Glial activation and pathological pain

Pain is a sensation we have all experienced. For most of us, the pain has been temporary. However, for patients with pathological pain, the pain experience is unending, with little hope for therapeutic relief. Pathological pain is characterized by an amplified response to normally innocuous stimuli, and an amplified response to acute pain. Pathological pain has long been described as the result of dysfunctional neuronal activity. While neuronal functioning is indeed altered, there is significant evidence showing that exaggerated pain is regulated by the activation of astrocytes and microglia. In exaggerated pain, astrocytes, and microglia are activated by neuronal signals including substance P, glutamate, and fractalkine. Activation of glia by these substances leads to the release of mediators that then act on other glia and neurons. These include a family of proteins called "proinflammatory cytokines" released from microglia and astrocytes. These cytokines have been shown to be critical mediators of exaggerated pain. Some patients with pathological pain also report "extra-territorial" and/or "mirror" image pain. That is, exaggerated pain is experienced not only in the area of trauma. In extra-territorial pain, pain is also perceived as arising from neighboring healthy tissues outside of the site of trauma. In the rare cases of mirror-image pain, such pain is perceived as arising from the healthy, corresponding body part on the opposite side of the body. New data suggest that activation of astrocyte communication via gap junctions may mediate such spread of pain. While traditional therapies for pathological pain have focused on neuronal targets, the following review describes glia as newly recognized mediators of exaggerated pain, and as new therapeutic targets. Moreover, the glial-neuronal interactions discussed here are likely not exclusive to pain, but rather are likely to play significant roles in other behavioral phenomena.     

Pain in Parkinson′s Disease: A Cross-Sectional Study of Its Prevalence,Types, and Relationship to Depression and Quality of Life

Pain is an important and distressing symptom in Parkinson’s disease (PD). Our aim was to determine the prevalence of pain, its various types and characteristics, as well as its impact on depression and quality of life (QoL) in patients with PD. How pain differs in early- and advanced-stage PD and male and female PD patients was of special interest. One hundred PD patients on dopaminergic medications had a neurological examination and participated in a structured interview on pain characteristics and completed standardized questionnaires. A total of 76% of the patients had pain. The following types of pain were present: musculoskeletal pain accounted for 41% of the total pain, dystonic pain for 17%, central neuropathic pain for 22%, radicular pain for 27%, and other pains (non-radicular low back pain, arthritic, and visceral pain) made up 24%. One type of pain affected 29% of all the subjects, two types 35%, three types 10%, and four types of pain were reported by 2%. All types of pain were more prevalent in advanced-stage PD subjects than in early-stage PD subjects, except for arthritic pain (subclassified under”other pain”). The frequency and intensity of actual, average, and worst experienced pain were significantly more severe in advanced-stage subjects. PD subjects with general pain and in advanced stages were more depressed and had poorer QoL. Depression correlated with worst pain in the last 24 hours and with pain periodicity (the worst depression score in patients with constant pain). QoL correlated with average pain in the last 7 days. Pain is a frequent problem in PD patients, and it worsens during the course of the disease.     

Persistent pain accelerates xenograft tumor growth of breast cancer in rat

Pain occurs at all stages of the patients who suffer from cancer. Owing to surgery and bone metastasis, breast cancer patients were usually disturbed by persistent pain. However, the pain-relief-right has not been respected enough in clinical cancer treatment. Whether pain has any adverse effects on cancer development is still unclear. In order to uncover this question, we established two preclinical animal models to explore the effects of pain on the tumor. For the first model, we mimicked neuropathic pain by sciatic nerve ligation on rats with xenograft tumor subcutaneously. For the second model, we mimicked the bone cancer pain by injecting tumor cell suspension into the tibial medullary cavity of rats with xenograft tumor subcutaneously. The rats with persistent pain showed higher tumor volume and tumor weight compared with the group without pain. Interestingly, when the neuropathic pain and bone cancer pain were relieved by drug administration, both the tumor volume and tumor weight were lowered compared with the group without pain relief. In summary, our study indicated that persistent pain acted as a contributing factor to tumor growth. Moreover, the pain relief could weakened the accelerating role of pain in tumor growth. Thus, we should be paid more attention to the cancer patients with persistent pain as well as cancer treatment.     

