Perception Of Noxious Stimuli Research Articles

Uncovering the role of neuropeptide receptor GPR83 in nociception

Nociception, the perception of noxious stimuli, is a critical function for the sensation of pain that protects us from damaging ourselves and helps protect the body following an injury. While pain is important, many people suffer from chronic pain due to a dysregulation of the mechanisms that detect noxious stimuli. G‐protein coupled receptors (GPCRs) are critical regulators of cell function making them frequent targets of therapeutic agents. The recent identification of the neuropeptide PEN as an endogenous ligand for the GPCR, GPR83, opens the possibility of exploring the neurobiological function of this receptor. Recent studies have provided evidence that GPR83 is expressed in a specific ascending spinal tract and that these neurons are highly sensitive to mechanical stimuli. New tools to study GPR83 include small molecule agonists and antagonists. Using these compounds, we have identified that GPR83 agonists blunt morphine antinociception while antagonists enhance morphine antinociception. Since morphine is the most effective therapeutic for pain this suggests that GPR83 is involved in the pain pathway however, it is unknown whether there is a direct impact of GPR83 on nociception. Moreover, the potential of targeting GPR83 to alleviate chronic pain has not been investigated. We have preliminary data suggesting that GPR83 antagonists increase sensitivity to mechanical stimuli while having no impact on thermal stimuli. Our study aims to further characterize GPR83’s role in nociception and to identify whether this receptor has any direct impact on pain itself, using the Complete Freud’s Adjuvant (CFA) model of inflammatory pain.

A Novel Progress: Glial Cells and Inflammatory Pain

Inflammatory pain is the perception of noxious stimuli that occurs during inflammation or an immune response. Glial cells are widespread in the central and peripheral nervous systems, supporting and guiding the migration of neurons, participating in the immune response, forming the myelin sheath and blood-brain barrier, and maintaining the concentration of potassium ions outside nerve cells. Recent studies have shown that glial cells have a significant connection with the production and development of inflammatory pain. This article reviews the relationship, mechanisms, therapeutic targets between five types of glial cells and inflammatory pain, and the medicine composition that can effectively inhibit inflammatory pain. It expands the study on the mechanism of glial cells regulating pain and provides new ideas for the therapy of inflammatory pain.

The Role of the Cerebellum in Pain Perception: A Brain SPECT Perfusion Study in Patients with Burn Injuries.

Virtual reality (VR) is a promising tool for distraction analgesia. This study aims to compare brain perfusion patterns while patients were undergoing burn wound care in two conditions-VR distraction and control (NoVR). With IRB approval, four patients hospitalized for acute burn care (three males and one female) participated in the study. All patients underwent wound care on two consecutive days; 1 day with standard analgesia and adjunctive VR, and the other day with standard analgesia alone, otherwise the wound care was very similar. Tc-99m ethyl cysteinate dimer was injected during wound care at the time of peak pain. Subjective patient reports on a 0-10 scale of pain intensity, time spent thinking about pain, and "fun" as well as opioid equivalent usage were analyzed. Voxel by voxel subtraction analysis of brain perfusion Single Photon Emission Computed Tomography (SPECT) images was performed at the group level. Statistical significance threshold was defined as P<.05. Mean group subjective scores (VR, NoVR, statistical significance, and P-value) were observed for maximal pain intensity (9.0, 8.8, insignificant, and P = .809), time spent thinking about pain (5.2, 10.0, significant, and P = .015), and fun (6.0, 2.5, significant, and P = .012). Subtraction group analysis demonstrated VR-induced modulation of brain activity with statistically significant relative suppression of cerebellar activation in the VR compared to intense cerebellar activation in the NoVR environments. Relative decrease in cerebellar perfusion based on stringent statistical threshold in the VR environment combined with improved subjective pain experience supports the hypotheses on the role of cerebellum in perception of noxious stimuli.

Sex and Gender Issues in Pain Management.

