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.     

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.     

Pain referral and regional deep tissue hyperalgesia in experimental human hip pain models

Hip disorder patients typically present with extensive pain referral and hyperalgesia. To better understand underlying mechanisms, an experimental hip pain model was established in which pain referrals and hyperalgesia could be studied under standardized conditions. In 16 healthy subjects, pain was induced by hypertonic saline injection into the gluteus medius tendon (GMT), adductor longus tendon (ALT), or gluteus medius muscle (GMM). Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a visual analogue scale (VAS), and subjects mapped the pain distribution. Before, during, and after injections, passive hip joint pain provocation tests were completed, together with quantitative sensory testing as follows: pressure pain thresholds (PPTs), cuff algometry pain thresholds (cuff PPTs), cutaneous pin-prick sensitivity, and thermal pain thresholds. Hypertonic saline injected into the GMT resulted in higher VAS scores than hypertonic injections into the ALT and GMM (P < .05). Referred pain areas spread to larger parts of the leg after GMT and GMM injections compared with more regionalized pain pattern after ALT injections (P < .05). PPTs at the injection site were decreased after hypertonic saline injections into GMT and GMM compared with baseline, ALT injections, and isotonic saline. Cuff PPTs from the thigh were decreased after hypertonic saline injections into the ALT compared with baseline, GMT injections, and isotonic saline (P < .05). More subjects had positive joint pain provocation tests after hypertonic compared with isotonic saline injections (P < .05), indicating that this provocation test also assessed hyperalgesia in extra-articular soft tissues. The experimental models may open for better understanding of pain mechanisms associated with painful hip disorders.     

Repeated intramuscular injections of nerve growth factor induced progressive muscle hyperalgesia,facilitated temporal summation,and expanded pain areas

Intramuscular injection of nerve growth factor (NGF) is known to induce deep-tissue mechanical hyperalgesia. In this study it was hypothesised that daily intramuscular injections of NGF produce a progressive manifestation of soreness, mechanical hyperalgesia, and temporal summation of pain. In a double-blind placebo-controlled design, 12 healthy subjects were injected on 3 days with NGF into the tibialis anterior muscle and with isotonic saline on the contralateral side. Assessments were performed before and after the injections on days 0, 1, and 2, and repeated on days 3, 6, and 10. The self-perceived muscle soreness was assessed on a Likert scale. Computer-controlled pressure algometry was used to assess the pressure pain thresholds (PPTs). Temporal summation of pain after repeated pressure stimulations was assessed by computer-controlled pressure algometry. The pain distribution following painful pressure stimulation was also recorded. Compared with baseline and isotonic saline, the NGF injections caused (P < 0.05): (1) progressively increasing soreness scores from 3 hours after the first injection until day 2, after which it remained increased; (2) decreased PPTs at days 1 to 3; (3) facilitated temporal summation of pressure pain at days 1 to 10; and (4) enlarged pressure-induced pain area after the injection on day 1 to day 6. The daily injections of NGF produced a progressive manifestation of muscle soreness, mechanical hyperalgesia, temporal summation of pressure pain, and pressure-induced pain distribution. These data illustrate that the prolonged NGF application affects peripheral and central mechanisms and may reflect process in musculoskeletal pain conditions.     

Sex differences in temporal characteristics of descending inhibitory control: an evaluation using repeated bilateral experimental induction of muscle pain

Little is known about sex differences in the temporal pattern of descending inhibitory mechanisms, such as descending noxious inhibitory control (DNIC). Sex differences in temporal characteristics of DNIC were investigated by measuring pressure pain thresholds (PPTs) over time in the trapezius muscles (local pain areas) and the posterolateral neck muscles (referred pain areas) following repeated bilateral injection of hypertonic versus isotonic saline into both trapezius muscles. Ten females and 11 males received two consecutive bilateral injections, with 15 min interval, of either 5.8% hypertonic saline (0.5 ml in each side for each bilateral injection) or isotonic saline as a control in a randomized manner. Following hypertonic saline injection, the maximal pain intensities of the first and second bilateral injections were significantly higher in females than in males. The PPTs in the trapezius muscles were significantly lower in females than in males. Significantly higher PPTs (hypoalgesia) in men than in women were shown 15 min after the first bilateral injection, and 7.5 and 15 min after the second bilateral injection in the referred pain areas. Importantly, the second bilateral injection failed to further increase the PPTs for both sexes. These results showed that there were sex differences in temporal characteristics of descending inhibition with long-lasting hypoalgesia in men than in women. Repeated noxious muscular stimuli may inhibit further build-up of DNIC, which may reflect a mechanism of plasticity of the descending inhibitory systems following recurrent nociceptive barrage for both sexes.     

