Pain and allodynia/hyperalgesia induced by intramuscular injection of serotonin in patients with fibromyalgia and healthy individuals

The aim of this study was to investigate the effect of injection of serotonin (5-HT) into the masseter muscle on pain and allodynia/hyperalgesia. Twelve female patients with fibromyalgia (FM) and 12 age-matched female healthy individuals (HI) participated in the study. The current pain intensity (CPI) and the pressure pain threshold (PPT) of the superficial masseter muscles were assessed bilaterally. 5-HT in one of three randomized concentrations (10(-3), 10(-5), 10(-7) M) or isotonic saline was then injected into either of the two masseter muscles in a double-blind manner. After the injections the CPI and PPT were recorded ten times during 30 min. The injections were repeated twice with the other concentrations of 5-HT after 1 and 2 weeks, respectively. In the FM-group there was a non-significant increase of CPI after injection that lasted during the entire 30-min period irrespective of whether 5-HT or saline was injected. Neither did the PPT change significantly. In the HI-group pain developed significantly after injection irrespective of whether 5-HT or saline was injected, but significantly more so after 5-HT at 10(-3) M than saline injection. CPI decreased quickly and then remained on a very low level for most of the experiment. 5-HT at both 10(-5) M and 10(-3) M caused a significantly greater decrease of PPT than saline. In conclusion, our results show that 5-HT injected into the masseter muscle of healthy female subjects elicits pain and allodynia/hyperalgesia, while no such responses occur in patients with fibromyalgia.     

Effect of propranolol and granisetron on experimentally induced pain and allodynia/hyperalgesia by intramuscular injection of serotonin into the human masseter muscle

We have previously reported that intramuscular injection of serotonin (5-HT) into the masseter muscle elicits pain and allodynia/hyperalgesia in healthy subjects. The aim of this study was to investigate whether the 5-HT(3) receptor antagonist granisetron or 5-HT(1A) receptor antagonist propranolol can reduce 5-HT induced pain and allodynia/hyperalgesia in the masseter muscle. Twenty-four healthy individuals (12 males and 12 females) without pain from the masseter muscle region participated. They were examined clinically including tenderness to digital palpation (TDP) and pressure pain threshold (PPT) of the masseter muscle. 5-HT in combination with granisetron or propranolol was randomly injected on one side in a double-blind manner. 5-HT in combination with saline was used on the contralateral side. After the injections the pain intensity and PPT were recorded 10 times during 30min. After the last recording the TDP was assessed again. The injections were repeated with the other antagonist within 1 week. All three combinations of substances elicited pain after injection, which lasted for 5-8min. 5-HT induced significantly more pain than granisetron+5-HT and propranolol+5-HT. The TDP increased significantly after injection of all combinations of substances, but there was no significant difference between them. The PPT decreased significantly after injection of 5-HT and increased significantly after injection of granisetron+5-HT, while it did not change significantly after injection of propranolol+5-HT. The difference between 5-HT and granisetron+5-HT was significant. In conclusion, the results of this study indicate that injection of granisetron and propranolol into the human masseter muscle reduces pain induced by local administration of 5-HT, but that the effect of granisetron is stronger than that of propranolol. In addition, granisetron totally abolishes allodynia/hyperalgesia.     

Intramuscular injection of granisetron into the masseter muscle increases the pressure pain threshold in healthy participants and patients with localized myalgia

OBJECTIVES: The aims of this study were to experimentally investigate whether an intramuscular injection of the 5-HT(3) antagonist granisetron into the masseter muscle increases the mechanical pain threshold in healthy participants and reduces masseter muscle pain or allodynia in patients with craniofacial myalgia. METHODS: Eighteen patients with bilateral localized myalgia of the masseter muscle and 24 healthy participants participated in this randomized, double-blind study, in which granisetron was injected on one side and isotonic saline on the other side. Pain (Visual Analog Scale) and pressure pain threshold (PPT) were recorded before and during 30 minutes after injections and the changes from baseline were analyzed with analysis of variance. RESULTS: In both groups, the PPT increased after injection of granisetron whereas it decreased after saline. The difference between substances was significant (patients: P=0.016; healthy participants: P=0.029). In the healthy participants there was also a significant time effect (P<0.001) and an interaction between time and substance (P=0.022). The post-hoc test showed that the difference between substances was significant 0 to 15 minutes after injections (Bonferroni t test; P<0.05). The pain intensity from the masseter muscle did not differ between substances, but there was a significant time effect (P<0.001) and an interaction between time and substance (P<0.001). The post-hoc test showed significantly lower pain intensity on the granisetron side 0 to 2 minutes after injections (Bonferroni t test; P<0.05). CONCLUSIONS: This study indicates that intramuscular injection of granisetron into the masseter muscle increases the PPT in healthy participants and in patients with craniofacial myalgia.     

