "2 peaks" at 9pA and 28pA, to 11 pA at 5 min and 14 pA, after 15 min of IL-1β incubation.…”

“…We recently reported that spontaneous glycinergic currents in CeA slices are modulated by IL-1β [22]. The described dual effect of IL-1β first increases glycinergic current amplitude by affecting GlyR channel opening and then reduces the amplitudes by disaggregating glycinergic clusters.…”

“…The described dual effect of IL-1β first increases glycinergic current amplitude by affecting GlyR channel opening and then reduces the amplitudes by disaggregating glycinergic clusters. This effect is caused by the interaction of IL-1β with at least one amino acid at the extracellular domain of βGlyR, a mechanism that could affect the availability of GlyR at the membrane, and how the amygdala perceives pain [22]. In the present work, we studied the glycinergic transmission in CeA slices and its modulation by IL-1β but in a condition of neuropathic pain induced by chronic constriction nerve injury of the sciatic nerve.…”

Autonomic Nervous System Dysfunction Is Related to Chronic Prostatitis/Chronic Pelvic Pain Syndrome

“…Interestingly, IL-1β is involved in the inflammatory response to chronic prostatitis and mediation of pain development. It increases spinal excitability and modulated pain sensitivity at the spinal cord level [ 114 115 ]. In addition, spinal astrocytes produce IL-1β, which activates astrocytes by binding to the IL-1 receptor (IL-1R), contributing to central sensitization and leading to long-term maintenance of chronic pain [ 116 ].…”

Excitatory and inhibitory neuronal signaling in inflammatory and diabetic neuropathic pain

“…Diminished synaptic inhibition has been reported as a critical element in rodent models of chronic inflammatory or neuropathic pain (Coull et al 2003 ). The cytokine IL-1β was shown to reduce GABAergic and glycinergic transmission in CNS neurons (Solorza et al 2021 ). Thus, restoration of lost inhibitory signaling in chronic pain would be a promising therapeutic approach.…”