Interleukin-1 signaling in the basolateral amygdala is necessary for heroin-conditioned immunosuppression

Abstract

Heroin administration suppresses the production of inducible nitric oxide (NO), as indicated by changes in splenic inducible nitric oxide synthase (iNOS) and plasma nitrate/nitrite. Since NO is a measure of host defense against infection and disease, this provides evidence that heroin can increase susceptibility to pathogens by directly interacting with the immune system. Previous research in our laboratory has demonstrated that these immunosuppressive effects of heroin can also be conditioned to environmental stimuli by repeatedly pairing heroin administration with a unique environmental context. Re-exposure to a previously drug-paired context elicits immunosuppressive effects similar to heroin administration alone. In addition, our laboratory has reported that the basolateral amygdala (BLA) and medial nucleus accumbens shell (mNAcS) are critical neural substrates that mediate this conditioned effect. However, our understanding of the contributing mechanisms within these brain regions is limited. It is known that the cytokine interleukin-1 (IL-1) plays an important role in learning and memory. In fact, our laboratory has demonstrated that inhibition of IL-1β expression in the dorsal hippocampus (DH) prior to reexposure to a heroin-paired context prevents the suppression of measures of NO production. Therefore, the present studies sought to further investigate the role of IL-1 in heroin-conditioned immunosuppression. Blockade of IL-1 signaling in the BLA, but not in the caudate putamen or mNAcS, using IL-1 receptor antagonist (IL-1Ra) attenuated heroin-conditioned immunosuppression of NO production as measured by plasma nitrate/nitrite and iNOS mRNA expression in spleen tissue. Taken together, these findings suggest that IL-1 signaling in the BLA is necessary for the expression of heroin-conditioned immunosuppression of NO production and may be a target for interventions that normalize immune function in heroin users and patient populations exposed to opiate regimens.

Cannabidiol modulates the expression of neuroinflammatory factors in stress‐ and drug‐induced reinstatement of methamphetamine in extinguished rats

“…In line with our data, it is shown that CBD could downregulate the expression of chemokines (CCL2 and CCL5) and the pro‐inflammatory cytokine IL‐1β, by reduction of the activation of microglia in the PFC in a viral model of multiple sclerosis, through the activation of adenosine A 2A receptors . The role of inflammatory cytokines, 5‐HT 1A , A 2A , and TRPV receptors in the reward system has been established in several studies, which all can be targeted by CBD in order to reduce inflammation . Therefore, we can propose that the reduction in inflammatory cytokines may play an important role in inhibitory effect of CBD on reinstatement of METH seeking.…”

“…Recent research studies have attempted to clarify the molecular aspects of the neural mechanisms underlying the behavioral effects of drug abuse in different parts of the reward circuitry. Although it is documented that inflammatory factors play roles in reward properties of drugs, there is no report on the possible changes of inflammatory factors in the PFC and hippocampus following the reinstatement of METH‐seeking behaviors.…”

“…Cytokines are divided into two groups according to their functional role: anti‐inflammatory factors such as interleukin‐10 (IL‐10) and pro‐inflammatory factors such as interleukin‐1β (IL‐1β), interleukin‐6 (IL‐16), and tumor necrosis factor α (TNF‐α). Several lines of evidence have suggested that inflammatory factors play an important role in the drug reward–associated behaviors . On the other hand, reduction of neuroinflammation by anti‐inflammatory agents such as ibudilast or minocycline inhibits reinstatement of METH .…”

Cell-Type-Specific Interleukin 1 Receptor 1 Signaling in the Brain Regulates Distinct Neuroimmune Activities

“…Understanding specialized cell-type-specific IL-1R1 functions could lead to the separation of pathogenic IL-1 activities from its physiological counterparts and isolation of the neurotoxic signaling pathways from neuroprotective ones. Thus far, endothelial cells , astrocytes (Moynagh, 2005), neurons (Hutson et al, 2017), resident microglia (Basu et al, 2004), and perivascular macrophages (Serrats et al, 2010) have been reported to respond to central IL-1. However, in vivo visualization of IL-1R1 in these cells remains challenging because of its low expression.…”

Conditioning the neuroimmune response to ethanol using taste and environmental cues in adolescent and adult rats

“…19 Studies have reported heroin-induced conditioned immunosuppression, which has been shown to depend on central cytokine signaling. 20,21 Data from our laboratory have also suggested an ethanol-induced, conditioned neuroimmune response. Specifically, rats received four pairings of a lemon odor CS with an ethanol (2.0 g/kg, intraperitoneal [i.p.])…”