Diffuse noxious inhibitory control evoked by tonic craniofacial pain in humans

Tonic pain in one body segment can inhibit the perception of pain in another body segment. This phenomenon is mediated by diffuse noxious inhibitory controls (DNIC), and its efficacy in craniofacial regions is investigated in this study. A compressive device that evoked a tonic, moderate/severe, headache‐like, conditioning pain (～8/10 on a visual analogue scale) was applied for 15 min. Eleven males participated in the study. Pressure pain threshold (PPT) and pressure pain tolerance (PPTol) at multiple heterosegmental body sites (right masseter, splenius capitis, second intermediate phalange, brachioradialis and tibialis anterior) were measured before, during and at multiple time points (5, 20 and 35 min) after the termination of the conditioning pain. PPTs and PPTols were compared within participants across two experimental sessions; one that included painful conditioning stimulation, and a separate control session on a different day. Painful conditioning increased PPT significantly during pain over the masseter (p <0.05) and over the tibialis anterior (p <0.01). PPTol was unchanged. In the period after the painful conditioning stimulation PPT was depressed compared to control. This study shows that pain evoked from the craniofacial region evokes DNIC‐like mechanisms on segmental as well as heterosegmental sites.     

Central sensitization in carpal tunnel syndrome with extraterritorial spread of sensory symptoms

Extraterritorial spread of sensory symptoms is frequent in carpal tunnel syndrome (CTS). Animal models suggest that this phenomenon may depend on central sensitization. We sought to obtain psychophysical evidence of sensitization in CTS with extraterritorial symptoms spread. We recruited 100 unilateral CTS patients. After selection to rule out concomitant upper-limb causes of pain, 48 patients were included. The hand symptoms distribution was graded with a diagram into median and extramedian pattern. Patients were asked on proximal pain. Quantitative sensory testing (QST) was performed in the territory of injured median nerve and in extramedian territories to document signs of sensitization (hyperalgesia, allodynia, wind-up). Extramedian pattern and proximal pain were found in 33.3% and 37.5% of patients, respectively. The QST profile associated with extramedian pattern includes: (1) thermal and mechanic hyperalgesia in the territory of the injured median nerve and in those of the uninjured ulnar and radial nerves and (2) enhanced wind-up. No signs of sensitization were found in patients with the median distribution and those with proximal symptoms. Different mechanisms may underlie hand extramedian and proximal spread of symptoms, respectively. Extramedian spread of symptoms in the hand may be secondary to spinal sensitization but peripheral and supraspinal mechanisms may contribute. Proximal spread may represent referred pain. Central sensitization may be secondary to abnormal activity in the median nerve afferents or the consequence of a predisposing trait. Our data may explain the persistence of sensory symptoms after median nerve surgical release and the presence of non-anatomical sensory patterns in neuropathic pain.     

NGF-evoked sensitization of muscle fascia nociceptors in humans

Nerve growth factor (NGF) induces local hyperalgesia for a few days after intramuscular injection, but longer-lasting muscle pain upon systemic administration. As the muscle fascia is densely innervated by free nerve endings, we hypothesized a lasting sensitization of fascia nociceptors by NGF. We administered 1 μg NGF (dissolved in 100 μL saline) ultrasound-guided to the fascia of the Musculus erector spinae muscle at the lumbar level of 14 male volunteers and assessed hypersensitivity after 6 hours, and 1, 3, 7, 14, and 21 days. Pain upon mechanical stimuli (constant pressure and dynamic impact), upon exercise and electrically induced M. erector spinae contraction, and upon injection of 100 μL phosphate buffer pH4 (at day 7 and 14 only) to the fascia of both NGF- and saline-treated muscles, was investigated. Injections into the muscle fascia did not cause acute pain. Local heat pain thresholds were unchanged following NGF and saline (control) administration. NGF evoked a lasting (days 1-7) and significant reduction of pressure pain, pressure thresholds, exercise-evoked muscle pain, and hyperalgesia to impact stimuli (12 m/s). Pain upon injected protons was significantly elevated (P<0.04) for 2 weeks. NGF induced a sensitization of the muscle fascia to mechanical and chemical stimuli lasting for up to 2 weeks. As nociceptors in the fascia appear to be particularly prone to sensitization, they may contribute to acute or chronic muscle pain.     

