A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve. The postoperative behavior of these rats indicated that hyperalgesia, allodynia and, possibly, spontaneous pain (or dysesthesia) were produced. Hyperalgesic responses to noxious radiant heat were evident on the second postoperative day and lasted for over 2 months. Hyperalgesic responses to chemogenic pain were also present. The presence of allodynia was inferred from the nocifensive responses evoked by standing on an innocuous, chilled metal floor or by innocuous mechanical stimulation, and by the rats' persistence in holding the hind paw in a guarded position. The presence of spontaneous pain was suggested by a suppression of appetite and by the frequent occurrence of apparently spontaneous nocifensive responses. The affected hind paw was abnormally warm or cool in about one-third of the rats. About one-half of the rats developed grossly overgrown claws on the affected side. Experiments with this animal model may advance our understanding of the neural mechanisms of neuropathic pain disorders in humans.

A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.

As humans, we perceive feelings from our bodies that relate our state of well-being, our energy and stress levels, our mood and disposition. How do we have these feelings? What neural processes do they represent? Recent functional anatomical work has detailed an afferent neural system in primates and in humans that represents all aspects of the physiological condition of the physical body. This system constitutes a representation of 'the material me', and might provide a foundation for subjective feelings, emotion and self-awareness.

How do you feel? Interoception: the sense of the physiological condition of the body.

Inefficient vascular supply and the resultant reduction in tissue oxygen tension often lead to neovascularization in order to satisfy the needs of the tissue. Examples include the compensatory development of collateral blood vessels in ischaemic tissues that are otherwise quiescent for angiogenesis and angiogenesis associated with the healing of hypoxic wounds. But the presumptive hypoxia-induced angiogenic factors that mediate this feedback response have not been identified. Here we show that vascular endothelial growth factor (VEGF; also known as vascular permeability factor) probably functions as a hypoxia-inducible angiogenic factor. VEGF messenger RNA levels are dramatically increased within a few hours of exposing different cell cultures to hypoxia and return to background when normal oxygen supply is resumed. In situ analysis of tumour specimens undergoing neovascularization show that the production of VEGF is specifically induced in a subset of glioblastoma cells distinguished by their immediate proximity to necrotic foci (presumably hypoxic regions) and the clustering of capillaries alongside VEGF-producing cells.

Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.

Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.

/pdf/central-sensitization-implications-for-the-diagnosis-and-18p4x3px9q.pdf

Central sensitization: implications for the diagnosis and treatment of pain.

The prevalence and cost of chronic pain is a major physical and mental health care problem in the United States today. As a result, there has been a recent explosion of research on chronic pain, with significant advances in better understanding its etiology, assessment, and treatment. The purpose of the present article is to provide a review of the most noteworthy developments in the field. The biopsychosocial model is now widely accepted as the most heuristic approach to chronic pain. With this model in mind, a review of the basic neuroscience processes of pain (the bio part of biopsychosocial), as well as the psychosocial factors, is presented. This spans research on how psychological and social factors can interact with brain processes to influence health and illness as well as on the development of new technologies, such as brain imaging, that provide new insights into brain-pain mechanisms.

/pdf/the-biopsychosocial-approach-to-chronic-pain-scientific-1047fjbjjh.pdf

The Biopsychosocial Approach to Chronic Pain: Scientific Advances and Future Directions

Rat glial tumors, induced by injections of N-nitrosomethylurea, were plated and propagated in culture. Among a few cell strains obtained, one clone contains S-100 protein, which is unique to brain in vertebrates. Stationary-phase cultures contain approximately ten times more S-100 protein per cell than exponentially growing cells. When injected into newborn rats, cells producing S-100 grew as a glial tumor, which contained S-100 protein.

https://science.sciencemag.org/content/sci/161/3839/370.full.pdf

Differentiated Rat Glial Cell Strain in Tissue Culture

In eight patients with intense chronic cutaneous pain, sensory nerves or roots. supplying the painful area were stimulated. Square-wave 0.1-millisecond pulses at 100 cycles per second were applied, and the voltage was raised until the patient reported tingling in the area. During this stimulation, pressure on previously sensitive areas failed to evoke pain. Four patients, who had diseases of their peripheral nerves, experienced relief of their pain for more than half an hour after stimulation for 2 minutes.

https://science.sciencemag.org/content/sci/155/3758/108.full.pdf

Temporary Abolition of Pain in Man

✓ The authors report their experience in the treatment of trigeminal neuralgia with controlled increments of radiofrequency heating from an electrode placed in the Gasserian ganglion or its posterior rootlets. Touch is preserved in some or all of a trigeminal zone rendered analgesic. The electrode tip is introduced through the foramen ovale and placed among the desired rootlets with the help of a combination of radiographs and the conscious patient's response to electrical stimulation with a square wave signal and gentle electrical heating. The degree of heat is measured by a thermister at the electrode tip. The patient's cooperation is maintained by the use of the neurolept anesthetic Innovar and the production of brief unconsciousness for the painful parts of the operation by methohexital (Brevital). Of 274 patients with facial pain so treated, 214 had trigeminal neuralgia; 91% of the latter group experienced relief of pain and 125 followed for 2½ to 6 years had a recurrence rate of 22%. In a total of 3...

Controlled thermocoagulation of trigeminal ganglion and rootlets for differential destruction of pain fibers. 1. Trigeminal neuralgia.

Pain and the neurosurgeon : a forty-year experience

✓ Rat glial tumors, induced by weekly injections of N-nitrosomethylurea for 8 months, were plated and propagated in culture. Cells grew as a glial tumor when injected back into various sites in newborn rats, and were then carried for many generations by transplantations from rat to rat or by alternate culture and animal passage. Light, phase, and electron microscopy of the cultured cells showed great variability among the glial types in all the primary tumors, in the cultures grown from them, and in the secondary in vivo tumors grown from the cultures. Many unmistakable stigmata of glia were conserved. Cloned cultures (derived from a single cell) were frozen and stored, and upon thawing resumed growth with their original histological appearance. Tumor lines from these cultured cloned strains showed much more constant growth rates and cell types; two stable lines were carried for many generations: a slow-growing astrocytoma and a faster growing glioblastoma. The distinctive neural protein called “S-100” wa...

William H. Sweet

Papers

Differentiated Rat Glial Cell Strain in Tissue Culture

Temporary Abolition of Pain in Man

Controlled thermocoagulation of trigeminal ganglion and rootlets for differential destruction of pain fibers. 1. Trigeminal neuralgia.

Pain and the neurosurgeon : a forty-year experience

Morphological and immunochemical studies of rat glial tumors and clonal strains propagated in culture.