Laser-evoked brain potentials in patients with dissociated loss of pain and temperature sensibility

Brief heat stimuli, elicited by a CO₂ laser (10.6 μm wave length), activate the most superficial cutaneous nerve terminals of the thin myelinated Aδ and unmyelinated C fibres which mediate heat and pain sensations. This paper investigates late cerebral potentials (SEPs) in response to laser pulses in comparison with those to conventional electrical stimulation in 18 patients with a dissociated sensory deficit (intact mechanosensibility and disturbed temperature and pain sensation). Patients were stimulated in the most disturbed limb (affected area) and in a corresponding control area.In all 18 patients the SEPs elicited by laser stimuli were able to identify the body site with heaviest disturbances in pain and thermosensibility: the SEPs from the affected area were reduced or delayed, compared to the control area. In contrast, no alterations in SEPs could be observed after conventional electrical nerve stimulation, in agreement with the normal mechanosensibility. However, the degree of SEP modulation in response to cutaneous heat stimuli did not correspond to the severity of the subjectively reported sensory deficit. Highest correlations between sensory deficits and abnormal SEPs were found in all those patients in whom computer tomography or MR imaging documented a localized destructive process in the CNS. All patients with the smallest SEP modulations despite a considerable sensory deficit had an inflammatory aetiology. Preliminary criteria to define a laser-evoked SEP as pathological are discussed.     

Pain and suffering in invertebrates?

All animals face hazards that cause tissue damage and most have nociceptive reflex responses that protect them from such damage. However, some taxa have also evolved the capacity for pain experience, presumably to enhance long-term protection through behavior modification based on memory of the unpleasant nature of pain. In this article I review various criteria that might distinguish nociception from pain. Because nociceptors are so taxonomically widespread, simply demonstrating their presence is not sufficient. Furthermore, investigation of the central nervous system provides limited clues about the potential to experience pain. Opioids and other analgesics might indicate a central modulation of responses but often peripheral effects could explain the analgesia; thus reduction of responses by analgesics and opioids does not allow clear discrimination between nociception and pain. Physiological changes in response to noxious stimuli or the threat of a noxious stimulus might prove useful but, to date, application to invertebrates is limited. Behavior of the organism provides the greatest insights. Rapid avoidance learning and prolonged memory indicate central processing rather than simple reflex and are consistent with the experience of pain. Complex, prolonged grooming or rubbing may demonstrate an awareness of the specific site of stimulus application. Tradeoffs with other motivational systems indicate central processing, and an ability to use complex information suggests sufficient cognitive ability for the animal to have a fitness benefit from a pain experience. Available data are consistent with the idea of pain in some invertebrates and go beyond the idea of just nociception but are not definitive. In the absence of conclusive data, more humane care for invertebrates is suggested.     

Identification of pain,intensity and P300 components in the pain evoked potential

This study examined the relationships among 3 components of the somatosensory evoked potential (SEP) to painful stimuli. Painful stimuli were produced using intracutaneous electrical stimulation of a fingertip and two levels of non-painful stimuli were produced by superficial electrical stimulation of a neighboring fingertip. SEPs were recorded from Cz-A1 and Pz-A1, and difference waves were computed for 3 components: (1) a pain component (the difference between SEPs to painful vs. strong but non-painful stimuli); (2) an intensity component that is not related to pain (the difference between SEPs to strong non-painful vs. mild non-painful stimuli); and (3) a P300 component (the difference between SEPs to the same stimuli under Target instructions vs. Standard instructions).The positive peaks in the 3 types of difference waves differed in both latency and topography, although with latency and topography overlap. The intensity component had an earlier positive peak than the pain component, and the pain component had an earlier positive peak than the P300 component. The pain and intensity components were larger at Cz than Pz, whereas the P300 component was larger at Pz than Cz. Under certain conditions, the pain evoked SEP consists of a weighted combination of the 3 components, complicating interpretation of the positive peaks in the recorded wave forms.     

