Potentiation of the Glycine Response by Bisphenol A, an Endocrine Disrupter, on the Substantia Gelatinosa Neurons of the Trigeminal Subnucleus Caudalis in Mice.

Lamina II, also called the substantia gelatinosa (SG) of the medullary dorsal horn (the trigeminal subnucleus caudalis, Vc), is thought to play an essential role in the control of orofacial nociception because it receives the nociceptive signals from primary afferents, including thin myelinated Aδ- and unmyelinated C-fibers. Glycine, the main inhibitory neurotransmitter in the central nervous system, plays an essential role in the transference of nociceptive messages from the periphery to higher brain regions. Bisphenol A (BPA) is reported to alter the morphological and functional characteristics of neuronal cells and to be an effector of a great number of ion channels in the central nervous system. However, the electrophysiological effects of BPA on the glycine receptors of SG neurons in the Vc have not been well studied. Therefore, in this study, we used the whole-cell patch-clamp technique to determine the effect of BPA on the glycine response in SG neurons of the Vc in male mice. We demonstrated that in early neonatal mice (0-3 postnatal day mice), BPA did not affect the glycine-induced inward current. However, in the juvenile and adult groups, BPA enhanced the glycine-mediated responses. Heteromeric glycine receptors were involved in the modulation by BPA. The interaction between BPA and glycine appears to have a significant role in regulating transmission in the nociceptive pathway.

Potentiation of the glycine response by serotonin on the substantia gelatinosa neurons of the trigeminal subnucleus caudalis in mice.

The lamina II, also called the substantia gelatinosa (SG), of the trigeminal subnucleus caudalis (Vc), is thought to play an essential role in the control of orofacial nociception. Glycine and serotonin (5-hydroxytryptamine, 5-HT) are the important neurotransmitters that have the individual parts on the modulation of nociceptive transmission. However, the electrophysiological effects of 5-HT on the glycine receptors on SG neurons of the Vc have not been well studied yet. For this reason, we applied the whole-cell patch clamp technique to explore the interaction of intracellular signal transduction between 5-HT and the glycine receptors on SG neurons of the Vc in mice. In nine of 13 neurons tested (69.2%), pretreatment with 5-HT potentiated glycine-induced current (IGly). Firstly, we examined with a 5-HT1 receptor agonist (8-OH-DPAT, 5-HT1/7 agonist, co-applied with SB-269970, 5-HT7 antagonist) and antagonist (WAY-100635), but 5-HT1 receptor agonist did not increase IGly and in the presence of 5-HT1 antagonist, the potentiation of 5-HT on IGly still happened. However, an agonist (α-methyl-5-HT) and antagonist (ketanserin) of the 5-HT2 receptor mimicked and inhibited the enhancing effect of 5-HT on IGly in the SG neurons, respectively. We also verified the role of the 5-HT7 receptor by using a 5-HT7 antagonist (SB-269970) but it also did not block the enhancement of 5-HT on IGly. Our study demonstrated that 5-HT facilitated IGly in the SG neurons of the Vc through the 5-HT2 receptor. The interaction between 5-HT and glycine appears to have a significant role in modulating the transmission of the nociceptive pathway.

Enhanced GABA action on the substantia gelatinosa neurons of the medullary dorsal horn in the offspring of streptozotocin-injected mice.

Peripheral neuropathy is a frequent complication of diabetes mellitus and a common symptom of neuropathic pain, the mechanism of which is complex and involves both peripheral and central components of the sensory system. The lamina II of the medullary dorsal horn, called the substantia gelatinosa (SG), is well known to be a critical site for processing of orofacial nociceptive information. Although there have been a number of studies done on diabetic neuropathy related to the orofacial region, the action of neurotransmitter receptors on SG neurons in the diabetic state is not yet fully understood. Therefore, we used the whole-cell patch clamp technique to investigate this alteration on SG neurons in both streptozotocin (STZ)-induced diabetic mice and offspring from diabetic female mice. STZ (200 mg/kg)-injected mice showed a small decrease in body weight and a significant increase in blood glucose level when compared with their respective control group. However, application of different concentrations of glycine, gamma-aminobutyric acid (GABA) and glutamate on SG neurons from STZ-injected mice did not induce any significant differences in inward currents when compared to their control counterparts. On the other hand, the offspring of diabetic female mice (induced by multiple injections of STZ (40 mg/kg) for 5 consecutive days) led to a significant decrease in both body weight and blood glucose level compared to the control offspring. Glycine and glutamate responses in the SG neurons of the offspring from diabetic female mice were similar to those of control offspring. However, the GABA response in SG neurons of offspring from diabetic female mice was greater than that of control offspring. Furthermore, the GABA-mediated responses in offspring from diabetic and control mice were examined at different concentrations ranging from 3 to 1,000 µM. At each concentration, the GABA-induced mean inward currents in the SG neurons of offspring from diabetic female mice were larger than those of control mice. These results demonstrate that SG neurons in offspring from diabetic mice are more sensitive to GABA compared to control mice, suggesting that GABA sensitivity may alter orofacial pain processing in offspring from diabetic female mice.