褪黑色素对缰核痛神经元单位放电的影响及可能机制

目的通过观察褪黑色素对缰核痛神经元单位放电的影响,进一步证明褪黑色素的中枢镇痛作用及可能机制。方法：应用细胞外神经元单位放电记录方法,记录缰核神经元痛相关神经元放电,并观察外侧缰核痛神经元在褪黑色素作用下电活动的改变,及对伤害性刺激痛敏感性的改变,在此基础上观察纳洛酮的翻转作用。结果：褪黑色素影响外侧缰核痛神经元的电活动,并使外侧缰核痛神经元对伤害性刺激敏感性降低,此种作用可被纳洛酮翻转。结论：褪黑色素可通过作用于外侧缰核的阿片受体而影响其痛相关神经元对痛刺激的反应,这可能是褪黑色素中枢镇痛机制之一。     

Effect of experimental muscle pain on maximal voluntary activation of human biceps brachii muscle

Muscle pain has widespread effects on motor performance, but the effect of pain on voluntary activation, which is the level of neural drive to contracting muscle, is not known. To determine whether induced muscle pain reduces voluntary activation during maximal voluntary contractions, voluntary activation of elbow flexors was assessed with both motor-point stimulation and transcranial magnetic stimulation over the motor cortex. In addition, we performed a psychophysical experiment to investigate the effect of induced muscle pain across a wide range of submaximal efforts (5-75% maximum). In all studies, elbow flexion torque was recorded before, during, and after experimental muscle pain by injection of 1 ml of 5% hypertonic saline into biceps. Injection of hypertonic saline evoked deep pain in the muscle (pain rating ～5 on a scale from 0 to 10). Experimental muscle pain caused a small (～5%) but significant reduction of maximal voluntary torque in the motor-point and motor cortical studies (P < 0.001 and P = 0.045, respectively; n = 7). By contrast, experimental muscle pain had no significant effect on voluntary activation when assessed with motor-point and motor cortical stimulation although voluntary activation tested with motor-point stimulation was reduced by ～2% in contractions after pain had resolved (P = 0.003). Furthermore, induced muscle pain had no significant effect on torque output during submaximal efforts (P > 0.05; n = 6), which suggests that muscle pain did not alter the relationship between the sense of effort and production of voluntary torque. Hence, the present study suggests that transient experimental muscle pain in biceps brachii has a limited effect on central motor pathways.     

Effect of pulsed electromagnetic field therapy on experimental pain: A double-blind,randomized study in healthy young adults

ABSTRACT

Previous studies suggested that pulsed electromagnetic field (PEMF) therapy can decrease pain. To date, however, it remains difficult to determine whether the analgesic effect observed in patients are attributable to a direct effect of PEMF on pain or to an indirect effect of PEMF on inflammation and healing. In the present study, we used an experimental pain paradigm to evaluate the direct effect of PEMF on pain intensity, pain unpleasantness, and temporal summation of pain. Twenty-four healthy subjects (mean age 22 ± 2 years; 9 males) participated in the experiment. Both real and sham PEMF were administered to every participant using a randomized, double-blind, cross-over design. For each visit, PEMF was applied for 10 minutes on the right forearm using a portable device. Experimental pain was evoked before (baseline) and after PEMF with a 9 cm² Pelletier-type thermode, applied on the right forearm (120 s stimulation; temperature individually adjusted to produce moderate baseline pain). Pain intensity and unpleasantness were evaluated using a 0–100 numerical pain rating scale. Temporal summation was evaluated by comparing pain intensity ratings obtained at the end of tonic nociceptive stimulation (120 s) with pain intensity ratings obtained after 60 s of stimulation. When compared to baseline, there was no change in pain intensity and unpleasantness following the application of real or sham PEMF. PEMF did not affect temporal summation. The present observations suggest that PEMF does not directly influence heat pain perception in healthy individuals.     

Glutamate transporter: an unexpected target for some antibiotics

Molecular pain is a relatively new and rapidly expanding research field that represents an advanced step from conventional pain research. Molecular pain research addresses physiological and pathological pain at the cellular, subcellular and molecular levels. These studies integrate pain research with molecular biology, genomics, proteomics, modern electrophysiology and neurobiology. The field of molecular pain research has been rapidly expanding in the recent years, and has great promise for the identification of highly specific and effective targets for the treatment of intractable pain. Although several existing journals publish articles on classical pain research, none are specifically dedicated to molecular pain research. Therefore, a new journal focused on molecular pain research is needed. Molecular Pain, an Open Access, peer-reviewed, online journal, will provide a forum for molecular pain scientists to communicate their research findings in a targeted manner to others in this important and growing field.     

