Targeting α7 nicotinic acetylcholine receptors for chronic pain

Abstract

Despite rapid advances in the field of chronic pain, it remains extremely challenging in the clinic. Pain treatment strategies have not improved for decades as opioids remain the main prescribed drugs for chronic pain management. However, long-term use of opioids often leads to detrimental side effects. Therefore, uncovering the mechanisms underlying the development and maintenance of chronic pain may aid the discovery of novel therapeutics to benefit patients with chronic pain. Substantial evidence indicates downregulation of α7 nicotinic acetylcholine receptors (α7 nAChR) in the sciatic nerve, dorsal root ganglia, and spinal cord dorsal horn in rodent models of chronic pain. Moreover, our recent study and results from other laboratories demonstrate that potentiation of α7 nAChR attenuates pain behaviors in various murine models of chronic pain. This review summarized and discussed the preclinical evidence demonstrating the therapeutic potential of α7 nAChR agonists and allosteric modulators in chronic pain. This evidence indicates that potentiation of α7 nAChR is beneficial in chronic pain, mostly by alleviating neuroinflammation. Overall, α7 nAChR-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.

Inhibition of nicotinic acetylcholine receptors by oligoarginine peptides and polyamine-related compounds

“…Our attention was mostly focused on the inhibition of α9α10 nAChR, since it opens the possibility to develop new effective drugs reducing neuropathic pain ( Hone and McIntosh, 2023 ; Shelukhina et al, 2023 ). In this connection testing the interaction of the polyamine-related compounds with α7 nAChR seemed necessary because activation of this receptor subtype is important in the cholinergic anti-inflammatory pathway ( Zhou et al, 2022 ; Shelukhina et al, 2023 ) and its inhibition would limit possible application of polyamines as probable analgesics. As can be seen from Figure 2A , “cyclo”R8 inhibits α9α10 nAChR almost as effectively as R8 itself ( Lebedev et al, 2019 ).…”

“…Muscle relaxant activity mediated by controlled muscle nAChR inhibition ( Shelukhina et al, 2018 ) may be profitable in complex analgesic therapy, but excessive affinity to muscle nAChR may lead to paralysis as in the case of the selective snake α-neurotoxins or α-conotoxins. Potentiation of α7 nAChR is beneficial in chronic pain, mostly by alleviating neuroinflammation ( Zhou et al, 2022 ; Shelukhina et al, 2023 ), therefore, it is necessary to control its inhibition, which may lead to the opposite effect in vivo .…”

α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

“…The expression of α7 nAChR along pain transmission pathways has been known for a long time (reviewed in [ 177 ]). Moreover, the protein level of α7 nAChR is significantly downregulated in the sciatic nerve, dorsal root ganglion (DRG) and spinal cord in animal pain models of different etiology, providing a cellular and molecular basis for the known alleviation of chronic pain, including neuropathic pain, inflammatory pain and cancer-induced bone pain owing to activation or positive modulation of α7 nAChR (reviewed in [ 178 ]). Consistent with this was the observed decrease in the expression of α7 and β2 nAChR in the spinal cord and midbrain periaqueductal gray of hyperalgesic rats, which was reversed by analgesic electroacupuncture stimulation [ 179 ].…”

“…Potentially, not only homopentameric α7 but also heteromeric α7β2 nAChRs might be involved in pain regulation. There are some excellent recent reviews about the role of α7 nAChR and its specific ligands in pain modulation [ 177 , 178 , 180 ]. In this article, we are going to briefly review the newest tendencies and studies published in this field in the last two years.…”

“…Potent antinociceptive effects have been shown for α7 nAChR-targeting full, partial and silent agonists and positive allosteric modulators (reviewed in [ 177 , 178 , 180 ]). However, there is a tendency toward the reconsideration of the subtype-specificity of compounds acting on nAChRs.…”