Post-operative pain behavior in rats is reduced after single high-concentration capsaicin application

Surgical procedures associated with tissue injury are often followed by increased sensitivity to innocuous and noxious stimuli in the vicinity of the surgical wound. The aim of this study was to evaluate the role of transient receptor potential vanilloid 1 receptor (TRPV1) containing nociceptors in this process, by their functional inactivation using a high-concentration intradermal injection of capsaicin in a rat plantar incision model. Paw withdrawal responses to mechanical stimuli (von Frey filaments 10-367mN) and to radiant heat applied on plantar skin were tested in animals treated with capsaicin or the vehicle 6 days and 24h before or 2h after the incision was made. In the vehicle-treated animals, mechanical and thermal sensitivity increased significantly 1-96h following the incision. Capsaicin applied 24h before the surgery was most effective and significantly diminished the development of post-incisional mechanical allodynia and hyperalgesia. Thermal hypoalgesia was present in the incised paw after the capsaicin treatment. Capsaicin application 6 days before the incision induced thermal hypoalgesia before the incision but did not prevent completely the thermal hyperalgesia after the incision, while there was also a reduction of mechanical hypersensitivity. Application of the capsaicin injection after the incision showed its first effect at 2h after the injection and at 24h the effect was comparable with the 6 days pretreatment. Our results show an important role of TRPV1-containing nociceptors in the development of post-surgical hypersensitivity and suggest that local, high-concentration capsaicin treatment could be used to reduce it.     

General trigeminospinal central sensitization and impaired descending pain inhibitory controls contribute to migraine progression

Migraine is a chronic disease with episodic manifestations. In a subgroup, attack frequency increases over time, leading to chronic migraine. One of the most important risk factors for migraine progression is frequency of headache attacks at baseline. Unfortunately, the actual effects of repeated activation of dural nociceptors are poorly known. We investigated the behavioral, anatomical, and electrophysiological changes induced by repeated low- and high-intensity stimulation of meningeal nociceptor by injecting an inflammatory soup in rats. Single high-intensity, but not low-intensity, stimulation produces a reversible cephalic allodynia. Upon repetition, however, low-intensity stimulation, too, induces a reversible cephalic allodynia, and high-intensity, reversible cephalic and extracephalic allodynia. Moreover, cephalic allodynia becomes, in part, persistent upon repeated high-intensity stimulation. Fos expression reveals that a single high-intensity stimulation already leads to widespread, trigeminal, and spinal central sensitization, and that such general central sensitization potentiates upon repetition. Trigeminovascular nociceptive neurons become persistently sensitized and their diffuse noxious inhibitory controls (DNIC) concomitantly impaired. Thus, compared with single stimulation, repeated dural nociceptor activation specifically leads to: 1) a gradual worsening of cutaneous hypersensitivity and general neuronal hyperexcitability and 2) spreading of cutaneous hypersensitivity superimposed on 3) persistent cephalic cutaneous hypersensitivity and trigeminal central sensitization. Such repetition-induced development of central sensitization and its consequence, cutaneous allodynia, may arise from both the general neuronal hyperexcitability that results from DNIC impairment and hyperexcitability that likely develops in trigeminal nociceptive neurons in response to their repetitive activation. These neuronal changes may in turn elevate the risk for developing chronic migraine.     

Acidic buffer induced muscle pain evokes referred pain and mechanical hyperalgesia in humans

While tissue acidosis causes local deep-tissue pain, its effect on referred pain and mechanical muscle hyperalgesia is unknown. The aim of this study was to investigate a human experimental acidic muscle pain model using a randomized, controlled, single-blinded study design. Seventy-two subjects (36 female) participated in three visits, each involving one 15 min intramuscular infusion into the anterior tibialis muscle: acidic phosphate buffer (pH 5.2) at 40 ml/h (N=69) or 20 ml/h (N=54), normal phosphate buffer (pH 7.3) at 40 ml/h (N=70), or isotonic saline at 40 ml/h (N=19). Pain ratings and pressure sensitivity of superficial and deep tissues were assessed before, during, and 20 min after infusion. Acidic buffer produced light to moderate, rate-dependent, muscle pain (not sex-dependent) compared to the control infusions, that referred pain to the ankle in 80% of women and 40% of men. Pain did not vary across self-reported menstrual phases. Pressure pain thresholds (PPTs) were reduced over the infused muscle with acidic infusion, defined as primary mechanical hyperalgesia. PPTs decreased at the ankle in those with referred pain in response to acidic buffer, i.e. referred mechanical hyperalgesia, but not at the foot. No pain or changes in PPTs occurred in the contralateral leg. These results demonstrate muscle acidosis can lead to local and referred pain and hyperalgesia, with significant sex differences in development of referred pain.     