Opposing effects of expectancy and somatic focus on pain

High-pain expectancy increases pain and pain-related brain activity, creating a cycle of psychologically maintained pain. Though these effects are robust, little is known about how expectancy works and what psychological processes either support or mitigate its effects. To address this, we independently manipulated pain expectancy and "top-down" attention to the body, and examined their effects on both a performance-based measure of body-focus and heat-induced pain. Multi-level mediation analyses showed that high-pain expectancy substantially increased pain, replicating previous work. However, attention to the body reduced pain, partially suppressing the effects of expectancy. Furthermore, increased body-focus had larger pain-reducing effects when pain expectancy was high, suggesting that attempts to focus on external distractors are counterproductive in this situation. Overall, the results show that attention to the body cannot explain pain-enhancing expectancy effects, and that focusing on sensory/discriminative aspects of pain might be a useful pain-regulation strategy when severe pain is expected.     

GCH1-polymorphism and pain sensitivity among women with provoked vestibulodynia

ABSTRACT: BACKGROUND: Provoked vestibulodynia (PVD) is a pain disorder localized in the vestibular mucosa. It is the most common cause of dyspareunia among young women and it is associated with general pain hypersensitivity and other chronic pain conditions. Polymorphism in the guanosine triphosphate cyclohydrolase (GCH1) gene has been found to influence general pain sensitivity and the risk of developing a longstanding pain condition. The aim of this study was to investigate GCH1-polymorphism in women with PVD and healthy controls, in correlation to pain sensitivity. RESULTS: We found no correlation between the previously defined pain-protective GCH1-SNP combination and the diagnosis of PVD. Nor any correlation with pain sensitivity measured as pressure pain thresholds on the arm, leg and in the vestibule, coital pain scored on a visual analog scale and prevalence of other bodily pain conditions among women with PVD (n = 98) and healthy controls (n = 102). However, among patients with current treatment (n = 36), there was a significant interaction effect of GCH1-gene polymorphism and hormonal contraceptive (HC) therapy on coital pain (p = 0.04) as well as on pressure pain thresholds on the arm (p = 0.04). PVD patients carrying the specified SNP combination and using HCs had higher pain sensitivity compared to non-carriers. In non-HC-users, carriers had lower pain sensitivity. CONCLUSIONS: The results of this study gave no support to the hypothesis that polymorphism in the GCH1-gene contributes to the etiology of PVD. However, among patients currently receiving treatment an interaction effect of the defined SNP combination and use of hormonal contraceptives on pain sensitivity was found. This finding offers a possible explanation to the clinically known fact that some PVD patients improve after cessation of hormonal contraceptives, indicating that PVD patients carrying the defined SNP combination of GCH1 would benefit from this intervention.     

Altered Pain Sensitivity in Elderly Women with Chronic Neck Pain

Background

Age-related changes occur in both the peripheral and central nervous system, yet little is known about the influence of chronic pain on pain sensitivity in older persons. The aim of this study was to investigate pain sensitivity in elders with chronic neck pain compared to healthy elders.

Methods

Thirty elderly women with chronic neck pain and 30 controls were recruited. Measures of pain sensitivity included pressure pain thresholds, heat/cold pain thresholds and suprathreshold heat pain responses. The pain measures were assessed over the cervical spine and at a remote site, the tibialis anterior muscle.

Results

Elders with chronic neck pain had lower pressure pain threshold over the articular pillar of C5-C6 and decreased cold pain thresholds over the cervical spine and tibialis anterior muscle when compared with controls (p < 0.05). There were no between group differences in heat pain thresholds and suprathreshold heat pain responses (p > 0.05).

Conclusion

The presence of pain hypersensitivity in elderly women with chronic neck pain appears to be dependent on types of painful stimuli. This may reflect changes in the peripheral and central nervous system with age.     

Adaptive modifications of cold pain (author's transl)]

38 healthy subjects 22-28 years of age underwent the cold-pressor-test seven times on each of 21 consecutive days always at the same time of day. The subjective sensations of cold pain and the objective circulatory reactions were registered. There was observed only a very distinct subjective cold pain habituation from one exposition to the other. The habituation effect on blood pressure reaction however was of expected extent. The long term adaptation showed to have effect on the predominance of the two components of pain perception the epicritic and protopathic pain experience. Initially the cold stimulus produced an overwhelmingly protopathic sufferenig whilst at the end of the three weeks of adaptation there remained only a reduced and localized epicritic pain sensation. Typological differences of pain reactions and pain adaptation are discussed.     

The development of nociceptive circuits

The study of pain development has come into its own. Reaping the rewards of years of developmental and molecular biology, it has now become possible to translate fundamental knowledge of signalling pathways and synaptic physiology into a better understanding of infant pain. Research has cast new light on the physiological and pharmacological processes that shape the newborn pain response, which will help us to understand early pain behaviour and to design better treatments. Furthermore, it has shown how developing pain circuitry depends on non-noxious sensory activity in the healthy newborn, and how early injury can permanently alter pain processing.     

