Relationships between the paradoxical painful and nonpainful sensations induced by a thermal grill

The simultaneous application of innocuous cutaneous warm and cold stimuli with a thermal grill can induce both paradoxical pain and paradoxical warmth (heat). The goal of this study was to investigate further the relationships between these paradoxical sensations. Stimuli were applied to the palms of the right hands of 21 volunteers with a thermode consisting of 6 bars, the temperature of which was controlled by Peltier elements. We assessed the quality and intensity of the sensations evoked by series of stimuli consisting of progressively colder temperatures combined with a series of given warm temperatures. We applied a total of 116 series of stimuli, corresponding to 785 combinations of warm and cold temperatures. The 2 paradoxical phenomena were reported for most of the series of stimuli (n = 66). In each of these series, the 2 phenomena occurred in the same order: paradoxical warmth followed by paradoxical pain. The difference between the cold–warm temperatures eliciting paradoxical warmth was significantly smaller than that producing paradoxical pain. The intensities of the warmth and unpleasantness evoked by the stimuli were directly related to the magnitude of the warm–cold differential. Our results suggest that there is a continuum between the painful and nonpainful paradoxical sensations evoked by the thermal grill that may share pathophysiological mechanisms. These data also confirm the existence of strong relationships between the thermoreceptive and nociceptive systems and the utility of the thermal grill for investigating these relationships.     

Pharmacological dissection of the paradoxical pain induced by a thermal grill

We investigated the role of the glutamatergic and endogenous opioidergic systems in the paradoxical pain evoked by the simultaneous application of innocuous warm and cold stimuli to the skin with a "thermal grill". Two parallel randomized, double-blind, cross-over studies, including two groups of 12 healthy volunteers, were carried out to compare the effects of i.v. ketamine or naloxone to those of placebo, on the sensations produced by a thermode (i.e. thermal grill) composed of six bars applied on the palmar surface of the right hand. The temperature of alternate (even- and odd-numbered) bars could be controlled independently by Peltier elements to produce various patterns of the grill. During each experimental session we measured the effects of ketamine, naloxone or placebo on the intensity of: (i) paradoxical pain; (ii) "normal" thermal (heat and cold) pain; and (iii) non-painful thermal (warm and cool) sensations. Ketamine administration resulted in a significant reduction of paradoxical pain intensity but did not alter normal pain or non-painful thermal sensations. By contrast, naloxone had no effect on paradoxical pain, normal pain or non-painful thermal sensations. This study demonstrates for the first time that the "thermal grill illusion of pain" can be modulated pharmacologically. This paradoxical pain, which involves the glutamatergic systems, acting through the NMDA receptors, but not the tonic endogenous opioids systems, might share some mechanisms with pathological pain.     

The spatial characteristics of the painful thermal grill illusion

Interlaced cold and warm stimuli may induce a paradoxical burning sensation termed the "thermal grill illusion". Studies on the grill illusion have yielded contradictory results regarding its quality and intensity, which in turn led to controversies concerning the underlying mechanism. Some controversies may result from testing the illusion with absolute temperatures thereby disregarding inter-subjects' variation in temperature sensitivity. Therefore, our aim was to measure the individual threshold of the painful grill illusion (PGI). Another aim was to measure, here for the first time, the spatial boundaries of the PGI by spatially separating between the cooling and warming stimuli. Subjects (10 males, 15 females) underwent measurements of heat-pain (HPT) and cold-pain thresholds (CPT) with 9 and 18 cm(2) stimulating probes, on the forearm. Subjects also underwent measurement of pain threshold (PT), with one cooling and one heating probe (9 cm(2) each) activated simultaneously, and separated by 0-30 cm (distances encompassing one or two dermatomes). Simultaneous cold and warm stimuli produced burning pain at all separation distances. PT (approximately 26 and 38 degrees C) was significantly lower than CPT and HPT, respectively, and was relatively fixed across all distances except for 30 cm at which PT increased towards CPT and HPT values. Gender did not affect the PGI. In conclusion, innocuous cold and warm stimuli can spatially summate, both within and between dermatomes and evoke a PGI. Possibly, non-nociceptive channels integrate onto 2nd or 3rd order nociceptive neurons which in turn induce a unique painful burning resulting from the blend of cold and warm sensations.     

