Traumatic brain injury (TBI) today remains a major health and social problem for both developed and developing countries. It is the leading cause of death and disability under the age of 40, and despite the significance of this public health problem, no effective therapy exists. While a number of factors have been shown to be associated with the development of irreversible tissue injury after TBI, the formation of oedema and opening of the blood brain barrier (BBB) have been shown to be of major significance to outcome. Oedema formation in the brain, when left uncontrolled, results in increased intracranial pressure that may lead to a decrease in brain tissue perfusion, localised hypoxia and ischemia, and ultimately tissue herniation and death. The mechanisms associated with the development of oedema are largely unclear, and accordingly, current therapies are generally ineffective, often resulting in dehydration, hypotension and renal problems. This thesis describes the characterisation of neurogenic inflammation in the development of post-traumatic brain oedema and functional deficits, and particularly the role of substance P (SP) in mediating their development, using rodent models of both focal and diffuse TBI. Results from this thesis demonstrate that increased SP immunoreactivity, particularly at the level of the vasculature, is a ubiquitous feature of TBI implying a potential role in the breakdown of the blood brain barrier (BBB) following TBI. This was confirmed through the use of the NK[subscript 1] receptor antagonists, which attenuated BBB and oedema formation as well as deleterious morphological events such as dark cell change and axonal injury. The NK[subscript 1] receptor antagonists also resulted in an associated improvement in both motor and cognitive deficits, as assessed using a battery of functional outcome tests. Possible mechanisms of action of the NK[subscript 1] receptor antagonist included effects on the BBB, SP release, intracellular free magnesium concentration and aquaporin-4 channels. Neuroprotection could be facilitated with administration of a non-lipid permeable NK[subscript 1] receptor antagonist in the immediate postinjury period, or up to 12 h after TBI with a lipid permeable NK[subscript 1] receptor antagonist, suggesting that this class of drugs have a clinically viable therapeutic window. We conclude that SP has a significant role in the secondary injury process following TBI and may offer a novel target for the development of interventional pharmacological strategies. / Thesis (Ph.D.)--School of Medical Sciences, 2006.

¡iAbstract¡j Neurogenic inflammation can be initiated by activation of sensory nerves to release neuropeptides, including tachykinins and calcitonin gene-related peptide. Capsaicin stimulation induces the release of substance P, the most important tachykinin and other neurotransmitters from sensory nerves to cause an increase of plasma leakage via the binding of substance P to NK1 receptors on endothelial cells. It has been proven that hyperthermic pretreatment decreases microvascular protein leakage and attenuates hypotension in anaphylactic shock in rats. Heat shock proteins¡]HSPs¡^are families of phylogenetically conserved molecules that have a protective role in all living cells under stress . Heat shock proteins are induced by whole-body hyperthermia and persist for 6 days. To establish the relationship between heat shock and neurogenic inflammation, the present study investigated whether whole-body hyperthermia pretreatment, at 42 ¢J for 15 min in rats 1 day earlier, could suppress inflammatory response in the lower airways and esophagus evoked by capsaicin (90 µg/ml/kg) or substance P (3 µg/ml/kg ). The magnitude of neurogenic inflammation in the trachea and bronchi was expressed by the area density of India ink-labeled leaky blood vessels in the airway mucosa. One day after heat shock pretreatment, capsaicin-evoked inflammation was reduced by one half to two thirds, and reduced substance P-evoked inflammation by one third. Six days after exposure to heat shock, neurogenic inflammation was not inhibited. HSPs appeared overexpressed in trachea and esophagus tissue in the rats one day after hyperthermia, but was less expressed 6 days after hyperthermia. It is suggested that exposure of the rats to whole-body hyperthermia caused an increased production of HSPs that might influence the affinity of the binding of substance P to NK1 receptors on venule endothelial cells, and reduce the amount of neurogenic plasma leakage.

Anxiety disorders, including social anxiety disorder (SAD) and posttraumatic stress disorder (PTSD) are common and disabling conditions. Largely based on animal and pharmacological studies, both the serotonergic and substance P/neurokinin-1 (SP/NK1) systems have been implicated in their underlying pathology. However, only few neuroimaging studies have directly assessed these neurotransmitter systems in human sufferers of anxiety disorders, and none have addressed possible between-systems relationships. The overall aim of this thesis was to study possible neurochemical alterations associated with anxiety disorders. To this end, three studies using positron emission tomography (PET) for in-vivo imaging of the brain serotonergic and SP/NK1 systems in patients with SAD and PTSD were conducted. The radiotracers [11C]5-HTP, [11C]DASB, and [11C]GR205171 were used to index serotonin synthesis rate, serotonin transporter (SERT) availability, and NK1 receptor availability respectively. In Study I, patients with SAD relative to controls exhibited enhanced serotonin synthesis rate and serotonin transporter availability. Serotonin synthesis rate in the amygdala was positively related to social anxiety symptom scores. Study II demonstrated increased NK1 receptor availability in the amygdala in patients with SAD relative to controls. In Study III, patients with PTSD showed elevated NK1 receptor availability in the amygdala as compared to controls. SERT availability in the amygdala was negatively related to PTSD symptom severity, a relationship that was moderated by NK1 receptor levels. The regional overlap between SERT and NK1 receptor expression was altered in patients with PTSD, with reduced overlap linked to more severe symptoms. Collectively, the findings are consistent with the view that serotonin in the amygdala induces rather than reduces anxiety and links exaggerated anxiety to an overactive presynaptic serotonin system. In addition, the involvement of the SP/NK1 system in stress and anxiety, as suggested by animal studies, was demonstrated in two common human anxiety disorders. Finally, PTSD symptomatology is better accounted for by interactions between the serotonergic and SP/NK1 systems in the amygdala than by each system separately. In conclusion, this thesis supports that both the serotonergic and SP/NK1 systems in and of themselves, but also interactively, may be important contributors to anxiety symptomatology.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 5 uppsatser.

