Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by γ-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 μL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.

Prevención de adherencias peritoneales postoperatorias mediante uso de antagonista de receptores de neurokinina tipo 1 / Peritoneal adhesions prevention: neurokinin-1 receptor antagonist

Background: The fibrinolytic activity plays an important role in Peritoneal Adhesions (PA) develop-ment. It's well known that de substance P decreased the fibrinolysis by binding the neurokinin-1 receptor, improving the PA formation. Objectives: To evaluate the effectiveness of intraperitoneal treatment with a Neurokinin-1 receptor antagonist (NK-R1A) in peritoneal adhesión prevention in animal model. Materials and Methods: In 40 male wistar rats, PA were induced, and then randomly assigned to 2 groups: A group treated with Aprepitant (NK-Rl A), and a control group. The animals were killed at 7 or 14 postoperative day, and the number, severity and histopathology of PA were evaluated. Results: NK-Rl A decreased the number (40 percent less) and severity (p = 0.001) of PA when compare to control group. The NK-Rl A group had less PA in manipulated and no manipulated organs during surgery. Besides presented less fibrosis (p = 0.001), less inflamation (p = 0.005) and less vascular proliferation (p = 0.047) than control group. Conclusions: The NK-Rl A is effective as in PA prevention.

Introducción: La actividad fibrinolítica juega un papel fundamental en el desarrollo de las adherencias peritoneales (AP), y se conoce que la Sustancia P al actuar sobre receptores de neurokinina tipo 1 a nivel peritoneal, disminuye la fibrinólisis, favoreciendo la formación de las mismas. Objetivos: Evaluar la efectividad del tratamiento intraperitoneal con antagonista de receptores 1 de neurokinina (NK-R1A) en la prevención de AP en modelo animal. Materiales y Métodos: A 40 ratas wistar se les practicó cirugía formadora de AP y fueron distribuidas de forma aleatoria en 2 grupos, un grupo que recibió Aprepitant (NK-R1A), y el otro como grupo control. Los animales fueron sacrificados a los 7 ó 14 días, y se evaluó el número, severidad e histopatología de las AP. Resultados: El NK-Rl A disminuyó el número (40 por ciento menos) y severidad de las AP (p = 0,001) en relación al grupo control y presentó menos AP en órganos manipulados y no manipulados durante la cirugía. Ademßs presentó menor grado de fibrosis (p = 0,001), menor inflamación (p = 0,005) y menor proliferación vascular (p = 0,047) que el grupo control. Conclusión: El tratamiento peritoneal con NK-R1A es eficaz en la prevención de la formación de AP.

Antagonista de receptores de neurokinina tipo 1 versus ácido hialurónico/carboximetilcelulosa en la prevención de adherencias peritoneales postoperatorias: estudio experimental en modelo animal / Neurokinin 1 receptor antagonist versus hyaluronic acid-carboxymethylcellulose in the prevention of postoperative peritoneal adhesions: experimental study in biomodels

La actividad fibrinolítica juega un papel fundamental en el desarrollo de las adherencias peritoneales (AP), y se conoce que la sustancia P al actuar sobre receptores de neurokinina tipo 1 a nivel peritoneal, disminuyen la fibrinólisis, favoreciendo la formación de las mismas. La efectividad de antagonistas de estos receptores como tratamiento preventivo de AP, ha sido evaluada, obteniendose resultados favorables. Comparar la efectividad del tratamiento intraperitoneal con antagonista de receptores 1 de neurokinina (NK-RIA) versus gel de ácido hialurónico/carboximetilcelulosa (AH/CMC) en la prevención de AP en modelo animal. A 60 ratas Wistar se les practicó cirugía formadora de AP y fueron distribuidas de forma aleatoria en 3 grupos, un grupo que recibió aprepitant (NK_RIA), otro recibió gel de AH/CMC y un grupo control. Los animales fueron sacrificados a los 7 ó 14 días, y se evaluó el número, severidad e histopatología de las AP. Tanto el NK-RIA como el AC/CMC disminuyeron el número (40% y 38% respectivamente) y severidad de las AP (p=0,001 y p=0,029 rerspectivamente) en relación al grupo control, sin diferencias estadísticas entre ellos (p=0,806). El grupo de NK-RIA presentó menos AP en órganos no manipulados durante la cirugía en relación a los otros 2 grupos. Ambos tratamientos presentaron menor grado de fibrosis que el control, sin embargo el grupo de NK-RIA tuvo menor inflamación (P=0,005) y proliferación vascular (P=0,047) que el AH/CMC. El NK-RIA tiene alta eficacia previendo la formación de AP, equiparable a la gel de AH/CMC.

The fibrinolytic activity play an important role in the peritoneal adhesions (PA) development. It’s well known that of substance P decreased the fibrinolysis by binding the neurokinin-1 receptor, improving the PA formation. Lot of investigation have evaluated the efficacy in PA prevention of antagonist of these receptors, with very good result. To compare the effectivences of intraperitoneal treatment with a neurokin-1 receptor antagonist (NK-RIA) versus hyaluronic acid/carboxymethylcellulose (HA/CMC) gel, in peritoneal adhesion prevention in animal model. In 60 male Wistar rats, PA were induced, and then randomly assigned to 3 groups. A group treated with aprepitant (NK-RIA), a second group treated with HH/CMC and a control group. The animals were killed at 7 or 14 postoperative day, and the number, severity and histopathology of PA were evaluated. NK-RIA and HA/CMC decreased the number (40% and 38% respectively) and severity (p=0,001 and p=0,029 respectively) of PA when compare to control group. The NKRIA group had less PA in no manipulated organs in surgery that the others 2 groups. Both treatments presented less fibrosis that control, however the NK-RIA group presented less inflammation (p=0,005) and vascular proliferation (p=0,047) than HA/CMC group. The NK-RIA is as effective as HC/CMC in preventing PA.