MULTIDISCIPLINARY PAIN ABSTRACTS: 16

The present double-blind, placebo-controlled study was designed to test quantitatively the effect and of nerve growth factor (NGF) injected into the masseter muscle. Pressure pain thresholds (PPT) and pressure tolerance thresholds (PTOL) were used as indices of mechanical allodynia and hyperalgesia in the jaw-closing muscles. In addition, perceived pain intensity was assessed by the subjects on a 0 to 10 numerical rating scale (NRS) with the jaw at rest and in relation to various oral functions (chewing, yawning, talking, swallowing, drinking and smiling). Repeated measures analysis of variance (ANOVA) was used to test for significant effects. Injection of NGF into the masseter muscle was associated with significantly reduced PPT for 7 days and PTOL for 1 day. Buffered isotonic saline injections into the masseter muscle also significantly lowered the PPT after 1 day and isotonic saline had no significant effect on PTOL. In contrast, assessment of PPT and PTOL in the noninjected temporalis muscles demonstrated a significant increase after 14 to 28 days, which may have reflected an adaptation to the test procedure. NRS scores of chewing and yawning were significantly increased for 7 days following NGF injection. Systemic adverse effects were noted in one subject who reported fever and slight discomfort about 8 hours after the NGF injection. In conclusion, this is the first study to show that injection of NGF into the human masseter muscle causes local signs of mechanical allodynia and hyperalgesia that persist for at least 7 days as well as pain during strenuous jaw movement. The present pain model is safe and may be used to gain further insight into the neurobiological mechanisms of muscle pain and sensitization.     

Injection of nerve growth factor into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia

Nerve growth factor (NGF) is a neurotrophic protein with a pivotal role in development and maintenance of the nervous system on one side and inflammatory and neuropathic pain states on the other. NGF causes clear signs of behavioral hyperalgesia in animal models and following intradermal and systemic administration in humans. The present double-blinded, placebo-controlled study was designed to test quantitatively the effect and duration (1h, 1, 7, 14, 21 and 28 days) of NGF (5 microg in 0.2 ml) injected into the masseter muscle. Pressure pain thresholds (PPT) and pressure tolerance thresholds (PTOL) were used as indices of mechanical allodynia and hyperalgesia in the jaw-closing muscles. In addition, perceived pain intensity was assessed by the subjects on a 0-10 numerical rating scale (NRS) with the jaw at rest and in relation to various oral functions (chewing, yawning, talking, swallowing, drinking and smiling). Repeated measures analysis of variance (ANOVA) was used to test for significant effects. Injection of NGF into the masseter muscle was associated with significantly reduced PPT for 7 days (ANOVA: P<0.001) and PTOL for 1 day (P<0.001). Buffered isotonic saline injections into the masseter muscle also significantly lowered the PPT after 1 day but to a significantly smaller extent than the NGF injections (P<0.001) and isotonic saline had no significant effects on PTOL. In contrast, assessment of PPT and PTOL in the non-injected temporalis muscles demonstrated a significant increase after 14-28 days (P<0.001), which may have reflected an adaptation to the test procedure. NRS scores of chewing and yawning were significantly increased for 7 days following NGF injection (P<0.001). Systemic adverse effects were noted in one subject who reported fever and slight discomfort about 8h after the NGF injection. In conclusion, this is the first study to show that injection of NGF into the human masseter muscle causes local signs of mechanical allodynia and hyperalgesia that persist for at least 7 days as well as pain during strenuous jaw movement. The present pain model is safe and may be used to gain further insight into the neurobiological mechanisms of muscle pain and sensitization.     

