Widespread mechanical pain hypersensitivity in patients with chronic migraine and temporomandibular disorders: relationship and correlation between psychological and sensorimotor variables.

OBJECTIVE: This study aimed to assess mechanical hyperalgesia in the trigeminal and extra-trigeminal regions in patients with chronic migraine (CM) and temporomandibular disorders (TMD) in comparison to asymptomatic subjects and to determine the association between sensorimotor variables and psychological and disability variables and evaluate the prediction of a sensorimotor variables though psychological and disability variables in patients with CM and TMD. MATERIAL AND METHODS: A total of 52 subjects with concomitant CM and TMD and 30 asymptomatic subjects were included in the study. The pressure pain threshold (PPT), maximal mouth opening (MMO) and a series of self-reported factors were compared. RESULTS: There were 52 CM and TMD (92.3% women and 7.7% men; age = 46.2 ± 9.5) and 30 asymptomatic subjects (80% women and 20% men; age = 47.4 ± 10). Differences were found between patients with CM and TMD and asymptomatic participants (p < .01) when comparing the PPTs in the trigeminal and extra-trigeminal regions. The PPT for the trigeminal region was predicted by depressive symptoms (variance of 18%) as well as disability and craniofacial pain (variance of 20%). The extra-trigeminal region PPT was predicted by depressive symptoms (variance of 10%), and pain-free MMO was predicted by disability and craniofacial pain (variance of 24%). CONCLUSIONS: This study suggests that patients with CM and TMD present with generalized mechanical hyperalgesia. In addition, an association between sensorimotor, psychological and disability variables was observed.

The role of self-reported and physiological stress in nocebo hyperalgesia.

Negative expectations can increase pain sensitivity, leading to nocebo hyperalgesia. However, the physiological and psychological factors that predispose individuals to this phenomenon are still not well understood. The present study examined whether stress induced by a social stressor affects nocebo hyperalgesia, and whether this effect is mediated by self-reported and physiological stress responses. We recruited 52 healthy participants (15 men) who were randomly assigned to either the Trier Social Stress Test (TSST) or a control condition (a friendly version of the TSST). Nocebo hyperalgesia was induced using negative suggestions combined with a validated pain conditioning paradigm. We assessed self-reported (anxiety and stress) and physiological (cortisol, alpha-amylase, heart rate, and skin conductance) responses to stress. Both groups exhibited significant nocebo hyperalgesia. The stress group showed higher levels of anxiety, self-reported stress, and cortisol levels compared to the control group while no significant differences were found in other physiological markers. The stress and control groups did not differ in the magnitude of nocebo hyperalgesia, but anxiety levels partially mediated the effects of the stress test on nocebo hyperalgesia. Our findings suggest that an external social stressor does not directly affect nocebo hyperalgesia, but that increased anxiety due to the stressor enhances its magnitude. Thus, it may be worthwhile to investigate whether reducing stress-related anxiety in clinical settings would help alleviate nocebo effects.

A rat model of temporomandibular joint pain with histopathologic modifications.

AIMS: To develop a rat model of temporomandibular joint (TMJ) pain and to characterize in it the development and temporal response of behavioral hypersensitivity as well as to evaluate if and to what extent a loading protocol is associated with histological changes in the TMJ consistent with osteoarthritic pathology. METHODS: A novel rat model of TMJ pain was developed using a noninvasive, mechanical loading protocol. Rats were exposed to steady mouth-opening for 7 days (2 N force, 1 hour/day), and mechanical hyperalgesia (increased pain response) was measured during the loading period and for 14 days thereafter. Histological modifications in the joint cartilage were also evaluated. Outcomes for the mouth-opening exposure were compared to age-matched controls. Thresholds for evoking responses were compared using a ranked ANOVA with repeated measures. RESULTS: Increased mechanical hypersensitivity in the temporomandibular region developed during daily loading and persisted even after the termination of the loading protocol. Histologic characterization revealed thinning of the cartilaginous structures of the joint and irregular zonal cellular arrangements in the condylar cartilage of rats subjected to the daily loading protocol. CONCLUSION: The injury model presented here is the first to demonstrate mechanically-induced behavioral hypersensitivity accompanied by osteoarthritic pathology in the TMJ.

Sleep disorders and their association with laboratory pain sensitivity in temporomandibular joint disorder.