Similarities between exercise-induced hypoalgesia and conditioned pain modulation in humans

Pain inhibitory mechanisms are often assessed by paradigms of exercise-induced hypoalgesia (EIH) and conditioned pain modulation (CPM). In this study it was hypothesized that the spatial and temporal manifestations of EIH and CPM were comparable. The participants were 80 healthy subjects (40 females), between 18 and 65 years of age in this randomized, repeated-measures cross-over trial that involved data collection on 2 different days. CPM was assessed by 2 different cold pressor tests (hand and foot). EIH was assessed by 2 intensities of aerobic bicycling exercises and 2 intensities of isometric muscle contraction exercises (arm and leg). Pressure pain thresholds (PPTs) were recorded before, during, after, and 15 minutes after conditioning/exercise at sites local to and remote from the extremity used for cold pressor stimulation and exercise. PPTs increased at local as well as at remote sites during both cold pressor tests and after all of the exercise conditions except low-intensity bicycling. EIH after bicycling was higher in women than in men. CPM and the EIH responses after isometric exercises were comparable in men and women and were not affected by age. The EIH response was larger in the exercising body part compared with nonexercising body parts for all exercise conditions. High-intensity exercise produced greater EIH responses than did low-intensity exercise. The change in PPTs during cold pressor tests and the change in PPTs after exercises were not correlated. The CPM response was not dominated by local manifestations, and the effect was seen only during the stimulation, whereas exercise had larger local manifestations, and the effects were also found after exercise.     

Effects of intra-articular ketamine on pain and somatosensory function in temporomandibular joint arthralgia patients

Recent studies have hypothesized that peripheral glutamate receptors could be implicated in deep craniofacial pain conditions. In this study 18 temporomandibular joint (TMJ) arthralgia patients received intra-articular injections of the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, or normal saline to study in a cross-over, double-blinded, placebo-controlled manner the effect on TMJ pain and somatosensory function. Spontaneous pain and pain on jaw function was scored by patients on 0-10 cm visual analogue scale (VAS) for up to 24h. Quantitative sensory tests (QST): tactile, pin-prick, pressure pain threshold and pressure pain tolerance were used for assessment of somatosensory function at baseline and up to 15 min after injections. There were no significant effects of intra-articular ketamine over time on spontaneous VAS pain measures (ANOVA: P=0.532), pain on jaw opening (ANOVA: P=0.384), or any of the somatosensory measures (ANOVA: P>0.188). The poor effect of ketamine could be due to involvement of non-NMDA receptors in the pain mechanism and/or ongoing pain and central sensitization independent of peripheral nociceptive input. In conclusion, there appears to be no rationale to use intra-articular ketamine injections in TMJ arthralgia patients, and peripheral NMDA receptors may play a minor role in the pathophysiology of this disorder.     

Bilateral activation of the trigeminothalamic tract by acute orofacial cutaneous and muscle pain in humans

The conscious perception of somatosensory stimuli is thought to be located in the contralateral cerebral cortex. However, recent human brain imaging investigations in the spinal system report bilateral primary somatosensory cortex (SI) activations during unilateral noxious stimuli and that this ipsilateral spinal representation may be independent of transcallosal connections. In the trigeminal system, there is primate evidence for an ipsilateral somatosensory pathway through the thalamus to the face SI. However, the organization of the trigeminal nociceptive pathway in the human is not clear. The aim of this study was to determine whether noxious stimuli applied to the face are transmitted to the cerebral cortex by bilateral pathways. We used functional magnetic resonance imaging (fMRI) to compare ipsilateral and contralateral activation of the thalamus, SI and secondary somatosensory cortex (SII) during muscle and cutaneous orofacial pain and innocuous facial stimulation in healthy human subjects. We found that both muscle and cutaneous noxious stimuli, from injections of hypertonic saline into the right masseter or overlying skin, evoked bilateral increases in signal intensity in the region encompassing the ventral posterior thalamus as well as the face region of SI and SII. In contrast, innocuous unilateral brushing of the lower lip evoked a strict contralateral ventroposterior thalamic activation, but bilateral activation of SI and SII. These data indicate that, in contrast to innocuous inputs from the face, noxious information ascends bilaterally to the face SI through the ventroposterior thalamus in humans.     

Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury

Sigma-1 receptor (σ₁R) is expressed in key CNS areas involved in nociceptive processing but only limited information is available about its functional role. In the present study we investigated the relevance of σ₁R in modulating nerve injury-evoked pain. For this purpose, wild-type mice and mice lacking the σ₁R gene were exposed to partial sciatic nerve ligation and neuropathic pain-related behaviors were investigated. To explore underlying mechanisms, spinal processing of repetitive nociceptive stimulation and expression of extracellular signal-regulated kinase (ERK) were also investigated. Sensitivity to noxious heat of homozygous σ₁R knockout mice did not differ from wild-type mice. Baseline values obtained in σ₁R knockout mice before nerve injury in the plantar, cold-plate and von Frey tests were also indistinguishable from those obtained in wild-type mice. However, cold and mechanical allodynia did not develop in σ₁R null mice exposed to partial sciatic nerve injury. Using isolated spinal cords we found that mice lacking σ₁R showed reduced wind-up responses respect to wild-type mice, as evidenced by a reduced number of action potentials induced by trains of C-fiber intensity stimuli. In addition, in contrast to wild-type mice, σ₁R knockout mice did not show increased phosphorylation of ERK in the spinal cord after sciatic nerve injury. Both wind-up and ERK activation have been related to mechanisms of spinal cord sensitization. Our findings identify σ₁R as a constituent of the mechanisms modulating activity-induced sensitization in pain pathways and point to σ₁R as a new potential target for drugs designed to alleviate neuropathic pain.     

Effects of subcutaneous administration of glutamate on pain, sensitization and vasomotor responses in healthy men and women

The present study aimed to investigate if (1) subcutaneous injection of glutamate induces pain, sensitization and vasomotor responses in humans and (2) if sex differences exist in these responses. Thirty healthy volunteers (men-15 and women-15) were included. Each subject received four subcutaneous injections (0.1ml; glutamate 100, 10, 1mM and isotonic saline 0.9%) into the forehead skin in two sessions separated by one week. Assessments of pain intensity (VAS), quality, distribution; area of pinprick hyperalgesia; pressure pain threshold (PPT) at the injection site; surface skin temperature and local blood flow were performed at predetermined time points. The highest concentration of glutamate evoked the highest pain intensity, the longest duration of pain and the largest pain area under the VAS-time curve (P<0.001) in both men and women, although responses in women were larger than in men (P<0.05). The face-chart pain area was the largest for the highest concentration of glutamate (P<0.001) and women drew a larger pain area than men (P=0.024). The area of pinprick hyperalgesia was the largest for glutamate 100mM (P<0.001) and women indicated a larger area than men (P<0.001). Concentration-dependent local vasomotor responses were found following the subcutaneous injection of glutamate but there was no sex difference in this effect. Glutamate 100mM significantly reduced the PPT values (P<0.001) without sex-related differences. The present study demonstrates for the first time that subcutaneous injection of glutamate evokes pain, vasomotor responses and pinprick hyperalgesia in human volunteers and that there are sex-related differences in some of these responses.     