New Insight into the Time-Course of Motor and Sensory System Changes in Pain

Background

Pain-related interactions between primary motor (M1) and primary sensory (S1) cortex are poorly understood. In particular, the time-course over which S1 processing and corticomotor output are altered in association with muscle pain is unclear. We aimed to examine the temporal profile of altered processing in S1 and altered corticomotor output with finer temporal resolution than has been used previously.

Methods

In 10 healthy individuals we recorded somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) in separate sessions at multiple time-points before, during and immediately after pain induced by hypertonic saline infusion in a hand muscle, and at 15 and 25 minutes follow-up.

Results

Participants reported an average pain intensity that was less in the session where SEPs were recorded (SEPs: 4.0±1.6; MEPs: 4.9±2.3). In addition, the time taken for pain to return to zero once infusion of hypertonic saline ceased was less for participants in the SEP session (SEPs: 4.7±3.8 mins; MEPs 9.4±7.4 mins). Both SEPs and MEPs began to reduce almost immediately after pain reached 5/10 following hypertonic saline injection and were significantly reduced from baseline by the second (SEPs) and third (MEPs) recording blocks during pain. Both parameters remained suppressed immediately after pain had resolved and at 15 and 25 minutes after the resolution of pain.

Conclusions

These data suggest S1 processing and corticomotor output may be co-modulated in association with muscle pain. Interestingly, this is in contrast to previous observations. This discrepancy may best be explained by an effect of the SEP test stimulus on the corticomotor pathway. This novel finding is critical to consider in experimental design and may be potentially useful to consider as an intervention for the management of pain.     

Is there “pain” in Invertebrates?

In contrast to nociception, the perception of pain, or pain experience, remains a subjective notion applicable to humans, but untestable with animals. Yet, when defined operationally as a physiological response induced in an animal by stimuli painful to humans, and resulting in a protective stimulus avoidance response, pain is amenable to testing with non-human subjects. This paper considers a series of examples showing responses to stimuli that are both painful (nociceptive) and responsible for eliciting natural self-preserving behavior in Invertebrates. Consideration is also given to the evolution and possible mechanism underlying the “pain-system” in Invertebrates.     

Biomechanics of musculoskeletal pain: dynamics of the neuromatrix.

Pain, due to mechanical stimuli, is a normal, indeed healthy, response of animals to potential or actual damage to tissues. Mammals in general, and humans in particular, have evolved a highly sophisticated system of pain perception, which is characterized in humans by complementary but distinct neural processing of the intensity and location of a noxious stimulus, and a motivational/emotional or affective response to the stimulus. The peripheral and central neurons that comprise this system, which has been called the 'neuromatrix', dynamically (temporally) respond and adapt to noxious biomechanical stimuli. However, phenotypic variability of the neuromatrix can be large, which can result in a host of musculoskeletal conditions that are characterized by altered pain perception, which can and often does alter the course of the condition. This neural plasticity has been well recognized in the central nervous system, but it has only more recently become known that peripheral nociceptors also adapt to their altered extracellular matrix environment. This work reviews the biomechanics of pain focusing on the relevant stimulus that initiates responses by nociceptors to the cognitive perception of pain.     