STUDY OBJECTIVES: We characterized sleep disorder rates in temporomandibular joint disorder (TMD) and evaluated possible associations between sleep disorders and laboratory measures of pain sensitivity. DESIGN: Research diagnostic examinations were conducted, followed by two consecutive overnight polysomnographic studies with morning and evening assessments of pain threshold. SETTING: Orofacial pain clinic and inpatient sleep research facility. PARTICIPANTS: Fifty-three patients meeting research diagnostic criteria for myofascial TMD. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: We determined sleep disorder diagnostic rates and conducted algometric measures of pressure pain threshold on the masseter and forearm. Heat pain threshold was measured on the forearm; 75% met self-report criteria for sleep bruxism, but only 17% met PSG criteria for active sleep bruxism. Two or more sleep disorders were diagnosed in 43% of patients. Insomnia disorder (36%) and sleep apnea (28.4%) demonstrated the highest frequencies. Primary insomnia (PI) (26%) comprised the largest subcategory of insomnia. Even after controlling for multiple potential confounds, PI was associated with reduced mechanical and thermal pain thresholds at all sites (P < 0.05). Conversely, the respiratory disturbance index was associated with increased mechanical pain thresholds on the forearm (P < 0.05). CONCLUSIONS: High rates of PI and sleep apnea highlight the need to refer TMD patients complaining of sleep disturbance for polysomnographic evaluation. The association of PI and hyperalgesia at a nonorofacial site suggests that PI may be linked with central sensitivity and could play an etiologic role in idiopathic pain disorders. The association between sleep disordered breathing and hypoalgesia requires further study and may provide novel insight into the complex interactions between sleep and pain-regulatory processes.

Voluntary biting behavior as a functional measure of orofacial pain in mice.

INTRODUCTION: Pain-related behavior secondary to masticatory function can be assessed with the rodent bite force model. A reduction of the bite force has been shown to be related to pain associated with the masseter muscle and jaw activity, while an increase in bite force suggests improvement of muscle function and less pain. To evaluate the usefulness of the bite force measure in studying long-lasting orofacial pain we analyzed biting parameters during prolonged myofascial pain induced by ligation injury of the masseter muscle tendon (TL) in mice. METHODS: C57Bl/6 mice were habituated to bite at a pair of aluminum plates attached to a force displacement transducer. The transduced voltage signals were amplified and converted to force through calibration with a standard weight set. Voluntary biting behavior was recorded for 100 s/session and those with bite forces ≥980 mN were analyzed. Nociception was also verified with von Frey, conditioned place avoidance (CPA) tests and mouse grimace scale. Persistent orofacial pain was induced with unilateral ligation of one tendon of the masseter muscle (TL). RESULTS: To reduce interference of random bites of smaller forces, the top 5 or 15 bite forces (BF5/15) were chosen as a measure of masticatory function and related to pain behavior. Both male and female mice exhibited similar BF5/15. For the first nascent test of all mice, mean bite force was significantly and positively correlated with the body weight. However, this correlation was less clear in the latter tests (2-8 w). TL induced a reduction of BF5/15 that peaked at 1 w and returned to the baseline within 3 w. The von Frey and CPA tests indicated that mechanical allodynia/hyperalgesia persisted at the time when the BF had returned to the pre-injury level. Infusion of pain-relieving bone marrow stromal cells improved biting behavior in both male and female mice as shown by significantly increased BF5/15, compared to vehicle-treated mice. CONCLUSIONS: Mouse voluntary biting behavior can be reliably measured and quantified with a simplified setup. The bite force showed an inverse relationship with the level of pain after TL and was improved by pain-relieving manipulations. However, the injury-induced reduction of bite force peaked early and did not parallel with other measures of nociception in the later phase of hyperalgesia. The results suggest that multiple factors such as the level of habituation, cognitive motive, physical status, and feeding drive may affect random voluntary biting and confound the biting parameters related to maintained hyperalgesia.

Triathletes Lose Their Advantageous Pain Modulation under Acute Psychosocial Stress.

