Excitatory and inhibitory neuronal signaling in inflammatory and diabetic neuropathic pain

**Background:** Pain is an essential protective mechanism mediated by specialized nociceptors and complex signaling networks. This narrative review covers the molecular mechanisms of nociception, including peripheral and central sensitization, the roles of glial cells, and the balance between excitatory and inhibitory neurotransmission in pain modulation. A particular focus is on diabetes-associated neuropathic pain and the potential involvement of glycine receptors.

**Methods:** This is a narrative review synthesizing published literature on pain signaling pathways, with emphasis on inflammatory and neuropathic pain, diabetes-associated neuropathy, and the roles of excitatory (glutamatergic) and inhibitory (GABAergic and glycinergic) neurotransmission. The authors discuss receptor systems (Table 1), glial cell types (microglia, astrocytes, satellite glial cells), and intracellular signaling cascades.

**Key Results:** The review reports that diabetes affected 9.3% of the world's adult population in 2019, with projections for further increase. Around one third of patients with diabetic neuropathy report intermittent or continuous paresthesia and/or pain. Treatment-induced neuropathy in diabetes (TIND) occurs in approximately 10.9% of diabetic patients, with onset typically within 2–6 weeks of glycemic improvement. The authors describe that glucose and related sugars are positive modulators of recombinant α1-, α1/β-, and α3/β glycine receptors, with potentiation observed between 5.5 mM (90 mg/dl, no effect) and 10 mM (180 mg/dl, maximum effect) blood glucose. In a murine model of strychnine-induced pain, elevated glucose levels reduced touch sensitivity and relieved allodynia and heat hypersensitivity. The review notes that astrocytes and microglia account for approximately 30–61% and 6–9% of all glial cells in the human brain, respectively. A single astrocyte can oversee approximately 140,000 synapses. Microglial activation involves upregulation of markers such as CCR3/CD11b and IBA1, and involves MAP kinase pathways (ERKs, p38, JNK). The gap between SGC sheath and neuronal plasma membrane is only 20 nm, enabling effective signaling. SGC activation after nerve injury is very fast (~4 h), peaks at one week, and declines after three weeks. The review describes that PGE2 induces PKA-dependent phosphorylation of GlyR α3, reducing GlyR activity, and that GlyR α3β subunits are important mediators of glycinergic inhibitory neurotransmission in nociceptive circuits of the spinal dorsal horn. Intrathecal strychnine (GlyR antagonist) causes profound agitation and hypersensitization. The GABA_B receptor antagonist CGP35348 induced mechanical hypersensitivity in naïve rats, while the agonist baclofen reduced hyperalgesia in neuropathic rats.

**Clinical Implications:** The review highlights the complexity of pain signaling in diabetes, where both hyperglycemia (via chronic inflammation and upregulation of voltage-gated sodium channels) and hypoglycemia (as in TIND) can cause pain. The glycinergic system offers advantages over GABAergic targets for analgesic development, as GABA receptors are widely expressed throughout the nervous system leading to sedation side effects. The discovery of a novel potentiating site near the N-terminus of the GlyR protein targeted by a new class of analgesics is noted. Inhibition of GlyT2 glycine transporters alleviates chronic but not acute pain. The authors suggest that direct modification of nociceptive signaling by elevated blood glucose concentrations may be worth considering in clinical management of diabetes. The review concludes that increasing molecular understanding of pain signaling devices, transmitters, and modulators is the basis for developing more selective therapies targeting individual nociceptive pathways.