Systemic Administration of an Alpha-7 Nicotinic Acetylcholine Agonist Reverses Neuropathic Pain in Male Sprague Dawley Rats

Abstract

Alpha-7 nicotinic acetylcholine receptor (α7 nAChR) agonists attenuate pain and inflammation in preclinical models. This study tested whether systemic delivery of an α7 nAChR agonist attenuates neuropathic pain and associated immune-mediated pro-inflammation. Hind paw response thresholds to mechanical stimuli in male Sprague Dawley rats were assessed before and after sciatic chronic constriction injury (CCI) or sham surgery. Osmotic mini-pumps containing TC-7020, an α7 nAChR selective agonist, were implanted 10 to 14 days after surgery. TC-7020 (1, 3, and 10 mg/kg/d; s.c.) significantly attenuated CCI-induced allodynia, which lasted through 2 weeks of test compound administration. Spinal cords were collected after 2 weeks and processed for microglial and astrocyte activation markers within the ipsilateral L4-L6 dorsal horn. In addition, ipsilateral L4-5 dorsal root ganglia (DRGs) were processed for neuronal injury and satellite cell activation markers. CCI-induced central glial cell activation markers were not suppressed by TC-7020, even though TC-7020 is mildly blood-brain barrier permeable. However, TC-7020 downregulated the integrated density of activation transcription factor 3 (ATF3) but not the number of ATF positive cells. TC-7020 also downregulated phosphorylated extracellular signal kinase (p-ERK) and satellite cell activation in the CCI-affected DRGs. Therefore, systemic α7 nAChR agonist may be effective in treating neuropathic pain via reducing neuronal injury and immune cells activation occurring in the periphery. Perspective These studies demonstrated that TC-7020, an alpha7 nicotinic acetylcholine receptor agonist with partial blood-brain barrier permeability, reversed neuropathic pain in rats, likely via attenuation of inflammation in the DRG and/or the site of sciatic injury.

Biological phenotypes underpin the physio‐somatic symptoms of somatization, depression, and chronic fatigue syndrome

“…Finally, KYNA modulates the expression of receptors in the brain that are implicated in perception, cognition, and emotion, including the a4b2 nicotinic acetylcholine receptor and a7-nAChRs (143)(144)(145). The a7-nAChRs also has a role in pain regulation (146) and the a7-nAChRs levels and activity are significantly modulated by melatonin (147), the levels of which will be decreased by IDO and TDO induction of TRYCATs. As well as having circadian, antioxidant and anti-inflammatory effects, melatonin also has antinociceptive effects, suggesting that decreased melatonin will have direct impacts on nociceptive processing, as well as indirect effects via a7-nAChRs levels.…”

α-Conotoxin RgIA protects against the development of nerve injury-induced chronic pain and prevents both neuronal and glial derangement

“…Among nAChR subtypes, the α homopentamer has been implicated in neuroprotective processes [31]. In a trauma-induced model of neuropathic pain, selective activation of α7 nAChRs decreased pain perception, preserved peripheral nerve architecture and reduced degeneration and inflammation [44,37]. Furthermore, α4β2 agonists showed antinociceptive properties in different animal models of acute and chronic neuropathic pain [3].…”

Interactions of (2S,6S;2R,6R)‐Hydroxynorketamine, a Secondary Metabolite of (R,S)‐Ketamine, with Morphine

“…However, in other studies, activation of the mTOR pathway has been linked to the development of opioid tolerance and hyperalgesia [36,37]. Interestingly, a7-nACh receptor agonists have shown efficacy in pre-clinical models of neuropathic pain [38,39] and remifentanil-induced hyperalgesia [40] by reducing the release of glial pro-inflammatory cytokines. Finally, recent studies exploring the mechanisms of 6-hydroxynorketamine-induced antidepressive actions show that 6-hydroxynorketamine may indirectly increase excitatory a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor glutamatergic signalling [17,41].…”