Afferent Modulation of Warmth Sensation and Heat Pain in the Human Hand

The hands of 14 normal humans were used to determine the somatotopic organization of the modulation of warmth sensation and heat pain by different forms of cutaneous stimuli. Test stimuli were 5-sec heat pulses ranging from 36° to 51°C, delivered to the fingerpads of digits 1, 2, 4, and 5 with a contact thermode. Conditioning stimuli (15 sec) bracketed the test stimuli and included vibration, noxious and innocuous heat, cold, and electrical pulses delivered to the fingerpads of digits that were adjacent or nonadjacent to the tested digits. Noxious (48° ± 1.3°C), but not innocuous (43°C), heat stimuli increased the perceived magnitude estimation of innocuous test stimuli (36–43°C) by 20–37% when delivered to adjacent, but not to nonadjacent, digits. No other conditioning stimuli had any effect on the intensity of warmth perception. In contrast, both noxious and innocuous heat or electrical conditioning reduced the magnitude estimation of noxious (50–5°C), but not innocuous, test pulses by 12–22% when delivered to adjacent digits. Conditioning of nonadjacent digits was significantly less effective. The analgesic effects of noxious and innocuous conditioning were approximately equal. Vibratory (120 Hz, 3.5 μm) and cold (15°C) conditioning stimuli were ineffective. The results are consistent with a dermatomal somatotopic organization of tactile and heat modulatory influences on warmth sensation and heat pain. The results further suggest that the neural mechanisms subserving warmth mediate a negative feedback influence on heat pain intensity.     

大鼠杏仁核簇与痛觉调制的关系

目的：研究伤害性刺激对大鼠杏仁核簇中各亚核痛反应神经元电活动的影响。方法：用串电脉冲刺激坐骨神经作为伤害性刺激,用玻璃微电极引导神经元放电。结果：杏仁核簇中多个亚核均存在痛反应神经元。伤害性刺激使痛兴奋神经元(PEN)诱发放电频率增加;使痛抑制神经元(PIN)诱发放电频率降低,并出现放电频率极低现象;两类神经元电活动相互配合。腹腔注射吗啡(10mg／kg)可以对抗伤害性刺激对痛反应神经元的作用。结论：杏仁核簇中的部分亚核在感受、整合和传递痛觉信息方面起一定作用,是中枢神经系统控制和处理痛觉信息的一个组成部分。     

Attenuated pain responses in mice lacking Ca(V)3.2 T-type channels

Although T-type Ca(2+) channels are implicated in nociception, the function of specific subtypes has not been well defined. Here, we compared pain susceptibility in mice lacking Ca(V)3.2 subtype of T-type Ca(2+) channels (Ca(V)3.2(-/-)) with wild-type littermates in various behavioral models of pain to explore the roles of Ca(V)3.2 in the processing of noxious stimuli in vivo. In acute mechanical, thermal and chemical pain tests, Ca(V)3.2(-/-) mice showed decreased pain responses compared to wild-type mice. Ca(V)3.2(-/-) mice also displayed attenuated pain responses to tonic noxious stimuli such as intraperitoneal injections of irritant agents and intradermal injections of formalin. In spinal nerve ligation-induced neuropathic pain, however, behavioral responses of Ca(V)3.2(-/-) mice were not different from those of wild-type mice. The present study reveals that the Ca(V)3.2 subtype of T-type Ca(2+) channels are important in the peripheral processing of noxious signals, regardless of modality, duration or affected tissue type.     

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

The ability to perceive noxious stimuli is critical for an animal''s survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species.     

Neonatal repetitive needle pricking: Plasticity of the spinal nociceptive circuit and extended postoperative pain in later life

Repetitive exposure of neonates to noxious events is inherent to their health status monitoring in neonatal intensive care units (NICU). Altered basal nociception in the absence of an injury in later life has been demonstrated in ex‐NICU children, but the impact on pain hypersensitivity following an injury in later life is unknown. Also, underlying mechanisms for such long‐term changes are relatively unknown. The objective of this study is to investigate acute and long‐term effects of neonatal repetitive painful skin‐breaking procedures on nociception and to investigate plasticity of the nociceptive circuit. The repetitive needle prick animal model was used in which neonatal rats received four needle pricks into the left hind paw per day during the first postnatal week and control animals received nonpainful tactile stimuli. Repetitive needle pricking during the first week of life induced acute hypersensitivity to mechanical stimuli. At the age of 8 weeks, increased duration of postoperative hypersensitivity to mechanical stimuli after ipsilateral hind paw incision was shown in needle prick animals. Basal nociception from 3 to 8 weeks of age was unaffected by neonatal repetitive needle pricking. Increased calcitonin gene‐related peptide expression was observed in the ipsilateral and contralateral lumbar spinal cord but not in the hind paw of needle prick animals at the age of 8 weeks. Innervation of tactile Aβ‐fibers in the spinal cord was not affected. Ourresults indicate both acute and long‐term effects of repetitive neonatal skin breaking procedures on nociception and long‐term plasticity of spinal but not peripheral innervation of nociceptive afferents. © 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2013     