➢ Differences exist between men and women in response to noxious stimuli.➢ Sex-based differences in the perception of noxious stimuli and gender-based differences in the expression of, or behavioral response to, pain have been identified, but much of the current research is difficult to extrapolate to clinical settings.➢ The response to opioids and the risks of misuse or addiction vary between men and women, although many studies of addiction do not assess data on the basis of sex or gender.

Breast Feeding as Analgesia in Neonates: A Randomized Controlled Trial

Introduction: Major myth regarding neonatal pain suggests that neonates because of their neurological immaturity do not experience pain. Although exact mechanism is not known, it is proposed that breast feeding through combination of various senses and the closeness of the infant’s mother, saturates the senses thus reducing perception of noxious stimuli. The objective of this study was to investigate the analgesic effect of breastfeeding during blood sampling through heel lance in healthy term neonates.Material and Methods: This was a Randomized controlled trial done in a Tertiary level Neonatal Intensive Care Unit. Sixty healthy term newborns, undergoing heel prick were included in study. Neonates were randomly assigned to two groups: Group I (breastfed) with; Group II (not breast fed). Babies were given heel prick and crying time, Heart rate, SpO2 and BP monitored. Changes in various physiological parameters following a heel prick were studied in two groups.Results: Neonates in both groups expressed pain by crying, increase in heart rate, fall in transcutaneous oxygen saturation and rise in blood pressure. Compared to control group, the babies who were breast fed were found to have lesser crying time (40.04 sec and 69.09 sec respectively, p&lt;0.05) and lesser rise in heart rate (rise of 21.78 and 34.46 bpm respectively, p&lt;0.03). In the breast fed group there was a trend to a lesser decrease in oxygen saturation and lesser rise in blood pressure though this was not statistically significant.Conclusion: Breast feeding offers a quick and effective means of reducing pain in neonates during routine neonatal procedures.J Nepal Paediatr Soc 2016;36(3):238-242

Pharmacological modulation of aversive responsiveness in honey bees

Within a honey bee colony, individuals performing different tasks exhibit different sensitivities to noxious stimuli. Noxious-stimulus sensitivity can be quantified in harnessed bees by measuring the sting extension response (SER) to a series of increasing voltages. Biogenic amines play a crucial role in the control of insect responsiveness. Whether or not these neurotransmitters affect the central control of aversive responsiveness, and more specifically of electric-shock responsiveness, remains unknown. Here we studied the involvement of the biogenic amines octopamine, dopamine and serotonin, and of the ecdysteroid 20-hydroxyecdisone in the central control of sting responsiveness to electric shocks. We injected pharmacological antagonists of these signaling pathways into the brain of harnessed bees and determined the effect of blocking these different forms of neurotransmission on shock responsiveness. We found that both octopamine and 20-hydroxyecdisone are dispensable for shock responsiveness while dopamine and serotonin act as down-regulators of sting responsiveness. As a consequence, antagonists of these two biogenic amines induce an increase in shock responsiveness to shocks of intermediate voltage; serotonin, can also increase non-specific responsiveness. We suggest that different classes of dopaminergic neurons exist in the bee brain and we define at least two categories: an instructive class mediating aversive labeling of conditioned stimuli in associative learning, and a global gain-control class which down-regulates responsiveness upon perception of noxious stimuli. Serotonergic signaling together with down-regulating dopaminergic signaling may play an essential role in attentional processes by suppressing responses to irrelevant, non-predictive stimuli, thereby allowing efficient behavioral performances.

