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extracellular antagonists and agonists as well as the balance of intracellular synergizing and dysynergizing signal transduction networks. Drugs can help restore the balance of endogenous agonist/antagonist activity. Drugs do not cure diseases, but facilitate the ability of the body to cure itself. This is similar to the American Indian theory of balance in health and the Chinese theory of health that depends on the proper balance of yin (cold) and yang (hot). Yin is also the female or inhibiting aspect of the body. Yang is the male or activating aspect of the body.

The receptor approach is further complicated by the following factors. Typical receptor-based research has reasonably focused on the ligand binding site of the receptor. As in enzymology, there may well be alternate sites on the receptor that are amenable to drug action.1 An example in the GPCR realm is the interface between receptor and G protein.2 Agonist or antagonist substances binding to any of a number of available regulatory sites between receptor and G protein could influence tra cking through the coupled signal transduction system.

Further downstream in the transducing system there could be drug targets that influence other enzymes or targets in the pathway, and in these targets a multiplicity of possible interactive locations, from ligand binding sites to allosteric sites, could occur. Specificity has long been a concern and goal of pharmacology, and for some disorders this approach is likely to be the best. In other cases, and migraine headache may be one of these, an agent or agents that hit in many locations may be preferable. Natural products like cannabis come to mind in this regard. Tetrahydrocannabinol (THC) or cannabidiol (CBD) alone or even THC and CBD in combination may not be the most e ective therapeutic approach. Rather the combination of cannabinoids, terpenoids and other substances found in crude cannabis preparations may allow for the greatest coverage of useful target sites.

1.2 Experimental Approaches to Disease Treatment

The Chinese have experimentally found ways to stimulate yin and yang in order to restore balance between proinflammatory and anti-inflammatory factors and treat disease.3 Too much yin can be caused by an insu cient flow of vital forces, such as blood, lymph and chi. Too much yang can be caused by excessive flow of vital forces. Chi is the source of life and is a life force carried in the body by the acupuncture channels. Chi is required to regulate the balance between yin and yang. It is possible that chi and the intracellular signal transduction networks accomplish the same purposes. Regulation of gene transcription is also involved in chi. It is also possible that endogenous extracellular ligands accomplish the same purposes as yin and yang.

The brain and nervous system depend on endogenous ligands and signal transduction networks, just like other organs. In addition, neurons modify each other’s signals through synaptic interactions. Therefore, the brain has

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intracellular signal transduction networks, extracellular ligands and synaptic interactions that are important in the production of neuronal impulses.

However, the brain also depends on perceptions that alter signal transduction networks. Perceptions come from a variety of stimuli outside or inside the body and are translated into neural signals and synaptic impulses in the brain. Perceptions are important in anxiety disorders, delusions, depression and other disorders. Even Parkinson’s disease is more common in people who are more prone to anxiety. Unfortunately, very little is understood about how perceptions are involved in altering signal transduction networks and endogenous ligands in the brain. It is possible that a balance exists between perceptions of comfort and discomfort that is needed for proper brain health.

The involvement of perceptions in pain processing can be taken another step into the realm of an a ective component of pain. In gate theory4 once the original nociceptive signal is processed in a perceptual sense in the brain, an a ective or emotional component of feedback is sent to the periphery to further gate in other words allow for increased or decreased movement of sensory information into the input pathway. Additionally, in this context, local signals in the periphery that involve non-pain input may further influence the strength of the pain signal. All of these aspects of pain processing suggest multiple sites for therapeutic intervention either alone or in some complex interacting fashion. These aspects are probably also important in the placebo e ect that is prominent in pain treatment.

Before antibiotics were discovered, the treatment of infectious fevers involved aspirin and cold baths to bring down the fever. The patient usually died anyway because only the symptom was being treated, not the cause. This is true of many diseases today. Only the symptoms are known, not the causes. However, advances are being made that will be discussed in the current work. Diseases for which no cures (and sometimes no causes) are known include hypertension, heart disease, diabetes, arthritis, Alzheimer’s disease, Parkinson’s disease, migraine headache, neuropathic pain, fibromyalgia and others. Advances are being made with hypertension, heart disease, diabetes and arthritis. However, it is important to realize with all of these diseases that the most powerful drugs available to treat the symptoms do not cure the diseases.

1.3 Adipokines and Disease Causation

Recently, fat cells, especially visceral fat cells, have been found to secrete adipokines, such as visfatin, leptin, resistin, C-reactive protein, angiotensin II, tumor necrosis factor alpha, and interleukin 6, that are released into the blood and have e ects throughout the body (proinflammatory factors). Macrophages, in obese patients, can also secrete adipokines. Obesity, caused by a sedentary and overindulgent lifestyle, produces more fat, more adipokines and more toxic lipids, such as ceramide and endocannabinoids. These adipokines and toxic lipids induce inflammation and alter the balance of signal

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transduction networks necessary for normal health. In addition, many adipokines alter the secretion of other adipokines.

