Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model

Abstract

The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP.

ErbB4 in Spinal PV Interneurons Regulates Mechanical Allodynia in Neuropathic Pain via Modulation of Glycinergic Inhibitory Tone

“…12 Consistently, a recent study found that increasing cerebrospinal fluid glycine content by applying glycine transporter inhibitors results in an obvious antiallodynic effect in a rat model of neuropathic pain, indicating an important role for glycine in the regulation of mechanical allodynia. 33,34 Activation of ErbB4 by NRG1 has been shown to increase AMPAR endocytosis in hippocampal neurons. 20 Furthermore, previous studies have indicated that AMPAR endocytosis-mediated long-term depression is involved in spinal glycinergic neuron-mediated disinhibition.…”

Shedding Light on the Pharmacological Interactions between μ-Opioid Analgesics and Angiotensin Receptor Modulators: A New Option for Treating Chronic Pain

“…Taken together, in cases of acute or inflammatory pain types, opioid analgesics can provide adequate pain control, which is somewhat hampered by above mentioned unwanted effects. However, in the case of neuropathic pain, the desired analgesia itself is often unachievable, consequently demanding dose-escalation, therefore causing more pronounced side effects (Figure 1A) (Karádi and Al-Khrasani, unpublished data) and (Figure 1B) (adopted from our previous work [16]). In each treatment group, 4-7 animals were used.…”

“…In each treatment group, 4-7 animals were used. These results were adopted from our previous work [16].…”

“…In the former case, for instance, applying opioid receptor ligands that display agonist and non-opioid effects, such as tapentadol, display both the MOR agonist and norepinephrine reuptake inhibitory effects in the same molecule [15]. Recently, our group reported on the promising effect of the combination of glycine transporter 1 and 2 inhibitors in the management of neuropathic pain evoked by sciatic nerve ligation [16]. In such a strategy, we need to consider how the individual drugs affect pain transmission.…”

“…Asterisks indicate the significant differences compared to the saline group (one-way ANOVA, Newman-Keuls post-hoc test; *** p < 0.001).In each treatment group, 4-7 animals were used. These results were adopted from our previous work[16].…”