Further characterization of nociception-related and arterial pressure-related neuronal responses in the nucleus reticularis gigantocellularis of the rat

The present study was undertaken to further characterize the nucleus reticularis gigantocellularis (NRGC) of the medulla oblongata in the central processing of nociceptive and cardiovascular signals, and its modulation by metenkephalin. In Sprague-Dawley rats anesthetized with pentobarbital sodium, we found that all 125 spontaneously active NRGC neurons that responded to noxious stimuli (tail clamp) also exhibited arterial pressure-relatedness. Forty neurons additionally manifested cardiac periodicity that persisted even during nociceptive responses. While maintaining their cardiovascular responsive characteristics, the nociception-related NRGC neuronal activity was blocked, naloxone-reversibly (0.5 mg/kg, i.v.), by morphine (5 mg/kg, i.v.). Microiontophoretically applied met-enkephalin suppressed the responsiveness of NRGC neurons to individually delivered tail clamp or transient hypertension induced by phenylephrine (5 µg/kg, i.v.). Interestingly, in NRGC neurons that manifested both nociception and arterial pressure relatedness, the preferential reduction in the response to noxious stimuli upon simultaneous elevation in systemic arterial pressure was reversed to one that favored nociception in the presence of met-enkephalin. All actions of met-enkephalin were discernibly blocked by the opioid receptor antagonist, naloxone. Our results suggest that individual NRGC neurons may participate in the processing of both nociceptive and cardiovascular information, or in the coordination of the necessary circulatory supports during nociception. In addition, neuropeptides such as met-enkephalin may exert differential modulation on neuronal responsiveness according to the prevailing physiologic status of the animal. They also showed that NRGC may be a central integrator for pain and cardiovascular-related functions.     

The effects of stimulus location on the gating of touch by heat- and cold-induced pain

The influence of heat- and cold-induced pain on tactile sensitivity, a "touch gate", was measured under conditions in which the location of the noxious stimuli was varied with respect to the tactile stimulus applied to the thenar eminence of humans. Vibrotactile thresholds were measured in the absence of pain and during administration of a painful stimulus, with the stimulus frequencies selected to activate independently the four psychophysical channels hypothesized to exist in human glabrous skin. Heat-induced pain produced by spatially co-localizing the noxious stimuli with the tactile stimuli was found, on average, to elevate threshold amplitude by 2.2 times (6.7 dB). Co-localized, cold-induced pain raised the average thresholds by about 1.5 times (3.6 dB). Heat-induced pain presented contralaterally produced no change in vibrotactile sensitivity indicating that the effect is probably not due to attentional mechanisms. Ipsilateral heat-induced pain caused an elevation in tactile thresholds even when the noxious and non-noxious stimuli were not co-localized, and the effect may seem to require that the painful stimulus be within the somatosensory region defined possibly in terms of dermatomal organization. Thus the effect is probably related to somatotopic organization and is not peripherally mediated. A brief discussion as to the possible locus of the touch gate within the nervous system is also given.     