Dopamine Precursor Depletion Influences Pain Affect Rather than Pain Sensation

Pain is a multidimensional experience, which includes sensory, cognitive, and affective aspects. Converging lines of evidence indicate that dopaminergic neurotransmission plays an important role in human pain perception. However, the precise effects of dopamine on different aspects of pain perception remain to be elucidated. To address this question, we experimentally decreased dopaminergic neurotransmission in 22 healthy human subjects using Acute Phenylalanine and Tyrosine Depletion (APTD). During APTD and a control condition we applied brief painful laser stimuli to the hand, assessed different aspects of pain perception, and recorded electroencephalographic responses. APTD-induced decreases of cerebral dopaminergic activity did not influence sensory aspects of pain perception. In contrast, APTD yielded increases of pain unpleasantness. The increases of unpleasantness ratings positively correlated with effectiveness of APTD. Our finding of an influence of dopaminergic neurotransmission on affective but not sensory aspects of phasic pain suggests that analgesic effects of dopamine might be mediated by indirect effects on pain affect rather than by direct effects on ascending nociceptive signals. These findings contribute to our understanding of the complex relationship between dopamine and pain perception, which may play a role in various clinical pain states.     

Nociceptor activation and pain

This paper reviews advances in our knowledge on the physiological properties of human nociceptors and their capacity to signal pain. Conventional microneurography was used in combination with intraneural microstimulation in subjects who estimated the magnitude of pain from nociceptor stimulation. The experimental evidence favours the notion that C polymodal nociceptors can provide a peripheral neuronal basis for determination of heat pain threshold and also an essential peripheral code for suprathreshold magnitude judgments of heat pain. Furthermore, sensitized C polymodal nociceptors can contribute to hyperalgesia after a mild heat injury to hairy skin. Temporal summation is documented for dull, delayed C fibre pain, which is different in quality and less accurately projected than the fast, sharp pain from high-threshold A delta nociceptors. A segmental organization is shown for projected and referred pain from deep structures. Examples are given of central inhibition of pain by a prostaglandin synthetase inhibitor, and by physical manoeuvres such as vibration and cooling. Recent reports on microneurographic findings after nerve injury indicate that the technique may be useful for future studies on pathophysiological pain mechanisms.     

The modification of cortical reorganization and chronic pain by sensory feedback

Recent neuroscientific evidence has revealed that the adult brain is capable of substantial plastic change in areas such as the primary somatosensory cortex that were formerly thought to be modifiable only during early experience. We discuss research on phantom limb pain as well as chronic back pain that revealed functional reorganization in both the somatosensory and the motor system in these chronic pain states. In phantom limb pain patients, cortical reorganization is correlated with the amount of phantom limb pain; in low back pain patients the amount of reorganizational change increases with chronicity. We present a model of the development of chronic pain that assumes an important role of somatosensory pain memories. In phantom limb pain, we propose that those patients who experienced intense pain prior to the amputation will later likely develop enhanced cortical reorganization and phantom limb pain. We show that cortical plasticity related to chronic pain can be reduced by behavioral interventions that provide feedback to the brain areas that were altered by somatosensory pain memories.     

The Disruptive Effects of Pain on Complex Cognitive Performance and Executive Control

Pain interferes and disrupts attention. What is less clear is how pain affects performance on complex tasks, and the strategies used to ensure optimal outcomes. The aim of the current study was to examine the effect of pain on higher-order executive control processes involved in managing complex tasks. Sixty-two adult volunteers (40 female) completed two computer-based tasks: a breakfast making task and a word generation puzzle. Both were complex, involving executive control functions, including goal-directed planning and switching. Half of those recruited performed the tasks under conditions of thermal heat pain, and half with no accompanying pain. Whilst pain did not affect central performance on either task, it did have indirect effects. For the breakfast task, pain resulted in a decreased ability to multitask, with performance decrements found on the secondary task. However, no effects of pain were found on the processes thought to underpin this task. For the word generation puzzle, pain did not affect task performance, but did alter subjective accounts of the processes used to complete the task; pain affected the perceived allocation of time to the task, as well as switching perceptions. Sex differences were also found. When studying higher-order cognitive processes, pain-related interference effects are varied, and may result in subtle or indirect changes in cognition.     