No description available.

Release of substance P-like immunoreactivity (SP-LI) was measured from isolated perfused guinea-pig hearts. Capsaicin (1 μM) caused a substantial increase in the amount of SP-LI detected in perfusate compared to values during exposure to vehicle or drug-free buffer. Tachyphylaxis developed to the effect of capsaicin on release of SP-LI and to its effect on physiological parameters. These data show SP-LI can be released from cardiac sensory nerves and suggest SP could mediate a portion of the response of the isolated heart to capsaicin.

No / Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT3) antagonist and a corticosteroid. The neurokinin-1 (NK1) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT3 antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK1 antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT3 antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK1 antagonist occurred within the first 8¿12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT3 antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8¿12 h following cisplatin-based chemotherapy, after which time substance P acting at NK1 receptors becomes the dominant mediator of vomiting.

Chronic pain is a major healthcare concern that directly affects over one hundred million people in the United States alone. While current treatment options like opioids and NSAIDs are effective, they are with significant drawbacks that prevent long term use. It is important to identify and understand new druggable targets for the treatment of pain. Recent findings have demonstrated substance P functions in the RVM to maintain hypersensitivity to noxious heat stimuli in models of persistent peripheral inflammatory injury in a manner dependent on presynaptic NMDA receptors. What remains unclear is how substance P assumes this pronociceptive role following peripheral inflammatory injury. The experiments detailed in this thesis investigated whether the levels and or release of substance P in the RVM was altered following peripheral inflammatory injury. The effect of peripheral inflammatory injury on levels of substance P in the RVM was tested at several time points. The data show that there were no changes in substance P levels in the ipsilateral or contralateral RVM of CFA injected rats compared to their saline controls at any of the time points tested. To assess whether changes in substance P levels occurred in a subset of neurons within the RVM, computer aided densitometry analysis was used to measure substance P immunoreactivity in sections from the RVM of rats treated with CFA or saline. Substance P immunoreactivity was increased in the ipsilateral RVM of the CFA group compared to the corresponding saline sections at the 4 day, but not the 2 week time point. No other changes were observed. Electron microscopy was used to demonstrate the presence of the NMDA receptor and substance P on the same axon terminals within the RVMs of rats treated with either CFA or saline. This colocalization is significant because it identifies NMDA receptors in position to regulate the release of substance P from axon terminals in the RVM. There were no obvious differences in the degree of colocalization between CFA and saline groups. Functional experiments were devised that tested whether substance P release (basal and evoked) in the RVM was increased following peripheral inflammatory injury, and whether said release was regulated by NMDA receptors. The data show that neither basal nor evoked (potassium or veratridine) release was increased following peripheral inflammatory injury. NMDA was able to facilitate the release of substance P in both the CFA and saline treatment groups, but the facilitation was not different between groups. In the absence of any depolarization stimulus, NMDA was unable to elicit any release of substance P beyond basal values. All told, the data show substance P levels in the RVM are not altered by peripheral inflammatory injury. Additionally, neither basal nor evoked release of substance P is altered by peripheral inflammatory injury. The data provide functional and anatomical evidence for modulation of substance P release by glutamate acting at presynaptic NMDA receptors, but do not support the idea of differential modulation of substance P release following peripheral inflammatory injury.

Bibliography: leaves 180-199. / xvii, 199, [68] leaves, [1] leaf of plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Primary aim was to determine whether levels of the endogenous peptide substance P (SP) would parallel and reflect the reported increased levels of the trophic agent nerve growth factor which is associated with the development of sympathetic hyperinnervation (and ultimately hypertension) in the genetic animal model for hypertension, the spontaneously hypertensive rat. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1995

Effects of spantide ([D-Arg1,D-Trp7,9,Leu11]substance P) on coronary resistance vessels were studied in isolated guinea pig hearts perfused at constant rate with isotonic buffer containing 20 or 40 mM KCl. Spantide (1 μM) caused a 20-fold rightward shift of the substance P (SP) dose-response curve for vasodilation with no change in maximum (KB=5.3×10-8 M). Bolus injections of 0.25 to 250 pmol spantide had no effect, but higher doses caused a brief vasodilation followed by a larger, more prolonged vasoconstriction. Histamine produced similar changes in perfusion pressure. Antihistamines (H1 and H2) reduced or blocked responses to spantide and histamine. These findings indicate spantide is a competitive antagonist to SP in guinea pig coronary resistance vessels. In addition, high doses of spantide can cause prominent vascular effects which are mediated by histamine.