P2X7 Receptor and Cytokines Contribute to Extra-territorial Facial Pain

The whisker pad area (WP) is innervated by the second branch of the trigeminal nerve and experiences allodynia and hyperalgesia following transection of the mental nerve (MN; the third branch of the trigeminal nerve). However, the mechanisms of this extra-territorial pain remain unclear. The ionotropic P2X7 ATP receptor (P2X7) in microglia is known to potentiate, via cytokines, the perception of noxious stimuli, raising the possibility that P2X7 and cytokines are involved in this extra-territorial pain. One day after MN transection (MNT), WP allodynia/hyperalgesia developed, which lasted for > 8 wks. Activation of microglia and up-regulation of P2X7, membrane-bound tumor necrosis factor (TNF)-α (mTNF-α), and soluble TNF-α (sTNF-α) in the trigeminal sensory nuclear complex (TNC) were evident for up to 6 wks after MNT. Allodynia/hyperalgesia after MNT was blocked by intracisternal administration of etanercept, a recombinant TNF-α receptor (p75)-Fc fusion protein. Intracisternal A438079, a P2X7 antagonist, also attenuated allodynia/hyperalgesia and blocked up-regulation of mTNF-α and sTNF-α in the TNC. We conclude that sTNF-α released by microglia following P2X7 activation may be important in both the initiation and maintenance of extra-territorial pain after MNT.

Pain Perception and Anaesthesia in Research Frogs

Frogs possess pain receptors and pathways that support processing and perception of noxious stimuli however the level of organization is less well structured compared to mammals. It was long believed that the experience of pain was limited to 'higher' phylums of the animal kingdom. However, it is now commonly accepted that amphibians possess neuro-anatomical pathways conductive of a complete nociceptive experience. Xenopus laevis frogs have been one of the most popular aquatic research models for developmental studies and genetic research. These frogs have been extensively use in research for their eggs, that can be collected following hormonal stimulation either naturally or by surgical intervention. Many anaesthetics have been used in amphibians such as bath solutions of MS-222, benzocaine and eugenol as well as systemic injections of ketamine or tiletamine, barbiturates, propofol and gas administrations of methoxyflurane, halothane and isoflurane. Most of these anaesthetic drugs produce variability in depth and duration of anaesthesia. MS-222 appears to be one of the most reliable anaesthetics. This review will focus on the evidence of pain perception in frogs and will compare the effectiveness and limitations of different anaesthetics used in Xenopus leavis frogs.

NaV1.7 Splice Variant from Human Heart Compared with Neuronal hNaV1.7

Perception of noxious stimuli can be profoundly affected by mutations in the gene SCN9A which encodes the α-subunit of the voltage-gated sodium channel NaV1.7. Mutantions of this channel are associated with chronic pain or complete absence of pain. Primary erythermalgia and paroxysmal extreme pain disorder are syndromes associated with attacks of severe pain resulting from mutations that enhance NaV1.7 channel activity. Non-sense mutations in SCN9A lead to complete loss of NaV1.7 function. Loss of NaV1.7 function produces complete insensitivity to pain and anosmia, but little other changes in functions or behaviors. The pain-specific nature of the mutant NaV1.7 phenotypes is in keeping with the notion that this channel is expressed primarily in dorsal root ganglia and, to a lesser extent in the sympathetic ganglia. These premises make NaV1.7 an ideal target for the development of novel non-addictive analgesics. However, expression of NaV1.7 has been detected in the heart, with 5- to 10-fold higher levels in human cardiac Purkinje fibres versus the right atrium and ventricle and bradycardia and cardiac asystole have been reported in patients with paroxysmal extreme pain disorder. While these events have usually been ascribed to autonomic effects of the NaV1.7 mutations, a more direct effect of altered NaV1.7 in the heart cannot be ruled out. We have set out to clone and characterize the specific NaV1.7 subtype expressed in the human heart. In the present study we cloned and characterized a NaV1.7 subtype predominantly expressed in the human heart. This novel splice variant, missing one exon, may impact drug safety for this emerging family of analgesics. Its biophysical and pharmacological properties have been studied and will be discussed in comparison to the neuronal variant.