Heart rate biofeedback and cold pressor pain: effects of expectancy

The study investigated the effects of expectancy on the reduction of cold pressor test pain using heart rate biofeedback training. Thirty-six male subjects were given an initial 45-sec cold pressor test, 25 heart rate decrease feedback training trials, and a final cold pressor test in which they were told to decrease their heart rate, but without the aid of feedback. Two levels of outcome expectancy (increase pain, decrease pain) and two levels of cold pressor water temperature (0 degrees C, 5 degrees C), resulting in four groups (N = 9 per group), were used to assess the interaction between expectancy and aversive stimulus intensity. Immediately prior to the final cold pressor test, the increase pain expectancy subjects were told that decreasing their heart rate during the ice water immersion would cause more pain. Decrease pain subjects were told that decreasing their heart rate would cause less pain. Expectancy was found to be the major determinant of pain reports. The decrease pain subjects consistently reported less pain on the final cold pressor, whereas the increase pain subjects consistently reported more pain. Contrary to prediction, expectancy effects were greater for the colder water. The findings indicate the importance of expectancy in the clinical use of biofeedback to control pain.     

Multicentre study of cancer pain and its treatment in France.

OBJECTIVE--To describe the treatment of cancer pain in France and to evaluate the predictive factors for inadequate management. DESIGN--Multicentre, representative cross sectional survey. SETTING--20 treatment centres, including cancer centres, university hospitals, state hospitals, private clinics, and one homecare setting (in which patients are supported at home). SUBJECTS--605 patients with cancer. MAIN MEASURES--Patients rated prevalence and severity of pain and functional impairment related to pain. Doctors reported patients'' cancer characteristic, performance status, pain severity, and analgesic drugs ordered. RESULTS--57% (340/601) of patients with cancer reported pain due to their disease, and, of those with pain, 69% (224/325) rated their worst pain at a level that impaired their ability to function. 30% (84/279) were reported as receiving no drugs for their pain. Of the 270 patients in pain for whom information on treatment was available 51% (137/270) were not receiving adequate pain relief, according to an index based on the World Health Organisation''s guidelines. French doctors were found to underestimate the severity of their patients'' pain. Younger patients, patients without metastatic disease, patients with a better performance status, and patients who rated their pain as more severe than their doctors did were at greater risk for undertreatment of their pain. CONCLUSIONS--In the light of the high prevalence and the severity of pain among patients with cancer, the assessment and treatment of cancer pain in France remain inadequate, emphasising the need for changes in patient care.     

Identifying and preventing pain during and after surgery in farm animals

Pain research in farm animals has focused on routine husbandry procedures such as dehorning; much less known about the pain associated with the other surgeries such as those required for displaced abomasum and caesarean delivery. We review the literature on pain in farm animals due to non-routine procedures including laporatomy, caesarean sections, ovariectomy and ovariohysterectomy, displaced abomasums, cannulations, vasectomy and claw removal. Where there are gaps in the farm animal literature, we describe relevant studies on wildlife, companion and lab animals. This review addresses both pain responses during surgery and the pain that animals experience in the hours and days that follow. Surgical procedures sometimes cause pain responses due to damage of somatic tissues (skin, muscle, joints, etc.) and the viscera, and there is some evidence that these pain responses differ. Overall conclusions from this review are that surgical pain in farm animals is under studied, and the resulting lack of knowledge, awareness, assessment tools and treatment protocols means that both intra-operative and post-operative pain are often under treated.     

The influence of rate of temperature change and peak stimulus duration on pain intensity and quality

An important aspect of experimental pain research is that the assessment methods can investigate the different aspects of pain perception. The aim of the present study was to investigate the influence of rate of temperature change and peak stimulus duration on heat evoked pain intensity and quality. All stimuli were applied within the medial aspect of the anterior forearm. The rate of temperature change was varied from 1 to 16 C/s without any effect on the pain threshold. The pain threshold decreased with an increasing peak stimulus duration from 0.1 to 2 s, but not from 2 to 3 s. The pain intensity for suprathreshold stimuli (46 C, 48 C, 50 C) increased for decreasing rates and increasing duration. The pain intensity was highly correlated with the energy of the stimulus. When the rates of temperature change (1-16 C/s) are varied, no differences between pricking and burning pain were present at either low stimulus intensity (46 C) or high stimulus intensity (50 C). At low stimulus intensity (46 C), the pricking pain was not influenced by the duration (0.1-3 s), but the burning pain was intensified when the duration was increased from 1.5 to 3 s. At high intensity stimuli (50 C), the pricking pain intensified with an increased duration, whereas burning pain did not. The heat pain threshold is influenced by the peak stimulus duration, and not by the rate of temperature change. If suprathreshold stimuli are used, both the rate of temperature change and the peak stimulus duration can strongly affect the pain intensity and the pain quality. Therefore, the same stimulus modality can be used to assess the modulation of different pain intensities and of the pricking and burning pain qualities simply by varying the stimulus configuration.