The effects of stimulus location on the gating of touch by heat- and cold-induced pain

The influence of heat- and cold-induced pain on tactile sensitivity, a "touch gate", was measured under conditions in which the location of the noxious stimuli was varied with respect to the tactile stimulus applied to the thenar eminence of humans. Vibrotactile thresholds were measured in the absence of pain and during administration of a painful stimulus, with the stimulus frequencies selected to activate independently the four psychophysical channels hypothesized to exist in human glabrous skin. Heat-induced pain produced by spatially co-localizing the noxious stimuli with the tactile stimuli was found, on average, to elevate threshold amplitude by 2.2 times (6.7 dB). Co-localized, cold-induced pain raised the average thresholds by about 1.5 times (3.6 dB). Heat-induced pain presented contralaterally produced no change in vibrotactile sensitivity indicating that the effect is probably not due to attentional mechanisms. Ipsilateral heat-induced pain caused an elevation in tactile thresholds even when the noxious and non-noxious stimuli were not co-localized, and the effect may seem to require that the painful stimulus be within the somatosensory region defined possibly in terms of dermatomal organization. Thus the effect is probably related to somatotopic organization and is not peripherally mediated. A brief discussion as to the possible locus of the touch gate within the nervous system is also given.     

Changes of somatosensory evoked potentials with increase of intracranial pressure in the rat's brain

Somatosensory evoked potentials (SEPs) to various combinations of two independent brain compression modalities (localized epidural pressure and intracerebral pressure evoked by an inserted balloon) were investigated in 24 rats. The SEP pattern in response to gradually expanding volume wihtout additional epidural pressure remained unchanged for a certain period. SEP changes occurred only shortly prior to death. On the other hand, remarkable SEP changes were observed in a gradually expanding intracerebral mass, when combined with epidural pressure application at about 50% of the lethal volume. SEP changes in response to intermittent and continuous epidural pressure, in addition to a small intracerebral mass, were investigated too. Intermittent application of minor epidural pressure led to specific P1 changes, which recovered after each pressure step. The same pressure, administered continuously, evoked SEP changes with only partial recovery in some instances. Severe epidural pressure, administered intermittently, gave rise to severe SEP changes with only partial recovery after each step. The same epidural pressure delivered continuously led to SEP changes with very small recovery. SEPs have proved to be a reliable method for signalling brain dysfunction corresponding to various modalities and degrees of intracranial pressure.     

Evolutionary Aspects of the Neuromodulation of Nociceptive Behaviors

There is accumulating evidence for a phylogentic continuityin the expression and regulation of fundamental behaviors ofessential survival value. The ability to detect and respondto aversive environmental stimuli is a basic feature of allanimals that is expressed in the term "nociception." Nociceptiveresponses provide an index of the sensitivity of individualsto actual or potential aversive physical stimuli. Measurementsof alterations in nociceptive responses (antinociception oranalgesia, hyperanalgesia) are commonly used to monitor thebehavioral and physiological status of animals following exposureto either noxious or potentially damaging stimuli. In this paperthe neuromodulation of the nociceptive and analgesic behaviorsof molluscs (the land snail, Cepaea nemoralis) and mammals (rodents)is considered. Behavioral and pharmacological evidence is presentedto suggest that opioid neuropeptides are similarly involvedin the modulation of the nociceptive responses of rodents andsnails. The FMRFamide-related family of neuropeptides are alsoshown to be involved in the modulation of nociceptive behaviors,though with apparently different roles in molluscs and mammals.It is proposed that comparative investigations of the mediationof basic phylogenetically conserved functions, such as nociception,are a useful means to determine and analyse, general featuresof behavioral neuromodulation by neuropeptides.     

The ankyrin repeat domain of the TRPA protein painless is important for thermal nociception but not mechanical nociception

The Drosophila TRPA channel Painless is required for the function of polymodal nociceptors which detect noxious heat and noxious mechanical stimuli. These functions of Painless are reminiscent of mammalian TRPA channels that have also been implicated in thermal and mechanical nociception. A popular hypothesis to explain the mechanosensory functions of certain TRP channels proposes that a string of ankyrin repeats at the amino termini of these channels acts as an intracellular spring that senses force. Here, we describe the identification of two previously unknown Painless protein isoforms which have fewer ankyrin repeats than the canonical Painless protein. We show that one of these Painless isoforms, that essentially lacks ankyrin repeats, is sufficient to rescue mechanical nociception phenotypes of painless mutant animals but does not rescue thermal nociception phenotypes. In contrast, canonical Painless, which contains Ankyrin repeats, is sufficient to largely rescue thermal nociception but is not capable of rescuing mechanical nociception. Thus, we propose that in the case of Painless, ankryin repeats are important for thermal nociception but not for mechanical nociception.     