Changes in morphine analgesia and side effects during daily subcutaneous administration in healthy volunteers

Tolerance to the anti-nociceptive effects of opioids develops rapidly in animals. In contrast, humans with chronic pain show little or no loss of pain relief in prospective opioid trials of 4-8 weeks duration. Employing the Brief Thermal Sensitization model to induce transient cutaneous secondary hyperalgesia, we tested the hypothesis that opioid analgesic tolerance would develop rapidly. In this outpatient randomized placebo-controlled study, subjects in the MMMMP group received two injections of subcutaneous morphine 6 mg (150 min apart) on Monday-Thursday (total 48 mg over 4 days) and matching saline placebo on Friday. Subjects in the PPPPM group received placebo on Monday-Thursday and morphine (total 12 mg) on Friday. Sixty-one healthy volunteers were enrolled; morphine side effects accounted for all nine non-completions. Compared to the first placebo day, the reduction in the area of secondary hyperalgesia on the first morphine day was significant and robust in both groups. Morphine suppression of the painfulness of skin heating and elevation of the heat pain detection threshold were also significant. During 4 days of twice-daily injections, the decline in anti-hyperalgesic effects of morphine did not reach statistical significance (p=0.06) compared to placebo. Morphine side effects did not correlate with anti-hyperalgesic effects and withdrawal symptoms did not emerge. As 4 days is the threshold for demonstrating analgesic tolerance to twice-daily morphine in animal models, a longer period of opioid exposure in healthy volunteers might be needed to detect analgesic tolerance.     

Experimental pain in human temporal muscle induced by hypertonic saline, potassium and acidity

The study was aimed at developing a reference model for experimental pain and tenderness in the human temporal muscle by the local injection of hypertonic saline, potassium chloride and acidic phosphate buffer, using isotonic saline as control. The design was randomized and double-blind. Twenty healthy subjects had 0.2 ml test solution injected into one temporal muscle and saline into the other. Following each injection, pain was rated on a 10-point ordinal scale and pressure-pain thresholds were measured every minute for 10 min by a pressure algometer. Hypertonic saline (n = 11) and potassium chloride (n = 12) induced significantly more pain than isotonic saline (ANOVA, p less than 0.0001). Compared to control injections, hypertonic saline and potassium chloride induced a significant reduction in pressure-pain threshold (ANOVA, p less than 0.0001 and p less than 0.05). Forty-eight percent of the injections led to the referral of pain most often to the jaws. A positive correlation between the relative occurrence of referred pain and pain intensity was observed (p less than 0.001) as was a negative correlation between the decrease in pressure-pain threshold and pain intensity (p less than 0.05).     

Interaction between histamine-induced itch and experimental muscle pain.

Itch sensation can be inhibited by simultaneously applied cutaneous pain at the same skin site via a central mechanism. Deep muscle pain is often associated with sensory changes in the corresponding dermatome. We investigated whether experimentally induced muscle pain has any influence on histamine-induced itch and vice versa in a double blind placebo-controlled study. Experiments were performed in 18 healthy subjects. In nine individuals control iontophoresis of histamine into the forearm produced a distinct itch sensation. Another nine individuals participated in an additional experiment in which histamine and saline were iontophoresed on the forearm in a randomized double-blinded two-way crossover design after intramuscular injection of capsaicin into the ipsilateral brachioradial muscle. Capsaicin-induced muscle pain reduced itch sensation significantly. In contrast, capsaicin-induced muscle pain increased significantly after cutaneous histamine application compared to muscle pain after iontophoresis of saline (placebo). These novel data indicate that muscle pain inhibits itch and histamine increases muscle pain. A bi-directional interaction between cutaneous histamine-sensitive afferents and nociceptive muscle afferents via central mechanisms is suggested.     

Temporal summation of heat pain in humans: Evidence supporting thalamocortical modulation

Noxious cutaneous contact heat stimuli (48 °C) are perceived as increasingly painful when the stimulus duration is extended from 5 to 10 s, reflecting the temporal summation of central neuronal activity mediating heat pain. However, the sensation of increasing heat pain disappears, reaching a plateau as stimulus duration increases from 10 to 20 s. We used functional magnetic resonance imaging (fMRI) in 10 healthy subjects to determine if active central mechanisms could contribute to this psychophysical plateau. During heat pain durations ranging from 5 to 20 s, activation intensities in the bilateral orbitofrontal cortices and the activation volume in the left primary (S1) somatosensory cortex correlated only with perceived stimulus intensity and not with stimulus duration. Activation volumes increased with both stimulus duration and perceived intensity in the left lateral thalamus, posterior insula, inferior parietal cortex, and hippocampus. In contrast, during the psychophysical plateau, both the intensity and volume of thalamic and cortical activations in the right medial thalamus, right posterior insula, and left secondary (S2) somatosensory cortex continued to increase with stimulus duration but not with perceived stimulus intensity. Activation volumes in the left medial and right lateral thalamus, and the bilateral mid-anterior cingulate, left orbitofrontal, and right S2 cortices also increased only with stimulus duration. The increased activity of specific thalamic and cortical structures as stimulus duration, but not perceived intensity, increases is consistent with the recruitment of a thalamocortical mechanism that participates in the modulation of pain-related cortical responses and the temporal summation of heat pain.     