Changes of Hypertonic Saline–Induced Masseter Muscle Pain Characteristics,by an Infusion of the Serotonin Receptor Type 3 Antagonist Granisetron

This study aimed to investigate whether granisetron reduces masseter muscle pain and allodynia induced by hypertonic saline. Fifteen healthy women and 15 age-matched healthy men participated in this randomized, placebo-controlled, double-blinded study. They first received bilateral injections of hypertonic saline into the masseter muscles (internal control). The evoked pain intensity and the pressure-pain threshold (PPT) were recorded during 30 minutes. Granisetron was then injected on one side and placebo (normal saline) on the contralateral side. Two minutes thereafter, the hypertonic saline injections were repeated. Pain and PPT were again recorded. The first injection of hypertonic saline induced pain of similar intensity, duration, and pain area on both sides, but with larger pain area in the women (P = .017). The PPT did not change significantly. The second injection of hypertonic saline induced considerably less pain (62.5%), of shorter duration (44.1%), and of smaller area (77.4%) on the side pretreated with granisetron (P = .005). The PPT was increased on the granisetron side in the men (P = .002). The results of this study show that local injection of a single dose of granisetron attenuates masseter muscle pain induced by hypertonic saline.PerspectiveThis article presents the changes of hypertonic saline–induced masseter muscle pain characteristics by infusion of granisetron. It appears that the pain-inducing effect in this experimental pain model is partly due to activation of 5-HT₃-receptors. Hence, the results indicate that granisetron might offer a new treatment approach for localized myofascial pain.     

Serotonin,glutamate and glycerol are released after the injection of hypertonic saline into human masseter muscles – a microdialysis study

Background

Chronic myalgia is associated with higher muscle levels of certain algesic biomarkers. The aim of this study was to investigate if hypertonic saline-induced jaw myalgia also leads to release of such biomarkers and if there were any sex differences in this respect.

Methods

Healthy participants, 15 men and 15 aged-matched women (25.7 ± 4.3 years) participated. Intramuscular microdialysis into masseter muscles was performed to sample serotonin (5-HT), glutamate, lactate, pyruvate, glucose and glycerol. After 2 hours 0.2 mL hypertonic saline (58.5 mg/mL) was injected into the masseter on one side and 0.2 mL isotonic saline (9 mg/mL) into the contralateral masseter close to the microdialysis catheter. Microdialysis continued for 1 hour after the injections. Pressure pain thresholds (PPT) and pain were assessed before and after injections.

Results

The median (IQR) peak pain intensity (0–100 visual analogue scale) after hypertonic saline was 52.5 (38.0) and after isotonic saline 7.5 (24.0) (p < 0.05). 5-HT, glutamate and glycerol increased after hypertonic saline injection (p < 0.05). Lactate, pyruvate and glucose showed no change. PPT after microdialysis was reduced on both sides (p < 0.05) but without side differences. Pain after hypertonic saline injection correlated positively to 5-HT (p < 0.05) and negatively to glycerol (p < 0.05).

Conclusions

5-HT, glutamate and glycerol increased after a painful hypertonic saline injection into the masseter muscle, but without sex differences. Since increased levels of 5-HT and glutamate have been reported in chronic myalgia, this strengthens the validity of the pain model. Glycerol warrants further investigations.     

Experimental human muscle pain and muscular hyperalgesia induced by combinations of serotonin and bradykinin.