Hippocampal Mechanisms Linking Chronic Pain and Depression

ABSTRACTThe emotional or affective component of pain regulates mood; it occurs primarily in the brain's limbic system; and a negative impact on affect is required in order for stimulus to be accurately portrayed as “painful.” The integration of sensory and affective components of pain and the ensuing activation of higher brain centers involved in the perception of noxious stimuli is an emerging topic within the field of pain neurobiology. A relationship between pain and mood has been supported by numerous clinical studies indicating significant comorbidity of chronic pain and various types of depressive illnesses. Besides the assumption that pain is simply a form of stress, the physiological basis for the coexistence of pain and depression is still being investigated. Studies described in this review address some of the cellular and molecular events occurring within the hippocampus that may be common to both pain and stress, possibly reflecting underlying mechanisms of chronic pain-related depression.

Personality traits associated with perception of noxious stimuli in women with vulvar vestibulitis syndrome

Vulvar vestibulitis syndrome (VVS) is associated with enhanced pain sensitivity. The present study explores the role of personality on the perception of noxious stimuli among women with VVS. More specifically, the aim of the study was to explore whether the personality traits assessed by Cloninger’s Tridimensional Personality Questionnaire (TPQ) (harm avoidance [HA], novelty seeking [NS], and reward dependence [RD]) are associated with the augmented pain perception in women with VVS. Quantitative sensory tests were applied to the forearm of 98 women with VVS and 135 control subjects, all of whom completed the TPQ. The women with VVS scored higher than the control subjects on HA and RD with no significant differences in NS. Linear regression analyses revealed that in the VVS group, lower pain thresholds and higher magnitude estimations of suprathreshold pain stimuli were associated with higher HA and RD scores. The enhanced pain perception among women with VVS might reflect their tendency to respond intensely to signals of reward and to elevate the perceived risk. This might lead them to avoid hazards by overestimating the level of potential harm, as represented by greater pain sensitivity. Perspective The association between personality traits assessed by Cloninger’s Tridimensional Personality Questionnaire, ie, harm avoidance, novelty seeking, and reward dependence, and the enhanced perception of noxious stimuli in vulvar vestibulitis syndrome might suggest neurochemical mechanisms of pain experience affected by personality, with possible application for future treatment approaches toward pain disorders.

Studies of Narcosis: Charles Ernest Overton Introduction

It is unnecessary to describe the horror of surgery prior to the demonstration of ether anaesthesia at Massachusetts General Hospital in 1846. It was clearly a nightmare for patients and must have been little better for the medical personnel involved in so terrifying an undertaking. What is less obvious is that the introduction of anaesthesia accomplished far more than the abolition of intraoperative pain. The solution of the problem of pain enabled the evolution of virtually all of modern surgical therapeutics. Prior to this development, the major characteristic of a technically brilliant surgeon was speed the ability to do a below-the-knee amputation in less than a minute made or unmade reputations. Intra-cavitary surgery; operations in the chest, abdomen or skull were largly unthinkable and when attempted, commonly led to the death of the patient, not because of pain per se, but because the surgeon had no time in which to think and take deliberate action. So practical were the properties of anaesthetics, that their clinical use spread rapidly throughout the medical world without the least understanding of the mechanisms by which the agents worked. The drugs obviously produced unconsciousness and freedom from the perception of noxious stimuli. It was also desirable that they did so as rapidly as possible, and that such effects were completely reversible with few physiological side effects. We would not dispute these requirements today. Within the context of thencurrent chemical knowledge, three agents appeared to fit all or some of this description. Diethyl ether, as used by Morton, became the standard for generations. Nitrous oxide provided all the correct attributes but one sufficient potency to cause unconsciousness and surgical anaesthesia. Chloroform also provided the requisite analgesia and unconsciousness and was used for decades, despite its potentially lethal side effects. The early lack of understanding and, indeed, concern about anaesthetic mechanisms of action should not be too surprising. Very few of the drugs then in use were understood in any detail. Drugs were found largely by trial and error in animals and humans. That they worked and were relatively safe was all that was required. In the context of this pragmatic medical world, Ernest Overton was a fascinating exception. Bom in Cheshire, England, in 1865, Overton was a distant relative of Charles Darwin. His maternal grandfather, Reverend W. Darwin Fox was an entomologist, second cousin and close friend of Darwin. With his family, Overton moved to Switzerland at the age of seventeen and there completed his education. He received

Interaction between vanilloid receptors and purinergic metabotropic receptors: pain perception and beyond.