Interleukin-6, tumor necrosis factor alpha, resistin, C-reactive protein, angiotensin II, ceramide and other ligands are involved in altering the balance of signal transduction mechanisms that leads to heart disease.5,6 Lipotoxicity, from ceramide, causes iNOS dysfunction resulting in oxygen radical production in the kidney leading to increased blood pressure. Adiponectin decreases due to increased endocannabinoids. Low adiponectin causes NO production to decrease. In endothelial cells, eNOS dysfunction leads to oxygen radical production. Angiotensin II and endothelin-1 increase, leading to increased peripheral resistance and more eNOS dysfunction. Resistin, TNFa and IL-6 decrease NO production. Wall defects develop in arteries, and are partially caused by leptin. Platelet, neutrophil and monocyte adhesion occurs due to increased production of adhesion proteins. TNFa, resistin and C-reactive protein may stimulate adhesion protein synthesis. Neutrophils invade arterial walls and start the inflammatory process. Monocytes and more neutrophils are activated and are stimulated to make oxygen radicals by visfatin and leptin. Oxidized LDL-C is taken up by macrophages making foam cells and plaque. Smooth muscle cell proliferation occurs due to the e ects of PDGF, angiotensin II and heparin binding epidermal growth factor-like growth factor. Plaque instability occurs due to C-reactive protein induced matrix metalloproteinase activity in macrophages.

Hypertension is caused by angiotensin II, resistin, visfatin, C-reactive protein, tumor necrosis factor alpha and other endogenous ligands.7,8 Vascular tone (blood pressure) is decreased by PGI2, NO, acetylcholine and vagal nerve stimulation (decreased cardiac output). Blood pressure is increased by adrenergic nerve stimulation, endothelin, angiotensin, renin, aldosterone and other factors. Adiponectin levels decrease in obesity leading to impaired vasorelaxation, due to less NO production, and higher levels of endothelin-1. CRP decreases eNOS and prostacyclin synthase activities leading to increased blood pressure. TNFa decreases iNOS activity and NO production. Visfatin inhibits vasodilation through an unknown mechanism. Resistin inhibits vasodilation induced by bradykinin and induces endothelin-1 transcription. Angiotensinogen is secreted to some extent by visceral fat, increases angiotensin II and blood pressure.

Diabetes is caused by endocannabinoids, ceramide, resistin, visfatin, inter- leukin-6, tumor necrosis factor alpha and others.9,10 Endocannabinoids decrease adiponectin production, and increase visfatin and TNFa production. Ceramide inhibits insulin receptor phosphorylation causing short-term insulin resistance. Ceramide also makes iNOS dysfunction, making oxygen radicals that destroy b cells. Resistin, RELMs and lipotoxicity cause short-term insulin resistance. Visfatin, IL-6 and TNFa are involved in long-term insulin receptor resistance.

Osteoarthritis is caused by endocannabinoids, leptin, resistin, TNFa, IL-6 and others.8,11,12 Endocannabinoids decrease adiponectin production and increase the production of other adipokines. However, rheumatoid arthritis

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patients have high adiponectin levels perhaps as a compensatory mechanism. Leptin levels increase and activate macrophages, T cells and chondrocytes, leading to increased production of oxygen radicals and cytokines that are inflammatory. Inflammation follows with macrophages and monocytes di erentiating into osteoclasts. This di erentiation is caused by colony stimulating factor-1 (CSF-1) from fibroblasts. TNFa is involved in the stimulation of CSF-1 production. Neutrophils are activated by leptin and visfatin and induce more inflammation. Macrophages secrete resistin that induces TNFa and IL-6 in a vicious cycle.

Clearly, a large portion of the economically important diseases in developed countries are caused by toxic lifestyles that produce toxic extracellular ligands that alter the normal balance of signal transduction networks in the body. It is also clear that a number of genes are involved in these disease processes to produce the adipokines and toxic lipids. Therefore, these diseases have a number of potential drug targets. In addition, it is clear that re-establishing a healthy lifestyle can alter the activities of many genes, leading to better disease treatment.

The current approach to many chronic diseases is to treat symptoms, such as hypercholesterolemia in heart disease, pain in arthritis and high blood glucose in diabetes. In Alzheimer’s disease, billions of dollars are being spent to try to find ways to prevent or reverse plaque formation in the brain. Treating symptoms can sometimes slow down the disease process and may be of benefit to patients. However, the chronic disease is not cured or reversed. Lifestyle changes may be able to prevent or reverse chronic diseases, by re-establishing the proper balance between proinflammatory and antiinflammatory factors.

1.4 Questions in Disease Treatment

A question that remains unanswered for many drugs is: Do drugs alter the activities of endogenous agonists and antagonists such that recovery from a disease is impeded? For instance, opioids cause receptor desensitization through receptor of G protein signaling (RGS) and other mechanisms. When patients try to stop taking opioids, the pain returns and is much worse than before. The pain is worse because the endogenous opioid agonists cannot function normally due to opioid receptor desensitization. Are there similar processes with other drugs, such that the normal balance of endogenous agonist and antagonist activity is so disturbed that proper health cannot be restored?

Despite recent advances, there is still much that is not known. For instance, muscles are vital to proper health. Do muscles secrete myokines that are involved in maintaining health? How does exercise promote the health of stem cells throughout the body? The guts produce hormones that are important for health. The guts are associated with a large array of immune tissue and nervous tissue. Are there unknown enterokines that are involved in the health of organs, the nervous system and the immune system? Similarly, it is not known if bone secretes osteokines that might maintain health in other organs. The brain,