In the present study, we assessed the muscle pain and possible development of muscular hyperalgesia to mechanical stimuli after two subsequent intramuscular infusions of serotonin (5-HT) and bradykinin (BKN). The pain intensity after the infusions was continuously scored on a visual analogue scale (VAS). The subjects drew the distribution of the pain areas on a map. Pressure pain thresholds (PPTs) and suprapressure pain thresholds (SPPTs) stimulations as 150% of the pre-infusion PPTs were assessed with a pressure algometer at the injection site (10 cm below the patella), at the ankle, and at the contralateral leg and ankle. Skin sensibility was assessed with a Von Frey hair at the same sites. This was done before and after an infusion into the tibialis anterior (TA) muscle on the right leg in ten volunteers. The first infusion in each combination was either serotonin (20 nmol) or isotonic saline (NaCl 0.9%). The second infusion was bradykinin (5 or 10 nmol) or isotonic saline. The two infusions were given over 20 s and separated by 3 min. The isotonic saline followed by BKN did not induce muscle pain or muscular hyperalgesia. However, the combination of 5-HT and BKN (10 nmol) produced: (1) significantly higher VAS scores (P < 0.05) compared with all other combinations; (2) significantly longer pain offset (P < 0.05) compared with the combinations of isotonic saline and BKN; (3) significantly lower PPTs at 5, 20, and 40 min post-infusion (P < 0.05) compared with baseline PPT and PPTs after all other combinations. Cutaneous sensibility to mechanical stimuli and SPPTs were not affected by any of the combinations. The combinations of serotonin and bradykinin produce experimental muscle pain and muscular hyperalgesia to mechanical stimuli. Pre-treatment with serotonin may enhance the effect of bradykinin in the generation of muscle pain and muscular hyperalgesia in humans.     

Involvement of ATP and its receptors on nociception in rat model of masseter muscle pain

The exact mechanism of the masseter muscle pain recognized as a prominent symptom in temporomandibular disorders remains unclear, although it is clinically known that excessive muscular contraction causes tenderness in masseter muscles. It has been demonstrated that P2X3 receptors (P2X3Rs) in sensory neurons play a role in pain signaling from the periphery. We determined the role of P2X(3)R on pressure pain and mechanical hyperalgesia in a newly developed rat model of masseter muscle pain. The pain in the masseter muscle was assessed by the pressure pain threshold (PPT), which was defined as the amount of pressure required to induce head flinching. In naive animals, systemic treatment with morphine was associated with increase of PPTs. Changes in PPTs were examined after administration of P2XR agonists or antagonists into the masseter muscle. The masseter muscle injection of alpha,beta-meATP (P2X(1,3,2/3)R-specific agonist) induced a significantly greater behavioral response than its vehicle. This enhanced response was completely blocked by the co-application of alpha,beta-meATP with PPADS (P2X(1,2,3,5,1/5,2/3)R-specific antagonist). Excessive contraction in masseter muscle was produced by electrical stimulation. The exerted masseter muscles showed a significant reduction in PPTs indicating the induction of mechanical hyperalgesia of the muscle. Moreover, administration of PPADS to the exerted masseter muscles produced a complete recovery of reducing PPT. Immunohistochemically, the number of P2X3R-positive neurons innervating the masseter muscles increased in the excessively contracted condition in trigeminal ganglia. Our results suggested that P2X3R plays an important role in pressure pain and mechanical hyperalgesia in masseter muscle caused by excessive muscular contraction.     

Experimental human muscle pain induced by intramuscular injections of bradykinin,serotonin, and substance P

After intramuscular (m. tibialis anterior) injection of three different algogenic substances, the pain intensity was continuously scored on a visual analogue scale (VAS) in eight volunteers. The subject drew the distribution of the local and referred pain areas on a map. Four times within the first hour after injection, the pressure pain–thresholds (PPTs) and supra pressure–pain thresholds were assessed at the injection point, 2 cm distal from the injection site, at the arm, and at the contralateral leg. Measurements were done before and after injection of 0.5 ml of the algogenic substance [bradykinin (BKN), serotonin (5-HT), substance P (SP)], and isotonic saline as control. Cutaneous sensitivity to mechanical stimuli was assessed with a Von Frey hair at the same location as PPT determinations. The pain intensity (VAS-peak) after BKN (2, 4, and 10 nmol) and 5-HT (2, 4, and 20 nmol) was significantly higher (p< 0.05) than after SP (0.2, 0.4, and 0.8 nmol) and isotonic saline. The VAS-peak after infusions of hypertonic saline was significantly higher (p< 0.05) compared with VAS-peaks after all other substances. A significantly larger (p< 0.05) local pain area was found after BKN compared with isotonic saline. After injections of hypertonic saline, the offsets of evoked pain were significantly longer (p< 0.05) and the local and referred pain areas were significantly larger (p< 0.05) compared with all other substances. There was no dose–response relation between the pain intensity and the different doses of BKN, 5-HT, and SP. PPTs and skin sensitivity were not affected by any of the injections. We conclude that under the present experimental conditions, BKN and 5-HT can produce low levels of muscle pain after intramuscular injection. In the used concentrations, however, BKN, 5-HT, and SP did not generate cutaneous or muscular hyperalgesia.     