The capsaicin or vanilloid receptor (VR) plays an important role in transducing thermal and inflammatory pain. The VR is a nonselective cation channel that possesses a high permeability to Ca2+ ( P Ca/ P Na ratio ≈10, similar to that of the N- methyl-d-aspartate receptor), exhibits strong outward rectification, and desensitizes after repeated stimulation (tachyphylaxis) (1). Two types of VRs (VR1, VR-L) and a splice variant (VR.5′sv) have been cloned (2–4). Generally, VRs are thought to be distributed in peripheral sensory nerve endings and involved in the perception of noxious stimuli. The activation of VRs depolarizes the sensory nerve endings and evokes a train of action potentials that propagates to the spinal cord and brain. Mice lacking the VR1 gene have deficits in thermal- or inflammation-induced hyperalgesia but are sensitive to noxious heat, which largely confirms a role in certain modalities of nociception (5, 6). On the other hand, purinergic receptors (P2Y) also are expressed in nociceptive sensory nerve endings. They are either coupled directly to ion channels (ionotropic) or to the G protein-mediated production of second messengers (metabotropic). Seven ionotropic (P2X1–7) and six genuine metabotropic receptors (P2Y1,2,4,6,11,12) (from a total of 13 P2Y-like cDNA clones) have been cloned. The P2X3 subtype is exclusively expressed in the peripheral nerve endings (7, 8). Algesic properties of ATP are thought to occur by the activation of P2X receptors. Although the source for extracellular ATP is a debated issue, a number of possibilities have been suggested: ( i ) mechanical stimulation; ( ii ) activation of connexin hemichannels; ( iii ) synaptic vesicle exocytosis; ( iv ) tissue damage; and ( v ) from nerve endings after noxious stimulation (7, 9). Activation of P2X3 receptors by ATP is not a favorable means of nociception because …

7-Nitroindazole, a selective inhibitor of neuronal nitric oxide synthase: effect on sevoflurane MAC and cerebellar cyclic GMP in mice.

Considerable evidence suggests that nitric oxide (NO) plays a role in synaptic transmission in the central and peripheral nervous systems. However, whether inhibition of NO synthesis decreases minimum alveolar concentration (MAC) of inhalational anesthetics is controversial. We examined the effects of 7-nitroindazole (7-NI), a selective inhibitor of neuronal NOS (nNOS), on the MAC of sevoflurane and cerebellar cyclic guanosine monophosphate (cGMP) levels in mice. Sevoflurane MAC and cerebellar cGMP levels were determined in mice after acute intraperitoneal or weeklong gavage feeding of 7-NI. Sevoflurane MAC and cerebellar cGMP levels after chronic treatment were measured on days 1, 4, and 7 and were repeated after an acute intraperitoneal dose of nitro g -L-arginine methylester (L-NAME). Acute and chronic treatment with 7-NI decreased the sevoflurane MAC by 20%-30%. Reduction of cerebellar cGMP levels was greater after intraperitoneal administration of NOS inhibitors than after gavage feeding of 7-NI. Acute or chronic selective inhibition of neuronal NOS decreases the sevoflurane MAC and cerebellar cGMP levels in mice. 7-NI permitted probing of the role of NO in perception of noxious stimuli.

