Venomous bites and stings can cause a variety of reactions depending upon the source of the venom and the sensitivity of the individual or animal. In some cases, venom from a bite or sting can cause anaphylaxis, an immediate hypersensitivity which can be life-threatening. In other cases, certain venoms can cause cutaneous "local" reactions. Cutaneous local reactions can be characterized as 1) "non-allergic" reactions which are of limited size and duration or as 2) "allergic" or "large" local reactions which are typically larger in size and longer in duration. With regard to Hymenoptera venoms (bee, wasp, hornet and yellowjacket), "the non-allergic local reaction is a toxic response to venom constituents, while the large local reaction appears to be caused by an allergic reaction to venom proteins." See, D. N. Wright, Local Reactions To Stinging Insects (Hymenoptera), Allergy Proc. 11(1):23-28 Jan.-Feb. 1990).
Upon receiving a venomous bite or sting, a variety of symptoms can be exhibited due to the venom, including pruritus, erythema, urticaria, angioedema, soft tissue swelling, inflammation of the affected area and pain in the affected area.
When injected subcutaneously, many venoms from bites and stings induce extravasation from adjacent blood vessels. See, V. Cattell, Focal Mesangial Proliferative Glomerulonephritis In The Rat Caused By Habu Snake Venom: The Role Of Platelets, British J. of Exp. Pathol., 60(2):201-208 (April 1979); In addition, the venoms induce platelet aggregation and mast cell degranulation, two components of inflammation along with extravasation. Serotonin release has also been associated with the injection of venoms. See, for instance, Y. Ozaki, et al, Mastoparan, A Wasp Venom, Activates Platelets Via Pertussis Toxin-Sensitive GTP-Binding Proteins, Biochem. Biophys. Res. Commun., 170(2):779-85 (Jul. 31, 1990) and C. Wang, et al, Experimental Study of Chinese Agkistrodon Actus Venom In Activation Of Rabbit Platelets In Vivo, Hua Hsi I Ko Ta Hsueh Hsueh Pao, 25(1):38-40 (March 1994).
Since the discovery of serotonin (5-hydroxytryptamine, 5-HT) over four decades ago, the cumulative results of many diverse studies have indicated that serotonin plays a significant role in the functioning of the mammalian body, both in the central nervous system and in peripheral systems as well. Morphological studies of the central nervous system have shown that serotonergic neurons, which originate in the brain stem, form a very diffuse system that projects to most areas of the brain and spinal cord. R. A. O'Brien, Serotonin in Mental Abnormalities, 1:41 (1978); H. W. M. Steinbusch, Handbook of Chemical Neuroanatomy, Volume 3, Part II, 68 (1984); N. E. Anden, et al., Acta Physiological Scandinavia, 67:313 (1966). These studies have been complemented by biochemical evidence that indicates large concentrations of 5-HT exist in the brain and spinal cord. H. W. M. Steinbusch, supra.
With such a diffuse system, it is not surprising that 5-HT has been implicated as being involved in the expression of a number of behaviors, physiological responses, and diseases which originate in the central nervous system. These include such diverse areas as sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, schizophrenia, and other bodily states. R. W. Fuller, Biology of Serotonergic Transmission, 221 (1982); D. J. Boullin, Serotonin in Mental Abnormalities 1:316 (1978); J. Barchas, et al., Serotonin and Behavior, (1973).
Serotonin plays an important role in peripheral systems as well. For example, approximately 90% of the body's serotonin is synthesized in the gastrointestinal system, and serotonin has been found to mediate a variety of contractile, secretory, and electrophysiologic effects in this system. Serotonin may be taken up by the platelets and, upon platelet aggregation, be released such that the cardiovascular system provides another example of a peripheral network that can release and respond to serotonin. Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists. In particular, receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, compulsive disorders, schizophhrenia, autism, neurodegenerative disorders, such as Alzheimer's disease, Parkinsonism, and Huntington's chorea, and cancer chemotherapy-induced vomiting. M. D. Gershon, et al., The Peripheral Actions of 5-HYDROXYTRYPTAMINE, 246 (1989); P. R. Saxena, et al., Journal of Cardiovascular Pharmacology, 15:Supplement 7 (1990).
Serotonin produces its effects on cellular physiology by binding to specialized receptors on the cell surface. Multiple types of receptors exist for many neurotransmitters and hormones, including serotonin. The existence of multiple, structurally distinct serotonin receptors has provided the possibility that subtype-selective pharmacologic agents can be produced. The development of such compounds could result in new and increasingly selective therapeutic agents with fewer side effects, since activation of individual receptor subtypes may function to affect specific actions of the different parts of the central and/or peripheral serotonergic systems.
An example of such specificity can be demonstrated by using the vascular system as an example. In certain blood vessels, stimulation of certain 5-HT receptors on the endothelial cells produces vasodilation while stimulation of certain 5-HT receptors on the smooth muscle cells produces vasoconstriction.
Currently, the major classes of serotonin receptors (5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3, 5-HT.sub.4, 5-HT.sub.5, 5-HT.sub.6, and 5-HT.sub.7) contain some fourteen to eighteen separate receptors that have been formally classified based on their pharmacological or structural differences. For an excellent review of the pharmacological effects and clinical implications of the various 5-HT receptor types, see Glennon, et al., Neuroscience and Behavioral Reviews, 14:35 (1990).! discoveries.
One class of serotonin receptors is the 5-HT.sub.2. Of this class, several subtypes are known to exist. These subtypes include 5-HT.sub.2A, 5-HT.sub.2B and 5-HT.sub.2C. The subtype 5-HT.sub.2A is located in many tissues, including but not limited to, the vascular smooth muscle, platelets, lung, CNS and gastrointestinal tract. This receptor is thought to be associated with several effects: for example, vasoconstriction, platelet aggregation, and bronchoconstriction. The 5-HT.sub.2B receptor is localized in the rat lung, stomach fundus, uterus, bladder, and colon. Interesting areas of 5-HT.sub.2B receptor localization in the human include, but are not limited, to the brain and blood vessels. Subtype 5-HT.sub.2C is located in the CNS with a high density in the choroid plexus.
Because of the widespread dissatisfaction with the current treatments for venomous bites and stings within the affected population, there exists a need for a more efficacious and safe treatment. The present invention provides such a treatment.