Health related quality of life and quantitative pain measurement in females with chronic non-malignant pain.

The aim of the present study was to assess, compare, and correlate the pain response to an experimental pain stimulus (hyperalgesia to pressure pain threshold (PPT) measured from different body sites), the pain intensity (VAS) of the habitual pain, and quality of life parameters (SF-36) in groups of females with chronic non-malignant pain syndromes. Forty female pain patients with fibromyalgia/whiplash (n = 10), endometriosis (n = 10), low back pain (n = 10), or rheumatoid arthritis (n = 10), as well as 41 age-matched healthy female controls participated in the study. The fibromyalgia/whiplash patients scored significantly higher (p < 0.04) VAS ratings (median rating = 7.0) than the endometriosis (6.0), low back pain (6.0), and rheumatoid arthritis (3.5) patients. All fours patient groups had significantly lower PPTs at all sites as compared with controls. The fibromyalgia/whiplash patients experienced the highest influence of pain on their overall health status, particularly vitality, social function, emotional problems, and mental health. A significant negative correlation was found between VAS rating and quality of life (p < 0.04). Significant correlation (p < 0.05) was found between pressure hyperalgesia measured at lowest PPT sites and the impairment of SF-36 physical function as well as mental health parameters. This study demonstrates significant generalised pressure hyperalgesia in four groups of chronic pain patients, correlations between degree of pressure hyperalgesia and impairment of some quality of life parameters, and increased pain intensity of the ongoing pain is associated with decreased quality of life.     

Peripheral 5-HT2A receptor antagonism attenuates primary thermal hyperalgesia and secondary mechanical allodynia after thermal injury in rats

Inflammation or injury of peripheral tissue causes release of chemical mediators, including 5-hydroxytryptamine (5-HT), which is involved in the facilitation of nociceptive transmission and the induction of hyperalgesia. The present study examined the effect of a selective 5-HT2A receptor antagonist, sarpogrelate, on hyperalgesia and allodynia induced by thermal injury in rats. Mild thermal injury to the hindpaw produces thermal hyperalgesia in the injured area (primary thermal hyperalgesia) and mechanical allodynia in sites adjacent to the primary area (secondary mechanical allodynia). Mechanical allodynia was assessed by paw withdrawal thresholds using von Frey filaments, and thermal hyperalgesia was assessed by paw withdrawal latencies upon exposure to a radiant heat source. Intraperitoneal administration (30-100 mg/kg) or local injection (30-300 microg) of sarpogrelate 10 min prior to thermal injury attenuated secondary mechanical allodynia in a dose-dependent manner. Intraperitoneal administration (3-100 mg/kg) or local injection (30-300 microg) of sarpogrelate 10 min prior to thermal injury attenuated primary thermal hyperalgesia in a dose-dependent manner. Intraplantar injection of sarpogrelate (300 microg) to the contralateral hindpaw had no effect on primary thermal hyperalgesia or secondary mechanical allodynia in the ipsilateral paw. The tissue concentration of 5-HT was measured using microdialysis. Concentrations of 5-HT increased after thermal injury in both primary and secondary areas, and the increase was not attenuated by pretreatment with sarpogrelate (100 mg/kg, i.p.). These data suggest that 5-HT released in peripheral tissues after thermal injury sensitizes primary afferent neurons and produces mechanical allodynia and thermal hyperalgesia via peripheral 5-HT2A receptors.     

Generalized deep-tissue hyperalgesia in patients with chronic low-back pain.