Effects of morphine on the experimental illusion of pain produced by a thermal grill

We compared the effects of systemic morphine on normal (heat and cold) pain and paradoxical burning pain evoked by the simultaneous application of innocuous warm and cold stimuli to the skin. Twelve healthy volunteers participated in a randomised, double-blind, cross-over study to compare the effects of intravenous administration of morphine (0.025 or 0.1mg/kg) or placebo (saline). Stimuli were applied to the palm of the right hand with a thermode ("thermal grill") composed of six bars, whose temperatures were controlled by Peltier elements. For each session, we measured the heat and cold pain thresholds and then successively measured the intensity of: (i) paradoxical pain evoked by a combination of non-noxious warm and cold stimuli; (ii) "normal" pain evoked by suprathreshold heat or cold stimuli; (iii) non-painful sensations evoked by warm or cold stimuli at temperatures used to produce paradoxical pain. Measurements were performed before 20min after the administration of morphine or placebo and 5min after the administration of the morphine antagonist, naloxone. The administration of 0.1mg/kg of morphine, but not 0.025mg/kg, induced a significant and naloxone-reversible reduction of paradoxical pain intensity, which was directly correlated with the reduction of normal cold pain. No differences were observed for non-painful thermal sensations. The paradoxical burning pain evoked by a thermal grill can be modified pharmacologically by analgesics and share some mechanisms with normal pain. This unique experimental "illusion of pain" may represent a new model to test analgesics in healthy volunteers.     

Painful sensation induced by a thermal cutaneous stimulus

This review emphasizes how little we know about pain induced by a thermal stimulus. The study of the intensity of pain evoked by heat is relatively exhaustive: the influence of various local, stimulus-dependent or general factors upon threshold values has been well studied, as has the relation between pain and stimulus intensities. On the contrary, few studies have used very cold stimuli, since highly efficient stimulators allowing accurate control of the stimulus parameters have been obtainable only recently. Only the influence of stimulation area and stimulation rate on cold pain thresholds have been studied. Moreover, old results obtained on pain quality cannot be used since the conditions of stimulation were not specified or not controlled accurately. It is only known that stimulus duration and stimulation area are determinant for thermal pain quality. There is still much work to be done in this field. All the more so as this type of study is absolutely necessary for the understanding of pain mechanisms--it describes what must be explained by the function of the nervous system. We have seen that at the periphery the intensity of heat pain is coded by the response of polymodal nociceptors, mechanothermal nociceptors, thermal nociceptors and possibly by the paradoxical discharge of cold receptors. If the stimulus is lower than 45 degrees C the activity of certain heat receptors comes into play. Although we lack information which would allow confirmation of this as a fact it seems likely that the activity of polymodal nociceptors, cold mechanothermal nociceptors and possibly certain cold receptors sensitive to very low temperatures code cold pain. These nociceptive impulses carried by A delta and C fibers reach the dorsal horn of the spinal cord through the dorsal roots. They are notably at the origin of the activation of the neurons in Rexed's layers I, V and VIII which are to a large extent at the origin of the spinothalamic and spinoreticulothalamic tracks [21,115,168] moving in the anterolateral quadrant of the spinal cord. At supraspinal level, the thermal information reappears in the reticular formation; there it appears to be solely relative to the pain threshold and not to the intensity of a supraliminary stimulus [55]. In the posterior group of nuclei [134] and the ventroposterolateral nucleus of the thalamus [103], on the contrary, the activity of the neurons reflects the intensity of the stimulation. It has been proved that the neurons of the ventroposterolateral nucleus project onto the SI cortex [103].(ABSTRACT TRUNCATED AT 400 WORDS)     

Qualitative and quantitative characterization of the thermal grill

Concurrent applications to the skin of spatially adjacent bands of innocuous warm and cool stimuli would elicit a peculiar sensation, known as the 'thermal grill illusion'. To validate the thermal grill as a research tool, this two-phase study qualitatively characterizes this peculiar sensation and further quantitatively establishes the temperature matching of the most intense/noxious thermal grill stimulations at two different time points. The temperature combinations (degrees C) tested were: 18/18, 42/42, 18/42, 20/20, 40/40, 20/40, 22/22, 38/38, 22/38, 24/24, 36/36 and 24/36. None of the subjects reported pain with single temperature combinations. However, hot associated with pain and burning sensations were reported in all mixed temperature combinations tested. The VAS scores for pain were significantly elevated for 20/40 and 18/42 in comparison to 22/38 and 24/36 (P<0.007). At the 3-second time point, the matching temperatures (+/-SD) of 20/40 and 18/42 were 45.7+/-1.8 (range 44-48) and 46.6+/-1.5 (range 44-48) degrees C, respectively, whereas the matching temperatures for the single temperature combinations were similar to the set temperatures. Importantly, at the 10-second time point, none of the combinations were significantly greater than the highest of the pair of stimuli. The time course variation in the perception of the combined stimuli suggests an adaptation occurred in central processing.     

