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Acute and delayed restraint stress-induced changes in nitric oxide producing neurons in limbic regions.
Neuroscience. 2004; 125(4):981-93.N

Abstract

RATIONALE

Microinjection into the dentate gyrus of the hippocampus of N(omega)-nitro-l-arginine methyl ester hydrochloride (l-NAME), a nitric oxide synthase (NOS) inhibitor, induces antinociceptive effect 5 days after a single restraint episode. The mechanisms of this stress-antinociceptive modulatory effect have not been investigated but may involve plastic changes in the hippocampal formation (HF).

OBJECTIVE

The objective of the present study was to investigate possible mechanisms of the stress-modulating effect on antinociception induced by NOS inhibition in the hippocampus. We analyzed the effects of restraint stress on neuronal NOS (nNOS) expression and nicotinamide adenine dinucleotide phosphate-diaphorase histochemical activity (NADPH-d) in the HF and related brain regions.

METHODS

Male Wistar rats (n=6-11/group) were submitted to a single (acute stress) or repeated (5 days) episodes of 2-h restraint. Control animals remained in their home cages being all animals daily handled during this period. In the fifth day, animals received unilateral microinjection of l-NAME (150 nmol/0.2 microl) or saline (control) into the dentate gyrus of the dorsal hippocampus (DG). Immediately before and after drug microinjection tail-flick reflex latency or hotplate licking reaction was measured. Animals were killed i. immediately; ii. 5 days after acute stress; or iii. after repeated stress. NADPH-d and nNOS expression were quantified in the HF, caudate-putamen, secondary somatosensorial, entorhinal and piriform cortices and amygdaloid complex.

RESULTS

Five days after one or five restraint episodes l-NAME microinjection into the DG elicited antinociceptive effect (analysis of variance [ANOVA], P<0.05). Acute restraint stress induced a significant increase in the density of neurons expressing NADPH-d and nNOS in the amygdaloid nuclei. nNOS expression increased also in the DG and piriform cortex. Five days after a single or repeated restraint stress there was an additional increase in NADPH-d- and nNOS-positive neurons in CA1, CA3, and entorhinal cortex. No changes were seen in non-limbic regions such as the caudate-putamen and secondary somatosensorial cortex.

CONCLUSION

The results confirm that the dorsal hippocampus participates in the modulation of stress consequences. They also show that a single stress episode causes acute changes in nitric oxide system in the amygdala complex and delayed modifications in the HF. The delayed (5 days) antinociceptive effect of NOS inhibition in the HF after a single restraint episode suggests that those latter modifications may have functional consequences. It remains to be tested if the acute amygdala and delayed hippocampal changes are causally related.

Authors+Show Affiliations

Department of Pharmacology, Medical School, Campus USP, Ribeirão Preto, SP, Brazil.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15120858

Citation

Echeverry, M B., et al. "Acute and Delayed Restraint Stress-induced Changes in Nitric Oxide Producing Neurons in Limbic Regions." Neuroscience, vol. 125, no. 4, 2004, pp. 981-93.
Echeverry MB, Guimarães FS, Del Bel EA. Acute and delayed restraint stress-induced changes in nitric oxide producing neurons in limbic regions. Neuroscience. 2004;125(4):981-93.
Echeverry, M. B., Guimarães, F. S., & Del Bel, E. A. (2004). Acute and delayed restraint stress-induced changes in nitric oxide producing neurons in limbic regions. Neuroscience, 125(4), 981-93.
Echeverry MB, Guimarães FS, Del Bel EA. Acute and Delayed Restraint Stress-induced Changes in Nitric Oxide Producing Neurons in Limbic Regions. Neuroscience. 2004;125(4):981-93. PubMed PMID: 15120858.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acute and delayed restraint stress-induced changes in nitric oxide producing neurons in limbic regions. AU - Echeverry,M B, AU - Guimarães,F S, AU - Del Bel,E A, PY - 2003/12/29/accepted PY - 2004/5/4/pubmed PY - 2004/8/3/medline PY - 2004/5/4/entrez SP - 981 EP - 93 JF - Neuroscience JO - Neuroscience VL - 125 IS - 4 N2 - RATIONALE: Microinjection into the dentate gyrus of the hippocampus of N(omega)-nitro-l-arginine methyl ester hydrochloride (l-NAME), a nitric oxide synthase (NOS) inhibitor, induces antinociceptive effect 5 days after a single restraint episode. The mechanisms of this stress-antinociceptive modulatory effect have not been investigated but may involve plastic changes in the hippocampal formation (HF). OBJECTIVE: The objective of the present study was to investigate possible mechanisms of the stress-modulating effect on antinociception induced by NOS inhibition in the hippocampus. We analyzed the effects of restraint stress on neuronal NOS (nNOS) expression and nicotinamide adenine dinucleotide phosphate-diaphorase histochemical activity (NADPH-d) in the HF and related brain regions. METHODS: Male Wistar rats (n=6-11/group) were submitted to a single (acute stress) or repeated (5 days) episodes of 2-h restraint. Control animals remained in their home cages being all animals daily handled during this period. In the fifth day, animals received unilateral microinjection of l-NAME (150 nmol/0.2 microl) or saline (control) into the dentate gyrus of the dorsal hippocampus (DG). Immediately before and after drug microinjection tail-flick reflex latency or hotplate licking reaction was measured. Animals were killed i. immediately; ii. 5 days after acute stress; or iii. after repeated stress. NADPH-d and nNOS expression were quantified in the HF, caudate-putamen, secondary somatosensorial, entorhinal and piriform cortices and amygdaloid complex. RESULTS: Five days after one or five restraint episodes l-NAME microinjection into the DG elicited antinociceptive effect (analysis of variance [ANOVA], P<0.05). Acute restraint stress induced a significant increase in the density of neurons expressing NADPH-d and nNOS in the amygdaloid nuclei. nNOS expression increased also in the DG and piriform cortex. Five days after a single or repeated restraint stress there was an additional increase in NADPH-d- and nNOS-positive neurons in CA1, CA3, and entorhinal cortex. No changes were seen in non-limbic regions such as the caudate-putamen and secondary somatosensorial cortex. CONCLUSION: The results confirm that the dorsal hippocampus participates in the modulation of stress consequences. They also show that a single stress episode causes acute changes in nitric oxide system in the amygdala complex and delayed modifications in the HF. The delayed (5 days) antinociceptive effect of NOS inhibition in the HF after a single restraint episode suggests that those latter modifications may have functional consequences. It remains to be tested if the acute amygdala and delayed hippocampal changes are causally related. SN - 0306-4522 UR - https://www.unboundmedicine.com/medline/citation/15120858/Acute_and_delayed_restraint_stress_induced_changes_in_nitric_oxide_producing_neurons_in_limbic_regions_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306452204001216 DB - PRIME DP - Unbound Medicine ER -