Torso muscle EMG profile differences between patients of back pain and control

Background

Electrophysiological criteria that identify and characterize low back pain can lead to better understanding of the afliction and possibly aid in its treatment.

Method

Nineteen male and 22 female subjects with chronic back pain, without lumbar radiculopathy; and 30 male and 33 female control subjects with no history of low back pain in the last 12 months, were recruited into the study. All subjects flexed, extended, laterally flexed, flexed anterolaterally and extended posterolaterally isometrically to 20% and 100% of their maximal voluntary contraction (MVC). Additionally, patients were asked to do these activities to their pain threshold levels and control subjects to 60% maximum voluntary contraction. Surface electromyograms (EMG) were recorded from lumbar erectores spinae, external obliques and rectus abdominis bilaterally. The electromyogram was subjected to magnitude, Fast Fourier Transform, and wavelet analyses. The median frequency and frequency bands were calculated with their power. The wavelet decomposition was done and a logistic discriminate analysis was carried out to classify patients and normal controls.

Findings

The normalized peak electromyograms of patients were significantly greater than controls (P < 0.01). The muscle conduction velocity was not disturbed by pain. Significant differences were found in total power between patients and controls (P < 0.01). The analysis correctly classified patients and controls 65% and 98% of the time, respectively at 20% MVC, 95.1% (patients) and 86.8% (controls) at pain threshold/60% MVC, and 74.3% (patients) and 86.4% (controls) at pain tolerance/MVC (P < 0.05).

Interpretation

The surface electromyography can be used in discriminating chronic low back pain patients and controls. This would be an objective test over and above other subjective tests, such as pain provocation.     

Experimental muscle pain and tenderness following infusion of endogenous substances in humans.

Several human models of myofascial pain exist, but none are similar to clinical pain. The aim of the present study was to develop a clinically relevant model of prolonged human myofascial pain using infusion of the naturally occurring endogenous substances. Initially, bradykinin (Bk), serotonin (5-hydroxytryptamine (5-HT)), histamine (His), prostaglandin E(2) (PGE(2)), adenosine-tri-phosphate (ATP), and their combinations were infused into the trapezius muscle of 36 healthy subjects in a total of 67 sessions to identify substances, which could induce a moderate muscle pain. PGE(2), ATP, and a combination of Bk, 5-HT, His, and PGE(2) produced the intended moderate pain. These substances were further examined in a randomised, blinded, placebo-controlled dose-finding design in 15 healthy subjects in 68 sessions. PGE(2) (3, 6, and 12 nmol/ml) induced mild pain and tenderness not different from placebo. ATP (9000, 18,000, and 36,000 nmol/ml) induced pain of moderate to strong intensity (P=0.04) and the dose of 18,000 nmol/ml furthermore produced moderate local tenderness (P=0.04). Because of unacceptable side effects in subsequent examinations, further studies of ATP in humans were suspended. Infusion of the combination of Bk (92 nmol), 5-HT (156 nmol), His (140 nmol), and PGE(2) (1.95 nmol) produced a moderate pain intensity (P=0.04) and mild tenderness (P=0.04) without inducing unacceptable side effects. Intramuscular infusion of a combination of Bk, 5-HT, His, and PGE(2) induced a prolonged moderate pain and tenderness in healthy humans, and this model may be a valuable tool in future studies of the pathophysiological mechanisms of myofascial pain.     

