A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.

A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.

The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, or heat (>43 degrees C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli. VR1-/- mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia.

http://science.sciencemag.org/content/sci/288/5464/306.full.pdf

Impaired Nociception and Pain Sensation in Mice Lacking the Capsaicin Receptor

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.

http://www.pgedf.ufpr.br/Referencias08/artigo%20do%20somatorio%20do%20cortisol%20RC.pdf

Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change

In ischemic and in inflamed tissues, pH levels down to 54 have been measured, and this local acidosis may contribute to pain and hyperalgesia in disease states To evaluate the role of acid pH in nociception, we have studied identified primary afferents in a rat skin-saphenous nerve preparation in vitro where the receptive fields can be superfused at the highly permeable corium side with controlled solutions The nerve endings were exposed to CO2-saturated synthetic interstitial fluid (SIF;pH 61) and to carbogen-gassed SIF phosphate buffered to different acid pH levels (5 min duration, 10 min intervals) Mechanical thresholds were repeatedly tested in a "blind" fashion by von Frey hair stimulation Low-threshold mechanosensitive A beta- (n = 12) and A delta-fibers (n = 11) were not excited or sensitized by acid pH levels In 24 of 96 nociceptor type C- and A delta-fibers, irregular low-frequency discharge with poor response characteristics was induced However, a distinct subpopulation of mechanoheat sensitive, "polymodal" C-units (n = 25; 38%) showed stimulus-related responses increasing with proton concentration and encoding the time course of the pH change Threshold levels were found to range from pH 69 to 61; mean maximum discharge was at pH 52 All such fibers responded to CO2 as well as to phosphate-buffered solution at the same pH 61 The CO2 responses, however, displayed significantly shorter latencies and more pronounced dynamic phases The carboanhydrase blocker acetazolamide markedly delayed and reduced the CO2 responses Prolonged application of acid pH (30 min) evoked nonadapting activity irrespective of oxygen supply Many, but certainly not all, fibers sensitive to protons were also driven by capsaicin (10(-6) M, 10(-5) M) and vice versa Repeated or prolonged treatment with low pH induced a significant and lasting decrease of the mechanical (von Frey) thresholds in almost all C-fibers tested (from 35 to 16 mN, on average), and this occurred whether or not a fiber was excited by protons The sensitizing effect was more pronounced the higher the initial von Frey thresholds (075 rank correlation) This sensitization to mechanical stimulation was in contrast to the combined action of other inflammatory mediators, bradykinin, 5-HT, histamine and prostaglandin E2 In conclusion, we suggest that pH sensitivity of nociceptors may be an important source of pain and hyperalgesia

https://www.jneurosci.org/content/jneuro/12/1/86.full.pdf

Protons selectively induce lasting excitation and sensitization to mechanical stimulation of nociceptors in rat skin, in vitro

Selective excitation by capsaicin of mechano-heat sensitive nociceptors in rat skin

SI nociceptive neurons participate in the encoding process by which monkeys perceive the intensity of noxious thermal stimulation.

Spinal lamina I projection neurons in the rat: collateral innervation of parabrachial area and thalamus.

1. Twenty-six nociceptive neurons in the primary somatosensory cortex (SI) of anesthetized monkeys were responsive to noxious thermal stimulation applied to the face. Thermode temperature increased...

Fernand Anton

Papers

Protons selectively induce lasting excitation and sensitization to mechanical stimulation of nociceptors in rat skin, in vitro

Selective excitation by capsaicin of mechano-heat sensitive nociceptors in rat skin

SI nociceptive neurons participate in the encoding process by which monkeys perceive the intensity of noxious thermal stimulation.

Spinal lamina I projection neurons in the rat: collateral innervation of parabrachial area and thalamus.

Responses of nociceptive SI neurons in monkeys and pain sensation in humans elicited by noxious thermal stimulation: effect of interstimulus interval