Neuronal Nitric Oxide Synthase Suppression Confers the Prolonged Analgesic Effect of Sciatic Nerve Block With Perineural Dexamethasone in Postoperative Pain Model Mice.

Dexamethasone supplementation to local anesthetics prolongs its action, yet the underlying mechanism is unclear. Previous studies have reported that increased p-p38 mitogen-activated protein kinase (MAPK) in the dorsal root ganglia (DRG) is associated with pain-associated behavior and that nitric oxide (NO), which is known to be a pronociceptive substance, directly inhibits sciatic nerve conduction. Here, we investigated the temporal changes in the hyperalgesic effect and p-p38 MAPK and NO synthase (NOS) expression levels in the DRG when dexamethasone was added to ropivacaine used for a sciatic nerve block (SNB) in postoperative pain model mice. Dexamethasone supplementation to ropivacaine significantly prolonged the analgesic effect of SNB via glucocorticoid receptor activation. Histological examination revealed that ropivacaine suppressed p-p38 MAPK expression in the DRG regardless of dexamethasone supplementation, suggesting that p-p38 MAPK was not involved in the prolonging effect of dexamethasone on nerve block. Contrastingly, plantar incision markedly increased the expression of neuronal NOS (nNOS) in DRG, and dexamethasone supplementation to ropivacaine significantly suppressed nNOS expression. Supplementation of L-NAME, an inhibitor of NOS, to ropivacaine markedly prolonged the effect of SNB, similar to dexamethasone. These results suggest that dexamethasone supplementation to local anesthetics prolongs the analgesic effect by inhibiting nNOS activity. PERSPECTIVE: The current study revealed that dexamethasone supplementation to local anesthetics prolongs the analgesic effect by inhibiting the activity of neuronal NOS and that p-p38 MAPK may not be involved in this phenomenon. Our findings offer a new target for the discovery of long-acting local anesthetics.

Differential effects in CGRPergic, nitrergic, and VIPergic myenteric innervation in diabetic rats supplemented with 2% L-glutamine.

The objective of this study was to investigate the effects of 2% L-glutamine supplementation on myenteric innervation in the ileum of diabetic rats, grouped as follows: normoglycemic (N); normoglycemic supplemented with L-glutamine (NG); diabetic (D); and diabetic supplemented with L-glutamine (DG). The ileums were subjected to immunohistochemical techniques to localize neurons immunoreactive to HuC/D protein (HuC/D-IR) and neuronal nitric oxide synthase enzyme (nNOS-IR) and to analyze varicosities immunoreactive to vasoactive intestinal polypeptide (VIP-IR) and calcitonin gene-related peptide (CGRP-IR). L-Glutamine in the DG group (i) prevented the increase in the cell body area of nNOS-IR neurons, (ii) prevented the increase in the area of VIP-IR varicosities, (iii) did not prevent the loss of HuC/D-IR and nNOS-IR neurons per ganglion, and (iv) reduced the size of CGRP-IR varicosities. L-Glutamine in the NG group reduced (i) the number of HuC/D-IR and nNOS-IR neurons per ganglion, (ii) the cell body area of nNOS-IR neurons, and (iii) the size of VIP-IR and CGRP-IR varicosities. 2% L-glutamine supplementation exerted differential neuroprotective effects in experimental diabetes neuropathy that depended on the type of neurotransmitter analyzed. However, the effects of this dose of L-glutamine on normoglycemic animals suggests there are additional actions of this beyond its antioxidant capacity.