Experimental cervical interspinous ligament pain altered cervical joint motion during dynamic extension movement

BackgroundAlthough the cervical interspinous ligament is a potential source of neck pain, the effects on cervical joint motion and pressure pain sensitivity has never been investigated. The understanding of the relationship will broaden our understanding of cervical biomechanics and improve diagnosis and treatment of neck pain.MethodsFluoroscopy videos of cervical flexion and extension movements and pressure pain thresholds over bilateral C2/C3 and C5/C6 facet joints were collected in fifteen healthy subjects before and after injections of hypertonic and isotonic saline in C4/C5 ISL. The videos were divided into 10 even epochs and the motion of individual joints during each epoch was extracted. Joint motion parameters including anti-directional motion, pro-directional motion, total joint motion and joint motion variability were extracted across epochs. Joint motion parameters and PPTs were compared before and after injection of hypertonic and isotonic saline separately.FindingsCompared with baselines: hypertonic saline injection 1) decreased anti-directional motion and joint motion variability at C4/C5 (P < 0.05) and increased at C2/C3 (P < 0.05) during extension; 2) increased total joint motion of C0/C1 during first half range (P < 0.05) and decreased during second half range of extension, and total joint motion of C2/C3 increased during second half range of extension (P < 0.05) and; 3) increased pressure pain thresholds over left C2/C3 facet joint (P < 0.01).InterpretationThe cervical interspinous ligament pain redistributed anti-directional motion between C4/C5 and C2/C3 during dynamic extension and decreased pressure pain sensitivity over the left C2/C3 facet joint.     

Experimental deep tissue pain in wrist extensors--a model of lateral epicondylalgia.

The aim of this experimental study was to develop an in vivo model demonstrating sensory and motor interactions comparable to those seen in patients presenting with lateral epicondylalgia (i.e., deep tissue pain and hyperalgesia localised to specific sites in the wrist extensors, attenuation of wrist extension force). The effect of saline-induced deep pain combined with delayed onset muscle soreness (DOMS) on deep tissue sensitivity and motor function in wrist extensors was examined. Muscle pain intensity (visual analogue scale: VAS), distribution, and quality were assessed in 12 subjects. Pressure pain thresholds (PPTs) were recorded at five different sites around the elbow. Maximal wrist extension force was recorded. In the absence of DOMS, hypertonic saline administrated into different parts of the wrist extensors (extensor carpi radialis brevis, supinator, common extensor origin) induced significantly (P<0.05) higher VAS scores and larger pain areas compared with a control injection of isotonic saline. The typical quality of saline-induced pain was described as "drilling", "taut", "nagging" and "intense". In non-exercised wrist extensors, hyperalgesia to pressure was not detected during saline-induced pain but maximal wrist extensor force decreased significantly (P<0.05) compared with pre-pain recordings and recordings post isotonic saline. DOMS induced by eccentric wrist extension contractions generated moderate levels of soreness but no resting pain up to 24h post exercise. PPTs and maximal wrist extension force were significantly decreased (P<0.05) during DOMS compared with baseline and 7 days post exercise (P<0.05). VAS scores to injection of hypertonic saline into the DOMS arm were significantly increased (P<0.05) compared with injections into the unexercised arm. This is another manifestation of muscle hyperalgesia. Saline-induced pain combined with DOMS further decreased maximal wrist extension force (P<0.05). The simultaneous deep tissue pain and hyperalgesia linked with force attenuation support the use of the saline-induced deep tissue pain combined with DOMS as an experimental model simulating the clinical sensorimotor correlates of lateral epicondylalgia.     

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.     

Sensory responses to mechanically and chemically induced tendon pain in healthy subjects

This investigation aimed to quantify and compare sensory responses to hypertonic saline‐induced pain in the tendoachilles and the common extensor tendon of the elbow. Healthy subjects (n =14; seven males) received in randomised order, injections of sterile saline (0.5 ml, 5.8% hypertonic or 0.9% isotonic saline) at each tendon bilaterally at two sessions separated by one week. Mechanical sensitivity (pressure pain threshold), muscle pain intensity (visual analogue scale; VAS area‐under‐curve, pain duration, peak pain) and pain distribution were assessed pre, immediately after and post saline injection. Hypertonic saline‐induced pain intensity (VAS area‐under‐curve, duration and peak) was significantly greater compared with control injections (P <0.001) and induced significantly greater VAS area (P <0.01) and longer pain duration (P <0.001) in tendoachilles compared with the common extensor tendon. Regardless of saline type and compared with pre and post injection, mechanical sensitivity increased significantly (P <0.01) immediately after injections at all injected tendon sites. Hypertonic saline‐induced referred pain was infrequent (tendoachilles: n =3 and common extensor tendon: n =4). Significant maximal force attenuation occurred immediately after hypertonic saline injections in both tendons (P <0.001) compared with control injections. The greater induced deep tissue pain and hyperalgesia demonstrated at tendoachilles compared with the common extensor tendon may relate to anatomical differences such as higher nociceptor density or increased vascular perfusion at the injection site. This translational tendon pain model may contribute to the further understanding of pain mechanisms in tendinopathic conditions.     

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.     

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.     