Some chronic painful conditions including e.g. fibromyalgia, whiplash associated disorders, endometriosis, and irritable bowel syndrome are associated with generalized musculoskeletal hyperalgesia. The aim of the present study was to determine whether generalized deep-tissue hyperalgesia could be demonstrated in a group of patients with chronic low-back pain with intervertebral disc herniation. Twelve patients with MRI confirmed lumbar intervertebral disc herniation and 12 age and sex matched controls were included. Subjects were exposed to quantitative nociceptive stimuli to the infraspinatus and anterior tibialis muscles. Mechanical pressure (thresholds and supra-threshold) and injection of hypertonic saline (pain intensity, duration, distribution) were used. Pain intensity to experimental stimuli was assessed on a visual analogue scale (VAS). Patients demonstrated significantly higher pain intensity (VAS), duration, and larger areas of pain referral following saline injection in both infraspinatus and tibialis anterior. The patients rated significantly higher pain intensity to supra-threshold mechanical pressure stimulation in both muscles. In patients, the pressure pain-threshold was lower in the anterior tibialis muscle compared to controls. In conclusion, generalized deep-tissue hyperalgesia was demonstrated in chronic low-back pain patients with radiating pain and MRI confirmed intervertebral disc herniation, suggesting that this central sensitization should also be addressed in the pain management regimes.     

Spatial pain propagation over time following painful glutamate activation of latent myofascial trigger points in humans

The aim of this present study was to test the hypothesis that tonic nociceptive stimulation of latent myofascial trigger points (MTPs) may induce a spatially enlarged area of pressure pain hyperalgesia. Painful glutamate (.2 mL, 1M) stimulation of latent MTPs and non-MTPs in the forearm was achieved by an electromyography-guided procedure. Pain intensity (as rated on the visual analog scale [VAS]) and referred pain area following glutamate injections were recorded. Pressure pain threshold (PPT) was measured over 12 points in the forearm muscles and at the mid-point of tibialis anterior muscle before and at .5 hour, 1 hour, and 24 hours after glutamate injections. The results showed that maximal pain intensity, the area under the VAS curve, and referred pain area were significantly higher and larger following glutamate injection into latent MTPs than non-MTPs (all, P < .05). A significantly lower PPT level was detected over time after glutamate injection into latent MTPs at .5 hour (at 4 points), 1 hour (at 7 points), and 24 hours (at 6 points) in the forearm muscles. However, a significantly lower PPT was observed only at 24 hours after glutamate injection into non-MTPs in the forearm muscles (at 4 points, P < .05) when compared to the pre-injection PPT. PPT at the mid-point of the tibialis anterior was significantly decreased at 1 hour only as compared to the pre-injection PPT in both groups (< .05). The results of the present study indicate that nociceptive stimulation of latent MTPs is associated with an early onset of locally enlarged area of mechanical hyperalgesia. PERSPECTIVE: This study shows that MTPs are associated with an early occurrence of a locally enlarged area of pressure hyperalgesia associated with spreading central sensitization. Inactivation of MTPs may prevent spatial pain propagation.     

Bilateral Mechanical-Pain Sensitivity Over the Trigeminal Region in Patients With Chronic Mechanical Neck Pain

The aim of this study was to investigate bilateral pressure-pain sensitivity over the trigeminal region, the cervical spine, and the tibialis anterior muscle in patients with mechanical chronic neck pain. Twenty-three patients with neck pain (56% women), aged 20 to 37 years old, and 23 matched controls (aged 20 to 38 years) were included. Pressure pain thresholds (PPTs) were bilaterally assessed over masseter, temporalis, and upper trapezius muscles, the C5-C6 zygapophyseal joint, and the tibialis anterior muscle in a blinded design. The results showed that PPT levels were significantly decreased bilaterally over the masseter, temporalis, and upper trapezius muscles, and also the C5-C6 zygapophyseal joint (P < .001), but not over the tibialis anterior muscle (P = .4) in patients with mechanical chronic neck pain when compared to controls. The magnitude of PPT decreases was greater in the cervical region as compared to the trigeminal region (P < .01). PPTs over the masseter muscles were negatively correlated to both duration of pain symptoms and neck-pain intensity (P < .001). Our findings revealed pressure-pain hyperalgesia in the trigeminal region in patients with mechanical chronic neck pain, suggesting spreading of sensitization to the trigeminal region in this patient population.PerspectiveThis article reveals the presence of bilateral pressure-pain hypersensitivity in the trigeminal region in patients with idiopathic neck pain, suggesting a sensitization process of the trigemino-cervical nucleus caudalis in this population. This finding has implications for development of management strategies.     

