An increasing body of evidence postulates that microglia are the main mediators of inflammation-related disorders, including depression. Since activated microglia produce a wide range of pro- and anti-inflammatory factors, the modulation of M1/M2 microglial polarization by antidepressants may be crucial in the treatment of depression. The current paper aimed to investigate the impact of tianeptine on the microglia’s viability/death parameters, and on M1/M2 microglial activation in response to lipopolysaccharide (LPS) stimulation. Furthermore, the molecular mechanisms via which tianeptine affected the LPS-evoked changes were investigated. The results revealed that tianeptine had partially protective effects on the changes in microglia viability/death evoked by LPS. Tianeptine attenuated microglia activation by decreasing the expression of cluster of differentiation 40 (CD40), and major histocompatibility complex class II (MHC II) markers, as well as the release of pro-inflammatory factors: interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor alpha (TNF-α), and chemokine CC motif ligand 2 (CCL2), and the production of nitric oxide and reactive oxygen species. In contrast, we did not observe an impact of tianeptine on M2 microglia measured by IL-4, IL-10, TGF-β, and insulin-like growth factor 1 (IGF-1) expression. Moreover, we demonstrated an inhibitory effect of tianeptine on the LPS-induced activation of the nucleotide-binding oligomerization domain-like (NOD-like) receptor pyrin-containing 3 inflammasome (NLRP3) inflammasome subunits, NLRP3 and caspase-1, as well as the ability of tianeptine to reduce Toll-like receptor 4 (TLR4) levels, as well as the phosphorylation of extracellular signal-related kinases 1 and 2 (ERK1/2) and of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Collectively, we demonstrated that tianeptine has protective properties and inhibits M1 polarization, thus attenuating the production of inflammatory mediators. Moreover, we found that M1 microglia suppression may be related to the NLRP3 inflammasome and TLR4 signaling. These findings suggest that a better understanding of the multifaceted mechanisms of tianeptine action on microglia may increase the effectiveness of therapy, where inflammation is a central hallmark.

Disturbances in the function of the mesostriatal dopamine system may contribute to the development and maintenance of chronic pain, including its sensory and emotional/cognitive aspects. In the present study, we assessed the influence of chronic constriction injury (CCI) of the sciatic nerve on the expression of genes coding for dopamine and opioid receptors as well as opioid propeptides in the mouse mesostriatal system, particularly in the nucleus accumbens. We demonstrated bilateral increases in mRNA levels of the dopamine D1 and D2 receptors (the latter accompanied by elevated protein level), opioid propeptides proenkephalin and prodynorphin, as well as delta and kappa (but not mu) opioid receptors in the nucleus accumbens at 7 to 14 days after CCI. These results show that CCI-induced neuropathic pain is accompanied by a major transcriptional dysregulation of molecules involved in dopaminergic and opioidergic signaling in the striatum/nucleus accumbens. Possible functional consequences of these changes include opposite effects of upregulated enkephalin/delta opioid receptor signaling vs. dynorphin/kappa opioid receptor signaling, with the former most likely having an analgesic effect and the latter exacerbating pain and contributing to pain-related negative emotional states.

Neuropathic pain represents a significant clinical problem because it is a chronic condition often refractory to available therapy. Therefore, there is still a strong need for new analgesics. Botulinum neurotoxin A (BoNT/A) is used to treat a variety of clinical diseases associated with pain. Glia are in continuous bi-directional communication with neurons to direct the formation and refinement of synaptic connectivity. This review addresses the effects of BoNT/A on the relationship between glia and neurons under neuropathic pain. The inhibitory action of BoNT/A on synaptic vesicle fusion that blocks the release of miscellaneous pain-related neurotransmitters is known. However, increasing evidence suggests that the analgesic effect of BoNT/A is mediated through neurons and glial cells, especially microglia. In vitro studies provide evidence that BoNT/A exerts its anti-inflammatory effect by diminishing NF-κB, p38 and ERK1/2 phosphorylation in microglia and directly interacts with Toll-like receptor 2 (TLR2). Furthermore, BoNT/A appears to have no more than a slight effect on astroglia. The full activation of TLR2 in astroglia appears to require the presence of functional TLR4 in microglia, emphasizing the significant interaction between those cell types. In this review, we discuss whether and how BoNT/A affects the spinal neuron–glia interaction and reduces the development of neuropathy.

Recent findings have highlighted the roles of CXC chemokine family in the mechanisms of neuropathic pain. Our studies provide evidence that single/repeated intrathecal administration of CXCR2 (NVP-CXCR2-20) and CXCR3 ((±)-NBI-74330) antagonists explicitly attenuated mechanical/thermal hypersensitivity in rats after chronic constriction injury of the sciatic nerve. After repeated administration, both antagonists showed strong analgesic activity toward thermal hypersensitivity; however, (±)-NBI-74330 was more effective at reducing mechanical hypersensitivity. Interestingly, repeated intrathecal administration of both antagonists decreased the mRNA and/or protein levels of pronociceptive interleukins (i.e., IL-1beta, IL-6, IL-18) in the spinal cord, but only (±)-NBI-74330 decreased their levels in the dorsal root ganglia after nerve injury. Furthermore, only the CXCR3 antagonist influenced the spinal mRNA levels of antinociceptive factors (i.e., IL-1RA, IL-10). Additionally, antagonists effectively reduced the mRNA levels of pronociceptive chemokines; NVP-CXCR2-20 decreased the levels of CCL2, CCL6, CCL7, and CXCL4, while (±)-NBI-74330 reduced the levels of CCL3, CCL6, CXCL4, and CXCL9. Importantly, the results obtained from the primary microglial and astroglial cell cultures clearly suggest that both antagonists can directly affect the release of these ligands, mainly in microglia. Interestingly, NVP-CXCR2-20 induced analgesic effects after intraperitoneal administration. Our research revealed important roles for CXCR2 and CXCR3 in nociceptive transmission, especially in neuropathic pain.

The ligands of chemokine receptors 2 and 5 (CCR2 and CCR5, respectively) are associated with the pathomechanism of neuropathic pain development, but their role in painful diabetic neuropathy remains unclear. Therefore, the aim of our study was to examine the function of these factors in the hypersensitivity accompanying diabetes. Additionally, we analyzed the analgesic effect of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, and its influence on the effectiveness of morphine. An increasing number of experimental studies have shown that targeting more than one molecular target is advantageous compared with the coadministration of individual pharmacophores in terms of their analgesic effect. The advantage of using bifunctional compounds is that they gain simultaneous access to two receptors at the same dose, positively affecting their pharmacokinetics and pharmacodynamics and consequently leading to improved analgesia. Experiments were performed on male and female Swiss albino mice with a streptozotocin (STZ, 200 mg/kg, i.p.) model of diabetic neuropathy. We found that the blood glucose level increased, and the mechanical and thermal hypersensitivity developed on the 7th day after STZ administration. In male mice, we observed increased mRNA levels of Ccl2, Ccl5, and Ccl7, while in female mice, we observed additional increases in Ccl8 and Ccl12 levels. We have demonstrated for the first time that a single administration of cenicriviroc relieves pain to a similar extent in male and female mice. Moreover, repeated coadministration of cenicriviroc with morphine delays the development of opioid tolerance, while the best and longest-lasting analgesic effect is achieved by repeated administration of cenicriviroc alone, which reduces pain hypersensitivity in STZ-exposed mice, and unlike morphine, no tolerance to the analgesic effects of CVC is observed until Day 15 of treatment. Based on these results, we suggest that targeting CCR2 and CCR5 with CVC is a potent therapeutic option for novel pain treatments in diabetic neuropathy patients.