Effects on muscle pain by intramuscular injection of granisetron in patients with fibromyalgia

We have previously reported that the level of 5-HT in the masseter muscle is increased in patients with fibromyalgia as compared with healthy subjects and that high intramuscular level of 5-HT is associated with muscle pain. We have also reported that injection of the 5-HT(3) receptor antagonist granisetron (GRA) into the masseter muscle of healthy subjects reduced pain induced by 5-HT and abolished allodynia/hyperalgesia. The aim of this study was to investigate whether GRA can influence pain and allodynia/hyperalgesia of the masseter muscle in patients with fibromyalgia. Eighteen female patients who met the criteria of fibromyalgia according to the American College of Rheumatology participated in the study. They were examined regarding pain intensity and pressure pain threshold (PPT) over the masseter muscle. One milliliter of GRA (1 mg/ml) was injected into the masseter muscle on one side and 1 ml of isotonic saline on the other side in a randomized and double-blind manner. After the injections, the pain intensity and PPT were recorded during 30 min. The pain intensity increased after injection of saline and to a lower degree after injection of GRA. The PPT increased after injection of GRA, while no such change was observed after saline. The difference between GRA and saline was, however, not significant. Eight of the patients responded to the GRA injection by an increase of PPT during the experimental period that differed from saline. They also showed a tendency to a lower increase of pain intensity after injection of GRA when compared to saline. In conclusion, the results of this study do not prove that injection of the 5-HT(3)-antagonist GRA into the masseter muscle influences local pain and allodynia/hyperalgesia in patients with fibromyalgia.     

Dysfunction of endogenous pain inhibition during exercise with painful muscles in patients with shoulder myalgia and fibromyalgia

The aim of this study was to investigate how exercise influenced endogenous pain modulation in healthy controls, shoulder myalgia patients and fibromyalgia (FM) patients. Twenty-one healthy subjects, 20 shoulder myalgia patients and 20 FM patients, all females, participated. They performed standardized static contractions, that is, outward shoulder rotation (m. infraspinatus) and knee extension (m. quadriceps). Pressure pain thresholds (PPTs) were determined bilaterally at m. infraspinatus and m. quadriceps. During contractions PPTs were assessed at the contracting muscle, the resting homologous contralateral muscle and contralaterally at a distant site (m. infraspinatus during contraction of m. quadriceps and vice versa). Myalgia patients had lower PPTs compared to healthy controls at m. infraspinatus bilaterally (p < 0.01), but not at m. quadriceps. FM patients had lower PPTs at all sites compared to healthy controls (p < 0.001) and myalgia patients (p < 0.001). During contraction of m. infraspinatus PPTs increased compared to baseline at the end of contraction in healthy controls (all sites: p < 0.003), but not in myalgia or FM patients. During contraction of m. quadriceps PPTs increased compared to baseline at the end of contraction in healthy controls (all sites: p < 0.001) and myalgia patients (all sites: p < 0.02), but not in FM patients. In conclusion, we found a normal activation of endogenous pain regulatory mechanisms in myalgia patients during contraction of the non-afflicted m. quadriceps, but a lack of pain inhibition during contraction of the painful m. infraspinatus. FM patients failed to activate their pain inhibitory mechanisms during all contractions.     

Effects of the 5-HT3 receptor antagonist, alosetron, in a rat model of somatic and visceral hyperalgesia

Conflicting results exist regarding the role of 5-HT3 receptors in somatic and visceral nociceptive processing. We aimed to investigate the effects of the 5-HT3 receptor antagonist, alosetron, in a rat model of somatic and visceral hyperalgesia. Two injections (100 microl) of either pH 4.0 or 7.2 saline were given unilaterally in the gastrocnemius (GN) muscle. In all groups, the paw withdrawal thresholds (PWT) to von Frey filaments and the visceromotor responses (VMR) to colorectal distension (CRD) were recorded before the saline injections and 72 h, and 1 week after the second injection. Intrathecal (i.t.) (25 nmol) or intravenous (i.v.) (100 microg/kg/day) alosetron was given daily following the second injection and compared to either i.v. or i.t. saline (vehicle). There was a significant decrease in the mean PWT bilaterally in all groups following pH 4.0 injections (p<0.05). Intravenous alosetron resulted in a significant increase in the PWT bilaterally on days 2 and 3. Intrathecal alosetron resulted in significant increase in the PWT starting at day 3 and was significantly higher than baseline on days 4-7 (p<0.05). At CRD pressures 30 mmHg, the VMR of pH 4.0 injected rats was significantly increased at 72 h and 1 week (p<0.05). Both i.v. and i.t. alosetron treated rats failed to demonstrate any alteration in the VMR. Control rats (pH 7.2) failed to show any alteration in the VMR and were unaffected by alosetron. Both, systemically and centrally administered alosetron, reversed the mechanical somatic hypersensitivity and prevented the development of visceral hyperalgesia, suggesting a centrally mediated effect.     

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.