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In 2002, Sota Omoigui published a new theory of pain in his book titled: The Biochemical Origin of Pain. . This theory stated that: The origin of all Pain is inflammation and the inflammatory response. Mediators of inflammation include cytokines, neuropeptides, growth factors, transcription factors, Histamine, Serotonin/5HT, arachidonic acid metabolites,kinins, nitric oxide, oxygen radicals and neurotransmitters. Activation of pain receptors, transmission and modulation of pain signals, neuro plasticity and central sensitization are all one continuum of inflammation and the inflammatory response. Irrespective of the type of pain whether it is acute or chronic pain, peripheral or central pain, nociceptive or neuropathic pain, the underlying origin is inflammation and the inflammatory response. Irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing or tingling, all pain arise from inflammation and the inflammatory response. Independent Review of the Inflammation Response Theory Page 18 in a Book Publication from Department of Pharmacology, Leiden /Amsterdam Center for Drug Research (LACDR), Faculty of Science, Leiden University and published by the Center for Drug Research, STATES: “we strongly support the hypothesis proposed by OmoiGui, which states that the origin of all pain is inflammation and inflammatory response (5;6).”. .

Soft tissue or nerve injury causes excitation of sensory nerve fibers.Antidromic firing of these sensory nerves causes release of the inflammatory mediators PG, Cytokines IL-1 beta, TNF alpha, 5 hydroxytryptamine, leukotrienes, and bradykinins. Mediators stimulate the release of other neuropeptides including CGRP, substance P, and cholecytokinin. Neuropeptides induce vasodilation, increase vascular permeability, attract other immune cells such as T helper cells and excite surrounding sensory nerve fibers -- neurogenic inflammation. Peripheral nociceptive impulses travel via A delta and C fibers to synapse in the lamina II and lamina V of the spinal cord. C fibers also synapse in Lamina I of the spinal cord. 2nd order neurons in Lamina I, respond to impulses from the C fibers. Wide dynamic range(WDR) neurons in Lamina V can be activated to produce wind-up. Neuropeptides glutamate and aspartate mediate fast synaptic transmission in lamina V. The neuropeptides bind and activate amino-3-hydroxyl-5-methyl-4-proprionic acid (AMPA) and Kainate (KAR) receptors that regulate Na+ and K+ ion influx. Glutamate and aspartate bind to NMDA receptors. Activated AMPA receptors produce a depolarization that dislodges a magnesium plug from the ion channel of the NMDA receptor. This initiates the entry of calcium ions into the neuron. Intracellular calcium accumulates. A chain of neurochemical and neurophysiologic changes leads to the rapid and independent firing of spinal neurons without stimulation. This results in magnification of all nerve traffic and pain stimuli that arrive in the spinal cord from the periphery. Activation of motor nerves results in excessive muscle tension. More inflammatory mediators are released, generating more nerve traffic and increased muscle spasm. Constant C-fiber nerve stimulation to the spinal cord results in even more release of inflammatory mediators but this time within the spinal cord.The origin of all pain is from inflammation and the inflammatory response. TNF-alpha and Interleukin 1-beta play an important role in rheumatoid arthritis by mediating cytokines that cause inflammation and joint destruction. TNF-alpha, Interleukin 1-beta and Substance P are elevated in the joint fluids in patients with rheumatoid arthritis. These inflammatory mediators are also elevated in the joint fluid in patients with osteoarthritis albeit to a far less extent. Along with mechanical factors, growth factors and cytokines such as TGF beta 1, IL-1 alpha, IL-1 beta and TNF-alpha may be involved in the formation and growth of osteophytes, since these molecules can induce growth and differentiation of mesenchymal cells. The incidence and size of osteophytes may be decreased by inhibition of direct or indirect effects of these cytokines and growth factors on osteoid deposition in treated animals. Inhibition of IL-1 receptor also decreases the production of metalloproteinase enzymes collagenase-1 and stomelysin-1 in the synovial membrane and cartilage. These enzymes are involved in connective tissue breakdown. Tendonitis or bursitis may be associated with diseases such as rheumatoid arthritis, gout, psoriatic arthritis, thyroid disease and diabetes. In one study of patients with rotator cuff diseases, the levels of the cytokine IL-1 beta was significantly correlated with the degree of pain. The combined results of immunohistochemistry indicated that both synovial lining and sublining cells