Interactions between glutamate and capsaicin in inducing muscle pain and sensitization in humans

The aim of the study was to investigate the interaction between glutamate and capsaicin in inducing muscle pain and sensitization in humans. Fifteen male volunteers participated. Glutamate or capsaicin or isotonic saline, in a paired‐sequence order, was injected randomly into the right or left masseter muscle. Two injections were given in a double‐blinded design 25min apart in 1session/week over 4 weeks: saline (A1) followed by glutamate (A2), capsaicin (B1) followed by glutamate (B2), saline (C1) followed by capsaicin (C2), and glutamate (D1) followed by capsaicin (D2). The subjects drew the area of perceived pain and scored pain intensity on a 0–10 visual analogue scale (VAS). Pressure pain threshold (PPT) at the injection site, at a site 2‐cm away, and on the contralateral side, as well as pressure pain tolerance (PPTol) at the injection site and contralateral site, were also measured before and after injection and subsequently at 5‐min intervals. Paired t‐test analyses showed that the pain drawing area was significantly smaller in the B2 compared to the A2 condition (P=0.028), and significantly larger in the D2 compared to the C2 condition (P=0.027). It also revealed significantly lower VAS peak pain intensity (P=0.008) and smaller VAS area under the curve (P=0.003) for the B2 compared to the A2 condition, and significantly higher VAS peak pain (P=0.015) and larger VAS area under the curve (P=0.037) for the D2 compared to the C2 condition. There was a significant PPT and PPTol decrease at the injection site after glutamate or capsaicin injection (ANOVA: P<0.028). The percentage decrease in PPT or PPTol (at the injection site) was not significantly different for the B2 compared to the A2 condition (Paired t‐test: P>0.682) or for the D2 compared to the C2 condition (P>0.133). Significant PPT changes were also observed at the site 2cm away, but not on the contralateral side. In conclusion, these findings indicate that intramuscular administrations of glutamate and capsaicin interact and influence pain and sensitization of muscle nociceptors: glutamate causes a sensitization to subsequent administration of capsaicin, whereas capsaicin is associated with a desensitization to subsequent injection of glutamate. These findings support previous animal data.     

Experimental pelvic pain facilitates pain provocation tests and causes regional hyperalgesia

The extra-articular sacroiliac joint (SIJ) structure is a potential source for low back and pelvic pain. This study hypothesised that experimental pain induced in a superficial pelvic ligament causes (1) hyperalgesia to pressure, (2) distinct pain referral, and (3) an increased frequency of positive pain provocation tests of the SIJ complex. Thirty healthy subjects (15 females) participated in this study designed as a randomised crossover trial. Pain was induced in the long posterior sacroiliac ligament by injection of hypertonic saline, with the contralateral ligament injected with isotonic saline as control. Pain intensity was assessed on an electronic visual analogue scale (VAS). Pressure pain thresholds (PPTs) and pain provocation tests were assessed on 3 occasions: at baseline, after injection, and when pain had subsided. PPT sites were located bilaterally at the injection site, lateral to spinous processes of S2 and L5, and at the gluteus medius and gastrocnemius muscles. Hypertonic saline caused significantly higher VAS scores and more extended pain referral than isotonic saline (P < 0.001). PPTs at the injection site and lateral to S2 were significantly reduced after hypertonic saline compared with baseline and isotonic saline (P < 0.002). Significantly more subjects had positive pain provocation tests after hypertonic (67% of subjects) compared with isotonic saline (20%; P < 0.001). These data demonstrate that the extra-articular SIJ structure accommodates nociceptors that are capable of inducing pain referral and regional hyperalgesia sensitive to manual pain provocation tests similar to what previously have been found in pelvic girdle pain patients.     