Identification of a Sex-Specific Quantitative Trait Locus Mediating Nonopioid Stress-Induced Analgesia in Female Mice

It is increasingly appreciated that the sexes differ in their perception of noxious stimuli and in their responsivity to exogenous and endogenous analgesic manipulations. We previously reported the existence of qualitative sex differences in the neurochemical mediation of nonopioid (i.e., naloxone-insensitive) stress-induced analgesia (SIA) produced by forced swims and suggested that female mice possess a sex-specific SIA mechanism. This female-specific system is now known to be estrogen-dependent, to be ontogenetically organized, and to vary with reproductive status; however, its neurochemical identity remains obscure. In an attempt to identify candidate genes underlying SIA in both sexes, we performed a two-phase quantitative trait locus (QTL) mapping experiment using the BXD/Ty recombinant inbred (RI) set derived from DBA/2J (D2) and C57BL/6J (B6) inbred mouse strains and (B6xD2)F2 hybrid mice derived from these same progenitors. All mice were subjected to 3 min forced swims in 15 degrees C water; nociceptive sensitivity on the 54 degrees C hot-plate assay was assessed immediately before and 2 min after cessation of the swim. We report the localization of a QTL statistically associated with SIA magnitude [p = 0.00000012; logarithm of the odds (LOD) = 6.1] in female mice only. This female-specific QTL, which we name Fsia1, is located on chromosome 8 at 52-84 cM from the centromere and accounts for 17-26% of the overall trait variance in this sex. The present data provide further evidence of the existence of a female-specific SIA mechanism and highlight the important role of both genetic background and gender in the inhibition of pain.

Pain perception in idiopathic cervical dystonia (spasmodic torticollis)

Cervical spinal pain is frequently found in conjuction with idiopathic cervical dystonia (ICD), a focal dystonia characterized by sustained deviation of the head. Since the perception of noxious stimuli has never been studied in ICD, we performed a controlled study to obtain more insight into the psychophysics of dystonia-related muscle pain by evaluating pressure-induced pain levels. In nine ICD patients and five gender- and age-matched asymptomatic control subjects, pain-pressure thresholds (PPTs) were determined in the sternocleidomastoid and upper trapezius muscles, both at resting activity and at maximal voluntary contraction (MVC). The masseter muscles served as non-pathological control regions. To determine the accuracy of PPT values, pain intensity and unpleasantness were rated at threshold on 100-mm visual analogue scales. Four replication measurements were obtained. The data were analyzed by multilevel procedures. For all muscles under investigation, average PPTs of the ICD patients were about two times lower than those of the control subjects ( P < 0.001–0.0005) and showed a smaller intra-subject variance. Further, average PPTs at MVC were about two times higher than those at resting activity ( P < 0.005). These results provide psychophysical evidence to suggest that, at controlled levels of muscle contractions, the threshold of pain perception is decreased in ICD. In addition, ICD patients seem to be better able to establish their own PPTs than control subjects, which might be due to a different setting of the discriminative aspect of pain in ICD. Surprisingly, lower intestiny and unpleasantness scores were found in ICD patients with coinciding painful and deviated sides than in ICD patients for whom the painful side was opposite to the deviated one ( P < 0.05). This finding might be of clinical importance for defining functional disability and predicting treatment outcome.

Effects of prenatal morphine treatment of rats on mortality, bodyweight and analgesic response in the offspring

A method is presented for the maternal ingestion of morphine in rats in order to investigate morphine's prenatal effects. Effects on the offspring of the treatment throughout pregnancy were compared with effects of treatment during specific periods of the pregnancy. Morphine treatment (25 mg/kg per day) throughout pregnancy resulted in 0% survival of the offspring. Morphine treatment up to gestational day 21 resulted in 65.4 ± 7.7% survival of the offspring, and up to gestational day 17 in 31.8 ± 13% survival. Reduction in the neonatal birth weight was maximal in animals treated with 25 mg/kg of morphine per day from gestational day 4 throughout pregnancy. The analgesic effect of morphine in the offspring was tested with the hot plate method. Male offspring treated with morphine from gestational day 1 to day 17 showed an elevated thermal response after morphine injections on day 80–90 post partum. These findings indicate a long-lasting, post-partum alteration in that part of the opiate system involved in the perception of noxious stimuli.