Leptin enhances NMDA-induced spinal excitation in rats: A functional link between adipocytokine and neuropathic pain

Recent studies have shown that leptin (an adipocytokine) played an important role in nociceptive behavior induced by nerve injury, but the cellular mechanism of this action remains unclear. Using the whole-cell patch-clamp recording from rat’s spinal cord slices, we showed that superfusion of leptin onto spinal cord slices dose-dependently enhanced N-methyl-d-aspartate (NMDA) receptor-mediated currents in spinal cord lamina II neurons. At the cellular level, the effect of leptin on spinal NMDA-induced currents was mediated through the leptin receptor and the JAK2/STAT3 (but not PI3K or MAPK) pathway, as the leptin effect was abolished in leptin receptor-deficient (db/db) mice and inhibited by a JAK/STAT inhibitor. Moreover, we demonstrated in naïve rats that a single intrathecal administration of leptin enhanced spontaneous biting, scratching, and licking behavior induced by intrathecal NMDA and that repeated intrathecal administration of leptin elicited thermal hyperalgesia and mechanical allodynia, which was attenuated by the noncompetitive NMDA receptor antagonist MK-801. Intrathecal leptin also upregulated the expression of NMDA receptors and pSTAT3 within the rat’s spinal cord dorsal horn, and intrathecal MK-801 attenuated this leptin effect as well. Our data demonstrate a relationship between leptin and NMDA receptor-mediated spinal neuronal excitation and its functional role in nociceptive behavior. Since leptin contributes to nociceptive behavior induced by nerve injury, the present findings suggest an important cellular link between the leptin’s spinal effect and the NMDA receptor-mediated cellular mechanism of neuropathic pain.     

Systematic review of movement-evoked pain versus pain at rest in postsurgical clinical trials and meta-analyses: a fundamental distinction requiring standardized measurement

To estimate frequency of movement-evoked pain (MEP) measurement in human postsurgical investigations, we reviewed thoracotomy, knee arthroplasty, and hysterectomy clinical trials and meta-analyses. Only 39% of trials measured MEP and 52% failed to identify pain outcome as pain at rest (PAR) or MEP. Temporal trending did not suggest that MEP measurement is becoming more frequent. Trials measuring both MEP and PAR suggest that MEP is 95-226% more intense than PAR in the first 3 postoperative days. Among trials measuring MEP, 38% did not specify the physical maneuver used to assess MEP. Five of 7 meta-analyses reviewed (71%) did not distinguish between PAR and MEP, and none of the 7 meta-analyses declared the 20-59% of reviewed trials that had failed to identify their pain outcome as PAR or MEP. These results suggest an unchanging neglect of MEP in postsurgical pain trials and frequent failure to identify pain outcome as PAR or MEP. This is an important problem because MEP is usually more severe than PAR; MEP exerts a more direct adverse impact on postsurgical functional recovery and several current and novel pain treatments differentially affect MEP vs PAR. Failure to distinguish between PAR and MEP and standardize their measurement threatens trial precision and ability to identify interventions with the most clinically relevant effects on pain. We therefore recommend developing consistent terminology regarding PAR and MEP, considering inclusion of MEP as a pain outcome in every postsurgical trial, and standardizing measurement of PAR and MEP on a procedure-specific basis.     

Habituation and sensitization to heat and cold pain in women with fibromyalgia and healthy controls

The purpose of this study was to examine differences in habituation to heat and cold pain in women with fibromyalgia (FM; n = 33) and in women who were healthy controls (HC; n = 44). Quantitative sensory testing (QST) was used to assess pain thresholds during five consecutive trials of ascending heat and descending cold stimulation. Anxiety, depression, fatigue, and pain during the previous week were assessed using self-report measures. The overall hypotheses were that there would be differences between groups in pain thresholds and in the rate of habituation to heat and cold pain stimuli. Multilevel modeling was used to test the hypotheses. There were large overall differences in pain thresholds, with the FM group showing greater sensitivity to heat and cold pain stimuli compared with the HC group. While habituation occurred in both of the groups for heat pain, the HC group had stronger habituation across trials than the FM group. Conversely, while the HC group habituated to cold pain stimuli, the FM group showed sensitization and had decreased cold pain thresholds across trials (they felt cold pain at higher temperatures). In addition, anxiety, depression, fatigue, and pain were related to decreased heat and cold pain thresholds in the overall sample. However, when group was controlled, none of these variables were related to thresholds or rates of habituation or sensitization. The differences between women with FM and healthy women in habituation and sensitization may have important implications for the etiology, diagnosis, and treatment of FM and other chronic pain conditions.