Gender differences in pain modulation evoked by repeated injections of glutamate into the human trapezius muscle

Gender differences in pain habituation, temporal summation, and pressure hyperalgesia evoked by repeated injections of glutamate into the dominant trapezius muscle were investigated. The glutamate-evoked muscle pain intensity and pressure pain threshold (PPT) were assessed. The PPTs were measured bilaterally in the trapezius muscles (local pain area) and posterolateral neck muscles (referred pain area) after glutamate injection in healthy and age-matched males and females (each n=14). Two glutamate injections (0.4 ml, 2M each) were injected with an interval of 5 min. One injection of glutamate (0.4 ml, 2M) served as a control. Males, but not females, rated the second injection (maximal pain intensity) significantly less painful than the first injection. The area under the visual analogue scale pain curve of the second injection was significantly larger than the first injection in females. Repeated glutamate injections, but not one-glutamate injection, significantly decreased PPTs in the local pain area, with no significant gender differences. No PPTs changes were observed either in the contralateral trapezius muscle or bilaterally in the referred pain areas in either sex. These results suggest that a less efficient pain habituation and a greater susceptibility to the development of temporal summation of muscle pain in females, but not in males, might be one of the contributing factors to the higher incidence of neck shoulder pain in females. In addition, the reduction of PPTs in the local pain area evoked by intramuscular glutamate injection may represent an early process of peripheral pressure hyperalgesia, which is most likely gender independent.     

Muscle fatigue increases the probability of developing hyperalgesia in mice.

Chronic muscle pain is a major clinical problem that is often associated with fatigue. Conversely, chronic fatigue conditions are commonly associated with muscle pain. We tested the hypothesis that muscle fatigue enhances hyperalgesia associated with injection of acidic saline into muscle. We evaluated mechanical sensitivity of the paw (von Frey) in mice after 2 intramuscular injections of saline (20 microL; pH 4, pH 5, pH 6, pH 7.2) in a fatigue and a control group. To induce fatigue, mice were run for 2 h/day for 2 days prior to the first injection and 2 h/day for 2 days prior to the second injection. Muscle lactate, pCO(2), pO(2), creatinine kinase, phosphate, and histology were examined after the fatigue task and compared to a control group. Grip force was significantly decreased after 2 h of running indicating fatigue. The fatigue task did not induce muscle damage as there was no difference in muscle lactate, pCO(2), pO(2), creatinine kinase, phosphate, or histology. The fatigue task altered the dose-response relationship to intramuscular acidic saline injections. Mechanical hyperalgesia was observed in both fatigue and control groups after intramuscular injection of pH 4.0, but only the fatigue group after injection of pH 5. Neither the fatigue nor the control group developed hyperalgesia in response to intramuscular injection of pH 6 or pH 7.2. In conclusion, fatigue modified the susceptibility of mice to acid injection of pH 5.0 to result in mechanical hyperalgesia after 2 injections of pH 5.0. The fatigue task did not produce measurable changes in the muscle tissue suggesting a central mechanism mediating the enhancement of hyperalgesia. PERSPECTIVE: These data therefore show that muscle fatigue can enhance the likelihood that one develops pain to a mild insult. Clinically, this could relate to the development of pain from such conditions as repetitive strain injury, and may relate to the interrelationship between chronic pain and fatigue.     

Intrathecal, but not intravenous adenosine reduces allodynia in patients with neuropathic pain

Intrathecal adenosine reduces allodynia from intradermal capsaicin in human volunteers, and reduces hypersensitivity to mechanical stimuli in animals with nerve injury. Although both intrathecal and intravenous adenosine have been reported to relieve pain in patients with neuropathic pain, there are no controlled trials of this therapy. In order to determine the effect of adenosine, seven patients with chronic neuropathic pain and stable areas of mechanical hyperalgesia and allodynia were recruited. Using a double-blind, cross-over design, patients were studied on two occasions - once with intrathecal adenosine, 2 mg and once with intravenous adenosine, 2 mg, using saline by the alternate route. Areas of hyperalgesia and allodynia and pain from von Frey stimulation in the area of allodynia were determined up to 24 h after drug injection. Intrathecal, but not intravenous adenosine reduced area of allodynia by approximately 25% (P<0.05) from 2 to 24 h after injection. Intrathecal adenosine reduced pain from von Frey filament stimulation in the area of allodynia by approximately 20% (P<0.05). Ongoing pain was unaffected by adenosine by either route. Intrathecal, but not intravenous adenosine, caused backache in five of seven patients, lasting 6 h. These results indicate that intrathecal adenosine reduces allodynia and pain from stimulation in the area of allodynia, whereas the same dose of adenosine intravenously was ineffective. Given the modest effect and common side effects, the role for intrathecal adenosine as a sole agent for the treatment of neuropathic pain may be limited.