Single-trial detection for intraoperative somatosensory evoked potentials monitoring

Abnormalities of somatosensory evoked potentials (SEPs) provide effective evidence for impairment of the somatosensory system, so that SEPs have been widely used in both clinical diagnosis and intraoperative neurophysiological monitoring. However, due to their low signal-to-noise ratio (SNR), SEPs are generally measured using ensemble averaging across hundreds of trials, thus unavoidably producing a tardiness of SEPs to the potential damages caused by surgical maneuvers and a loss of dynamical information of cortical processing related to somatosensory inputs. Here, we aimed to enhance the SNR of single-trial SEPs using Kalman filtering and time–frequency multiple linear regression (TF-MLR) and measure their single-trial parameters, both in the time domain and in the time–frequency domain. We first showed that, Kalman filtering and TF-MLR can effectively capture the single-trial SEP responses and provide accurate estimates of single-trial SEP parameters in the time domain and time–frequency domain, respectively. Furthermore, we identified significant correlations between the stimulus intensity and a set of indicative single-trial SEP parameters, including the correlation coefficient (between each single-trial SEPs and their average), P37 amplitude, N45 amplitude, P37-N45 amplitude, and phase value (at the zero-crossing points between P37 and N45). Finally, based on each indicative single-trial SEP parameter, we investigated the minimum number of trials required on a single-trial basis to suggest the existence of SEP responses, thus providing important information for fast SEP extraction in intraoperative monitoring.     

Somatosensory evoked potentials in the telencephalon of Atlantic salmon (<Emphasis Type="Italic">Salmo salar</Emphasis>) following galvanic stimulation of the tail

Electric activity in the brain which is time-locked to a given stimulation of the somatosensory system can be recorded as a somatosensory evoked potential (SEP). We investigated whether a galvanic stimulation of the tail base in Atlantic salmon (Salmo salar) would elicit a SEP in the telencephalon. The telencephalon is central in learning and memory, and activity here may be a prerequisite for processing of external stimuli on a cognitive or emotional level. Anaesthetized salmon (n = 11) were subjected to craniotomy and a recording electrode was inserted into the telencephalon. The fish were given stimulations of four intensities, i.e., 2, 5, 10 and 20 mA. A SEP was elicited in the contralateral dorsal telencephalon for all intensities. This result agrees with findings in other fish species. Furthermore, there was a significant difference between the maximum peak amplitude and mean amplitude of the SEP elicited by putative non-noxious (2 mA) and putative noxious (20 mA) stimulation intensities (P < 0.01). The stronger stimulation intensities also tend to introduce longer-latencies components in the SEP. The results added to the body of literature indicates that the exteroceptive senses are represented by processing within the telencephalon of the fish.     

Diurnal differences in opioid peptide levels correlated with nociceptive sensitivity

An increase in whole mouse brain total opioid levels, determined by mouse was deferens bioassay, was observed in mice sacrified in late afternoon (when they are least responsive to pain) compared to early morning (when they are most responsive to pain). There were no comparable increases in levels of met⁵- or leu⁵- enkephalin measured by RIA methodology. There were differences, however, in the effects of noxious stimuli on met⁵-enkephalin levels in the efternoon compared to the morning. In the afternoon, but not in the morning, the levels of met⁵-enkephalin in mice tested after hot plate stress were significantly increased compared to those of unstressed animals. Thus, there appears to be some correlation between activity in endogenous opioid systems and the ability of mice to withstand noxious stimuli.