produce IL-1beta, while synovial lining cells predominantly produce the anti-inflammatory intracellular InterLeukin-1 receptor antagonist (icIL-1ra) and sublining cells secrete secreted InterLeukin-1 receptor antagonist (sIL-1ra). In other studies, the levels of IL-1 beta were significantly higher in the shoulder joints in patients with anterior instability and chronic inflammation of the joint. In another study, immunohistological staining demonstrated the expression of Interleukin-1 beta (IL-1 beta), Tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), and basic fibroblast growth factor (bFGF) in subacromial bursa derived from the patients suffering from rotator cuff tear. Back and neck pain most commonly results from injury to the muscle, disk, nerve, ligament or facet joints with subsequent inflammation and spasm. Degeneration of the disks or joints produces the same symptoms and occurs subsequent to aging, previous injury or excessive mechanical stresses that this region is subjected to because of its proximity to the sacrum in the lower back. Herniated disk tissue (nucleus pulposus) produces a profound inflammatory reaction with release of inflammatory chemical mediators most especially Tumor Necrosis Factor Alpha. Subsequent to release of TNF-alpha, there is an increase in the formation of inflammatory mediator prostaglandin and Nitric Oxide. It is now known that Tumor Necrosis Factor Alpha is released by herniated disk tissue (nucleus pulposus), and is primarily responsible for the nerve injury and behavioral manifestations of experimental sciatica associated with herniated lumbar discs. This has been confirmed by numerous animal studies and research wherein application of disk tissue (nucleus pulposus) to a nerve results in nerve fiber injury, with reduction of nerve conduction velocity, intracapillary thrombus formation, and the intraneural edema formation. Fibromyalgia is a chronic, painful musculoskeletal disorder characterized by widespread pain, pressure hyperalgesia, morning stiffness, sleep disturbances including restless leg syndrome, mood disturbances, and fatigue. Several studies have shown that there are increased levels of the inflammatory transmitter Substance P (SP) and calcitonin gene related peptide (CGRP) in the spinal fluid of patients with fibromyalgia syndrome (FMS  The levels of platelet serotonin are also abnormal .  Furthermore, in patients with fibromyalgia, the level of pain intensity is related to the spinal fluid level of arginine, which is a precursor to the inflammatory mediator nitric oxide (NO) .  Another study found increases over time in blood levels of cytokines Interleukin -6, Interleukin -8 and Interleukin -1R antibody (IL-1Ra) whose release is stimulated by substance P. Migraine headache is caused by activation of trigeminal sensory fibers by known and unknown migraine triggers. There is subsequent release of inflammatory mediators from the trigeminal nerve. This leads to distention of the large meningeal blood vessels in the skull and brain and the development of a central sensitization within the trigeminal nucleus caudalis (TNC).A clear association between migraine and the release of inflammatory mediator calcitonin gene-related peptide (CGRP) and substance P (SP) has been demonstrated. Jugular plasma levels of the potent vasodilator, calcitonin gene-related peptide (CGRP) have been shown to be elevated in migraine headache. CGRP-mediated neurogenic dural vasodilation is blocked by anti-migraine drug dihydroergotamine, triptans, and opioids [57]. In cluster headache and in chronic paroxysmal hemicrania, there is additional release of inflammatory mediator vasoactive intestinal peptide (VIP) in association with facial symptoms (nasal congestion, runny nose) [58]. Immunocytochemical studies have revealed that cerebral blood vessels are invested with nerve fibers containing inflammatory mediator neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), substance P (SP), neurokinin A (NKA), and calcitonin gene-related peptide (CGRP). In addition, there are studies reporting the occurrence of putative neurotransmitters such as cholecystokinin, dynorphin B, galanin, gastrin releasing peptide, vasopressin, neurotensin, and somatostatin. Neuropathic pain, in contrast to nociceptive pain, is described as "burning", "electric", "tingling", and "shooting" in nature. It can be continuous or paroxysmal in presentation. Whereas nociceptive pain is caused by the stimulation of peripheral A-delta and C-polymodal pain receptors, by inflammatory mediators, (e.g. histamine bradykinin, substance P, etc.) neuropathic pain is produced by injury or damage to peripheral nerves or the central nervous system. The hallmarks of neuropathic pain are chronic allodynia and hyperalgesia. Allodynia is defined as pain resulting from a stimulus that