Excitation of feline cutaneous mechanosensitive C-fiber sensory units by intraarterial administration of potassium ions

Response of low- and high-threshold mechanosensitive C fiber sensory units (MSU) in n. saphenus to close-arterial injection of potassium ions in subnoxious and noxious concentrations (SC and NC) were investigated in anesthetized cats. Two groups of high-threshold units were found: 1) MSU reacting to K+ at both SC and NC, but responding very differently to each of these concentrations and 2) MSU responding to NC only. Findings would indicate that high-rather than lowthreshold MSU participate in the perception of noxious stimuli. The possibility of differentiation between subnoxious and noxious stimuli by a proportion of high-threshold MSU is considered. High-threshold MSU discharges accompanying excitation of these units by subnoxious and noxious chemical stimuli are quantified.

Cerebral responses to electrical tooth pulp stimulation in man. An objective correlate of acute experimental pain.

The pulp of individual teeth of 17 normal adult volunteers was electrically stimulated via pairs of electrodes implanted into dentine. Computer-summated responses recorded from the surface of the head were composed of two concurrent sequences of events, one of which was seen maximally over midline areas and the other over the lower portions of the postcentral regions. Appropriate tests demonstrated that these wave forms represented cerebral tooth pulp-evoked potentials. Because tooth pulp-evoked potentials represent objective, quantifiable, nonverbal concomitants of central events associated with the perception of noxious stimuli, they may prove helpful in investigating acute experimental pain in man.

Alteration of activity of single neurons in the nucleus centrum medianum following stimulation of the peripheral nerve and application of noxious stimuli.

Using unanesthetized cats, investigation of the perception of the sensory information in the CM-neuron was conducted by microelectrodical recording of the spontaneous discharge of the neuron, the driven unitary discharge following stimulation of the peripheral nerve and the action potential of the neuron in response to noxious stimuli. The prerequisite for the CM-neuron was to establish that convergence of the splanchnic and sciatic transmissions existed in the neuron and that the neuron responded to noxious stimuli. The present authors have analysed 82 units of the CM-neuron which fulfilled the prerequisites.The results were summarized in the following way.The spontaneous discharge of the CM-neuron had a frequency of 5 to 25 per second. The average interval showed 34.1 msec with a standard deviation of 13.8 msec. The deviation was relatively large. The spontaneous discharge did not show a burst-like volley as far as the animal was in an unanesthetic condition. The interval of the spontaneous firing became shortened as the frequency increased in stimulation of the peripheral nerve. When stimulation of 1 cps was applied to the peripheral nerve, the spontaneous discharge of the CM neuron succeeding from the driven unitary discharge increased in firing rate and was facilitated for 550 msec. When stimulation of 10 cps was applied to the peripheral nerve, the driven unitary discharge of the CMneuron did not follow an individual stimulus but the spontaneous unitary discharge was extremely facilitated. The spontaneous firing of the CM-neuron was facilitated in various modes following tetanic stimulation of the splanchnic nerve. The neurons in 59% showed a marked continuous facilitation of the spontaneous firing and some of these neurons showed a facilitation of the spontaneous firing in close relation to the spindle burst of the slow potential.And the neurons in 25% showed a marked inhibition of the spontaneous unitary discharge followed by a phasic facilitation.The receptive field of the CM-neuron responding to noxious stimuli was very large and covered the part on both sides of the body, extending to more than two limbs. The firing rate of action potential and the duration of after-discharge were different according to the site of the receptive field. The reactability of the CM-neuron to noxious stimuli was augmented to increase the frequency of action potential and to prolong the duration of of terdischarge, following brief train stimulation of the MRF or contralateral CM by 10 cps or 100 cps.The perception of noxious stimuli was mostly related to the spontaneous discharge of the CM-neuron and supported by excitation in the polysynaptic central core conduction.