INTRODUCTION: Triathletes, who constantly engage in intensely stressful sport, were recently found to exhibit greater pain tolerance and more efficient pain inhibition capabilities than nonathletes. However, pain inhibition correlated negatively with retrospective reports of mental stress during training and competition. The aim of the current study was to test pain inhibition capabilities of triathletes under acute, controlled psychological stress manipulation. METHODS: Participants were 25 triathletes and ironman triathletes who underwent the measurement of pain threshold, pain intolerance, tonic suprathreshold pain, and conditioned pain modulation before and during exposure to the Montreal Imaging Stress Task (MIST). Perceived ratings of stress and anxiety, autonomic variables, and salivary cortisol levels were obtained as indices of stress. RESULTS: The MIST induced a significant stress reaction manifested in the subjective and objective indices. Overall, a significant reduction in pain threshold and in conditioned pain modulation efficacy was observed after the MIST, which reached the baseline levels observed previously in nonathletes. Paradoxically, the magnitude of this stress-induced hyperalgesia (SIH) correlated negatively with the magnitude of the stress response; low-stress responders exhibited greater SIH than high-stress responders. CONCLUSION: The results suggest that under acute psychological stress, triathletes not only react with SIH and a reduction in pain modulation but also lose their advantageous pain modulation over nonathletes. The stronger the stress response recorded, the weaker the SIH. It appears that triathletes are not resilient to stress, responding with an increase in the sensitivity to pain as well as a decrease in pain inhibition. The possible effects of athletes' baseline pain profile and stress reactivity on SIH are discussed.

Inflammatory pain memory facilitates occlusal interference-induced masticatory muscle hyperalgesia in rats.

BACKGROUND: Patients with an orofacial pain history appear to be more susceptible to occlusal interference pain in dental practice for unknown reasons. Pain memory has a critical function in subsequent pain perception. This study aims to explore whether orofacial pain memory could affect the masticatory muscle pain perception for occlusal interference. METHODS: Cross-injection of 2% carrageenan into bilateral masseters in male rats was carried out to establish the inflammatory pain memory model. The effects of pain memory on masseter muscle nociception were tested by applying crowns with heights beyond the occlusal plane by 0.2 or 0.4 mm onto a maxillary molar 2 weeks after inflammation in the right masseter. The 0.4-mm crowns were removed on day 2 or day 4 after application to further confirm the effects of pain memory. Moreover, memory impairment was established using ibotenic acid (IBO) infusion into the bilateral hippocampus, followed by behaviour tests, including the Morris water maze test and the locomotor activity test. The relationship between pain memory and occlusal interference-induced masseter muscle pain perception was subsequently re-examined. The head withdrawal thresholds of masseters on both sides were measured to reflect the perception. RESULTS: Inflammatory pain memory aggravated the 0.2-mm crown-induced mechanical hyperalgesia of the masseters, but not in the 0.4-mm crown group. However, the recovery of the 0.4-mm crown-induced mechanical hyperalgesia was postponed. The effects of pain memory were reversed in rats with impaired mnemonic function of the hippocampus. CONCLUSIONS: Inflammatory pain memory facilitated occlusal interference-induced masseter muscle pain.

Tissue monocytes/macrophages in inflammation: hyperalgesia versus opioid-mediated peripheral antinociception.

BACKGROUND: Opioid-containing leukocytes migrate to peripheral sites of inflammation. On exposure to stress, opioid peptides are released, bind to opioid receptors on peripheral sensory neurons, and induce endogenous antinociception. In later stages of Freund's complete adjuvant-induced local inflammation, monocytes/macrophages are a major opioid-containing leukocyte subpopulation, but these cells also produce proalgesic cytokines. In this study, the role of tissue monocytes/macrophages in hyperalgesia and in peripheral opioid-mediated antinociception was investigated. METHODS: After intraplantar injection of Freund's adjuvant, leukocyte subpopulations and opioid-containing leukocytes were analyzed by flow cytometry in the inflamed paw in the presence or absence of monocyte/macrophage depletion by intraplantar injection of clodronate-containing liposomes (phosphate-buffered saline and empty liposomes served as controls). Paw volume was measured with a plethysmometer. Hyperalgesia was determined by measuring heat-induced paw withdrawal latency and paw pressure threshold. Paw pressure threshold was also measured after swim stress and injection of fentanyl. RESULTS: At 48 and 96 h of inflammation, it was found that (1). monocytes/macrophages were the largest leukocyte subpopulation (> 55% of all leukocytes) and the predominant producers of opioid peptides (71-77% of all opioid-containing leukocytes in the paw), (2). clodronate-containing liposomes depleted monocytes/macrophages by 30-35% (P < 0.05), (3). hyperalgesia was unaltered by liposome injection (P > 0.05), and (4) opioid-containing leukocytes and swim stress but not fentanyl-induced antinociception were significantly decreased by clodronate-containing liposomes (P < 0.05, P > 0.05, all by t test; opioid-containing cells and swim stress-induced increase of paw pressure threshold were reduced by 35-42% and 20%, respectively). CONCLUSION: Partial depletion of tissue monocytes/macrophages impairs peripheral endogenous opioid-mediated antinociception without affecting hyperalgesia.