Aprepitant: a substance P antagonist for chemotherapy induced nausea and vomiting.

The episodes of nausea and vomiting which follow each cycle of chemotherapy are the most troublesome side effect experienced by cancer patients. Introduction of ondansetron was a definite therapeutic advance in treating chemotherapy induced nausea and vomiting (CINV) with more effectiveness with corticosteroids. However, the protection remained largely limited to acute phase of CINV with little or no effect over delayed phase. Aprepitant, a drug that antagonizes the effect of substance P on neurokinin type 1 receptor showed promising results in controlling both phases of CINV. This drug is well absorbed orally with a t max of about four hours. The addition of aprepitant to ondansetron and dexamethasone was found to be superior to ondansetron and dexamethasone alone in clinical trials with patients taking high and moderate emetogenic chemotherapy. This drug also showed a good safety profile, but its inhibitory effect on CYP3A4 may result in clinically significant drug interactions needing dose modifications of co-administered drugs. The National Comprehensive Cancer Network guidelines for CINV recommends the use of aprepitant with high and moderately emetogenic anticancer drugs. Results of ongoing clinical trials with aprepitant and other agents of this new class of antiemetics are awaited and may alleviate the sufferings of cancer patients.

Pharmacologic characteriztion of bronchospasm induced by substance P [SP] and SP fragments in guinea - pig

Using pharmacologic approach, neurokinin receptor-mediated bronchoconstrictor responses in anesthetized guinea-pigs was characterized. Thus, the bronchospastic effects of substance P [SP] and SP fragments [all administrated intravenously] before and after giving vehicle or selective neurokinin receptor antagonists were compared. Ranking order of potency of SP or SP fragments for induction of bronchoconstriction was: SP4-11 >> SP5-11 = SP3-11 = SP2-11 > SP = SP6-11 [the number of amino acid in the sequence of SP fragments are shown by superscript]. The neurokinin 1 [NK1] receptor antagonists [CP 96,345 or CP 99,994, 3 mg kg-1, iv] did not change baseline values of pulmonary flow resistance [RL] and dynamic pulmonary elastance [EL] and did not eliminate bronchopulmonary responses to these peptides but decreased changes in RL and EL in response to SP and SP fragments. The neurokinin 2 [NK2] receptor antagonist SR 48,968 [1 mg kg-1, iv] failed to induce a rightward shift in dose-response curves to SP or SP fragments except to SP4-11. Combinations of NK1 and NK2 receptor antagonists shifted dose-response curves to SP and SP fragments more than that of NK1 receptor antagonists alone. These findings reveal that SP-induced bronchoconstriction is mediated by its C-terminal sequence and this response is mainly via NK1 receptors. Moreover, bronchopulmonary responses to SP and its C-terminal fragments are complex and there may be interactions between NK1 and NK2 receptors in the lungs

Blockade of NK-1 receptors in the lateral commissural nucleus tractus solitarii of awake rats had no effect on the cardiovascular responses to chemoreflex activation

The neurotransmission of the chemoreflex in the nucleus tractus solitarii (NTS), particularly of the sympatho-excitatory component, is not completely understood. There is evidence that substance P may play a role in the neurotransmission of the chemoreflex in the NTS. Microinjection of substance P (50 pmol/50 nl, N = 12, and 5 nmol/50 nl, N = 8) into the commissural NTS of unanesthetized rats produced a significant increase in mean arterial pressure (101 +/- 1 vs 108 +/- 2 and 107 +/- 3 vs 115 +/- 4 mmHg, respectively) and no significant changes in heart rate (328 +/- 11 vs 347 +/- 15 and 332 +/- 7 vs 349 +/- 13 bpm, respectively) 2 min after microinjection. Previous treatment with WIN, an NK-1 receptor antagonist (2.5 nmol/50 nl), microinjected into the NTS of a specific group of rats, blocked the pressor (11 +/- 5 vs 1 +/- 2 mmHg) and tachycardic (31 +/- 6 vs 4 +/- 3 bpm) responses to substance P (50 pmol/50 nl, N = 5) observed 10 min after microinjection. Bilateral microinjection of WIN into the lateral commissural NTS (N = 8) had no significant effect on the pressor (50 +/- 4 vs 42 +/- 6 mmHg) or bradycardic (-230 +/- 16 vs -220 +/- 36 bpm) responses to chemoreflex activation with potassium cyanide (iv). These data indicate that the activation of NK-1 receptors by substance P in the NTS produces an increase in baseline mean arterial pressure and heart rate. However, the data obtained with WIN suggest that substance P and NK-1 receptors do not play a major role in the neurotransmission of the chemoreflex in the lateral commissural NTS