ordinarily does not elicit a painful response (e.g. light touch). Hyperalgesia is defined as an increased sensitivity to normally painful stimuli. Examples of neuropathic pain include carpal tunnel syndrome, trigeminal neuralgia, post herpetic neuralgia, phantom limb pain, complex regional pain syndromes and the various peripheral neuropathies. Nerve injury is accompanied by a considerable increase in monocytes/macrophages and subsequent release of Interleukin -6 and TNF-alpha. Subsequent to nerve injury, there is increase in nerve traffic. Expression of sodium channels is altered significantly in response to injury thus leading to abnormal excitability in the sensory neurons. Nerve impulses arriving in the spinal cord stimulate the release of inflammatory protein Substance P. The presence of Substance P and other inflammatory proteins such as calcitonin gene-related peptide (CGRP) neurokinin A, vasoactive intestinal peptide removes magnesium induced inhibition and enables excitatory Inflammatory proteins such as glutamate and aspartate to activate specialized spinal cord NMDA receptors. This results in magnification of all nerve traffic and pain stimuli that arrive in the spinal cord from the periphery. Constant C-fiber nerve stimulation to transmission pathways in the spinal cord results in even more release of inflammatory mediators but this time within the spinal cord. The transcription factor, nuclear factor-kappa B (NF-kappaB), plays a pivotal role in regulating the production of inflammatory cytokines. Inflammation causes increased production of the enzyme cyclooxygenase-2 (Cox-2), leading to the release of chemical mediators both in the area of injury and in the spinal cord. Widespread induction of Cox-2 expression in spinal cord neurons and in other regions of the central nervous system elevates inflammatory mediator prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The major inducer of central Cox-2 upregulation is inflammatory mediator interleukin-1 in the CNS. Basal levels of the enzyme phospholipase A2 activity in the CNS do not change with peripheral inflammation.. The central nervous system response to pain can keep increasing even though the painful stimulus from the injured tissue remains steady. This "wind-up" phenomenon in deep dorsal neurons can dramatically increase the injured person’s sensitivity to the pain. Transection of a nerve fiber (axotomy) results in an increased production of inflammatory cytokines and induces marked changes in the expression of sodium channels within the sensory neurons [71]. Following axotomy the density of slow (tetrodotoxin-resistant) sodium currents decrease and a rapidly repriming sodium current appears. The altered expression of sodium channels leads to abnormal excitability in the sensory neurons. Studies have shown that these changes in sodium channel expression following axotomy may be attributed at least in part to the loss of retrogradely transported nerve growth factor. Abnormal development of sensory-sympathetic connections follow nerve injury, and contribute to the hyperalgesia (abnormally severe pain) and allodynia (pain due to normally innocuous stimuli). These abnormal connections between sympathetic and sensory neurons arise in part due to sprouting of sympathetic axons. Studies have shown that sympathetic axons invade spinal cord dorsal root ganglia (DRG) following nerve injury, and activity in the resulting pericellular axonal 'baskets' may underlie painful sympathetic-sensory coupling. Sympathetic sprouting into the DRG may be stimulated by neurotrophins such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin‑3 (NT‑3) and neurotrophin 4/5 (NT‑4/5). Osteoporosis is common with aging and in post Menopausal Women. It is often ascribed solely to abnormalities in calcium metabolism. However osteoporosis is associated with elevated levels of cytokines IL-6, IL-1 and TNF-alpha. IL-6 increases osteoclastic activity. Bone resorption occurs in inflammatory diseases such as Rheumatoid Arhritis, Chronic Regional Pain Syndrome/Reflex Sympathetic Dystrophy (CRPS/RSD). Elevated levels of IL-6 are found in multiple myeloma and in menopause. Estrogens block osteoblast secretion of IL-6 and decreased levels of estrogens occurs in menopause. Osteoporosis accounts for pain in 89% of Menopausal Women. Inflammatory mediators activate bone nociceptors and decrease their threshold for activation. Severe pain arises from fractures of compressed vertebrae or femoral neck, and facet joints. Bisphosphonates are used in the treatment of osteoporosis and act by decreasing IL-6 levels and osteoclastic activity. Another osteoporosis drug Prolia, inhibits transcription factor Receptor activator of NF-Kappa B ligand (RANKL. Receptor activator of NF-Kappa B ligand (RANKL) increases expression of osteoclastogenic cytokines.