Coolness both underlies and protects against the painfulness of the thermal grill illusion

We investigated the contributions of warm and cool signals in generating the thermal grill illusion (TGI), a phenomenon in which interlaced warm and cool bars generate an experience of burning, and under some conditions painful, heat. Each subject underwent 3 runs, 2 of which tested the effects of preadapting subjects to the grill’s warm or cool bars (while the interlaced bars were thermally neutral) on the subsequent intensity of the illusion. In a control run, all bars were neutral during the adaptation phase. Thermal visual analogue scale ratings during the warm and cool adaptation periods revealed significant and equivalent adaptation to the 2 temperatures. Adaptation to the grill’s cool bars significantly reduced pain and perceived thermal intensity of the TGI, compared to the control condition, while adaptation to the grill’s warm bars had little effect. These results suggest that the cool stimulus triggers the pain signals that produce the illusion. The inability of warm adaptation to attenuate the TGI is at odds with theories suggesting that the illusion depends upon a simple addition of warm and cool signals. While the grill’s cool bars are necessary for the TGI’s painfulness, we also observed that the more often a participant reported feeling coolness or coldness, the less pain he or she experienced from the TGI. These results are consistent with research showing that cool temperatures generate activity in both thermoreceptive-specific, pain-inhibitory neurons and nociceptive dorsal horn neurons.     

Turning on the alarm: the neural mechanisms of the transition from innocuous to painful sensation

The experience of pain occurs when the level of a stimulus is sufficient to elicit a marked affective response, putatively to warn the organism of potential danger and motivate appropriate behavioral responses. Understanding the biological mechanisms of the transition from innocuous to painful levels of sensation is essential to understanding pain perception as well as clinical conditions characterized by abnormal relationships between stimulation and pain response. Thus, the primary objective of this study was to characterize the neural response associated with this transition and the correspondence between that response and subjective reports of pain.Towards this goal, this study examined BOLD response profiles across a range of temperatures spanning the pain threshold. 14 healthy adults underwent functional magnetic resonance imaging (fMRI) while a range of thermal stimuli (44-49 °C) were applied. BOLD responses showed a sigmoidal profile along the range of temperatures in a network of brain regions including insula and mid-cingulate, as well as a number of regions associated with motor responses including ventral lateral nuclei of the thalamus, globus pallidus and premotor cortex. A sigmoid function fit to the BOLD responses in these regions explained up to 85% of the variance in individual pain ratings, and yielded an estimate of the temperature of steepest transition from non-painful to painful heat that was nearly identical to that generated by subjective ratings.These results demonstrate a precise characterization of the relationship between objective levels of stimulation, resulting neural activation, and subjective experience of pain and provide direct evidence for a neural mechanism supporting the nonlinear transition from innocuous to painful levels along the sensory continuum.     

A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel.

Paclitaxel, an effective anti-neoplastic agent in the treatment of solid tumors, produces a dose-limiting painful peripheral neuropathy in a clinically significant number of cancer patients. Prior work has demonstrated paclitaxel-induced neurodegeneration and sensory loss in laboratory rodents. We describe here an experimental paclitaxel-induced painful peripheral neuropathy. Adult male rats were given four intraperitoneal injections on alternate days of vehicle or 0.5, 1.0, or 2.0 mg/kg of paclitaxel (Taxol). Behavioral tests for pain using mechanical and thermal stimuli applied to the tail and hind paws, and tests for motor performance, were taken before, during and after dosing for 22-35 days. All three doses of paclitaxel caused heat-hyperalgesia, mechano-allodynia, mechano-hyperalgesia, and cold-allodynia, but had no effect on motor performance. Neuropathic pain began within days and lasted for several weeks. We did not detect any dose-response relationship. Tests at the distal, mid, and proximal tail failed to show evidence of a length-dependent neuropathy. Vehicle control injections had no effect on any measure. No significant systemic toxicities were noted in the paclitaxel-treated animals. Light-microscopic inspection of the sciatic nerve (mid-thigh level), L4-L5 dorsal root ganglia, and dorsal and ventral roots, and the gray and white matter of the L4-L5 spinal cord, showed no structural abnormalities. Electron microscopic examination of the sciatic nerve (mid-thigh level) and the L4-L5 dorsal root ganglia and dorsal horns demonstrated no degeneration of myelinated and unmyelinated axons in the sciatic nerve and roots, but revealed endoneurial edema. This model may be useful in understanding a significant source of pain in cancer patients, and in finding ways to avoid the neurotoxicity that limits paclitaxel therapy.     

Pain characteristics of painful ophthalmoplegia (the Tolosa-Hunt syndrome)

Pain characteristics of the Tolosa-Hunt syndrome were abstracted from the observations of five patients with repeated incidents of painful ophthalmoplegia. The pain was experienced either as pressure behind the ophthalmoplegic eye or as boring pain in one orbital region, fluctuating in intensity, sometimes worsening to knife stab-like pain in the eye. The unilateral pain did not shift side during a solitary incident of painful ophthalmoplegia and was never completely absent. The pain was increased when the eyes were strained, when cold wind blew against the face, and when a change in the weather took place. It was accompanied by a feeling of swelling in the affected region, but not by nausea nor vomiting. Conventional headache drugs provided little relief. All cases experienced tenderness when pressure was applied to the ipsilateral supraorbital foramen. The pain was suggested to be related to an increased load on the impaired venous blood flow in the region of the superior orbital fissure.     

Antimicrobial activity of a chelatable poly(arginyl-histidine) produced by the ergot fungus Verticillium kibiense

We have recently developed a convenient method of screening a broad range of microorganisms that produce epsilon-poly-L-lysine (M. Nishikawa and K. Ogawa, Appl. Environ. Microbiol. 68:3575-3581, 2002). Using this method, we found an ergot fungus that secretes a charged polypeptide other than epsilon-poly-L-lysine. It was identified as a new species on the basis of its 28S rRNA sequence and was named Verticillium kibiense (formerly Epichloe kibiensis). Peptide sequencing and mass spectrometry revealed that the polypeptide is a linear peptide composed of repeated units of arginyl-histidine. The numbers of repeated units were in most cases five and in some cases four or six. This peptide showed activity against a broad range of bacteria and fungi but lost its activity under conditions of high ionic strength. Zinc and copper ions specifically changed the circular dichroism spectra of the peptide and restored the antimicrobial activity from abrogation under high ionic conditions, although these ions had no reinforcing effect on antimicrobial activity when they were added to solutions at a low ionic strength. The peptide labeled with fluorescein was able to permeate the cell membranes of target microbes, but its ability to permeate cell membranes decreased under conditions of high ionic strength. This decreased ability was partially recovered specifically by the addition of zinc and copper ions. These results indicate that poly(arginyl-histidine) is a cationic polypeptide characterized by specific metal binding and resistance to salts.     

Inhibition in the spinal cord: a neuronal mechanism of hypalgesia produced by acupuncture (author's transl)

Central nervous system mechanisms of nociception and pain were studied electrophysiologically in the spinal cord of cats. A great proportion of dorsal horn neurons respond to noxious skin stimuli, for instance to heating to 50 degrees C; such stimuli predominantly activate afferent C fibres. These spinal neurons participate in the transmission of nociceptive information to the brain. The heat-evoked discharges of dorsal horn neurons are effectively inhibited by repetitive electrical stimulation of large;, low-threshold cutaneous A fibres. The inhibition reaches its maximum effect after several minutes of nerve stimulation, and declines at a slow rate after the end of stimulation. This long-term suppression is considered to be a neuronal mechanism underlying hypalgesia produced in man e.g. by acupuncture and by transcutaneous nerve stimulation.     

Physical gels of poly(vinylamine) by thermal curing

Physical gels are a versatile class of materials which can find application in sensors, electrochemistry, biomedicine or rheological modifiers. Herein, we present a hydrogen-bonded physical gel which is based on the interaction between phenylcarbonate telechelic poly(ethylene glycol) (PEG-PC) and poly(vinyl amine-co-acetamide) (p(VAm-co-VAA)). The critical gelation concentration was found to be 10 wt% by rheology and NMR. UV-vis spectroscopy and dynamic light scattering reveal the formation of aggregates in the gel. Rheology and differential scanning calorimetry (DSC) was used to show the effect of thermal curing on the mechanical properties of the physical gel.

Repeated heating cooling cycles can anneal inhomogeneity in physical gels and significantly improve their mechanical properties.     

Relieving effect of TENS on painful muscle contraction produced by an impairment of reciprocal innervation: an electrophysiological analysis

A young female outpatient experienced painful tonic contractions in the right triceps surae muscles as a result of a partial damage of the right peroneal nerve. Electrophysiological recordings of the soleus muscle showed a tonic EMG activity and an hyperexcitability of the monosynaptic H reflex (Hmax/Mmax ratio: 90%). Application of transcutaneous electrical nerve stimulation (TENS, 1-2 min) on the peroneal nerve trunk at the head of the fibula resulted both in a pain relief and in the disappearance of the tonic activity in the muscles supplied by the antagonist nerve. Simultaneously, the Hmax/Mmax ratio decreased to normal values (49%). This was followed by an after-effect lasting more than 30 min. The potential role of an impairment of reciprocal inhibition in the originating mechanism of these troubles is discussed.     

血清脂蛋白(a)的检测及其在临床诊断中的应用

目的探讨血清脂蛋白(a)在临床疾病诊断中的意义。方法采用免疫透射比浊法测定冠心病组患者54例,肾病组患者36例,急性感染组患者89例,以及100例正常对照组个体的血清脂蛋白(a)水平。结果冠心病组,肾病组,急性感染组的血清脂蛋白(a)水平与正常对照组血清脂蛋白(a)水平差异具统计学意义(P<0．001)。结论 LP(a)作为一种敏感的急性时相蛋白应引起临床关注。