Fong Wong

Deficiency in endogenous modulation of prolonged heat pain in patients with Irritable Bowel Syndrome and Temporomandibular Disorder

ABSTRACT Females with Irritable Bowel Syndrome (IBS) and Temporomandibular Disorder (TMD) are characterized by enhanced sensitivity to experimental pain. One possible explanation for this observation is deficiencies in pain modulation systems such as Diffuse Noxious Inhibitory Control (DNIC). In a few studies that used brief stimuli, chronic pain patients demonstrate reduced DNIC. The purpose of this study was to compare sensitivity to prolonged heat pain and the efficacy of DNIC in controls to IBS and TMD patients. Heat pain (experimental stimulus; 44.0–49.0 °C), which was applied to left palm, was continuously rated during three 30‐s trials across three separate testing sessions under the following conditions: without a conditioning stimulus; during concurrent immersion of the right foot in a 23.0 °C (control); and during noxious cold immersion in a (DNIC; 8.0–16.0 °C) water bath. Compared to controls, IBS and TMD patients reported an increased sensitivity to heat pain and failed to demonstrate pain inhibition due to DNIC. Controls showed a significant reduction in pain during the DNIC session. These findings support the idea that chronic pain patients are not only more pain sensitive but also demonstrate reduced pain inhibition by pain, possibly because of dysfunction of endogenous pain inhibition systems.

Lack of endogenous modulation and reduced decay of prolonged heat pain in older adults

&NA; This study supports the hypothesis that healthy older adults exhibit decreased endogenous pain inhibition compared to younger healthy controls. Twenty‐two older adults (56–77 years of age) and 27 controls aged 20–49 participated in five experimental sessions following a training session. Each experimental session consisted of five 60‐s trials in which the experimental heat stimulus was presented to the thenar eminence of the left palm with or without a conditioning stimulus (cold‐water immersion of the foot). The temperature for the palm (44–49 °C) and foot (8–16 °C) was customized for each subject. The intensity of experimental pain produced by the contact thermode was continuously measured during the 60‐s trial with an electronic visual analogue scale. No significant associations were found between subjects rating of concentration and the overall inhibitory effect. Older subjects failed to demonstrate conditioned pain modulation (CPM) and showed facilitation in the trials using painful concurrent immersion of the foot. A novel aspect of the study was that we recorded “pain offset” (i.e., after‐sensations) and found that ratings for the older sample decreased at a slower rate than observed for the group of younger adults suggesting increased central sensitization among the older sample. Decrements in CPM could contribute to the greater prevalence of pain in older age. Since a number of neurotransmitter systems are involved in pain modulation, it is possible age‐related differences in CPM are due to functional changes in these systems in a number of areas within the neuroaxis.

Characterization of mouse orofacial pain and the effects of lesioning TRPV1-expressing neurons on operant behavior

BackgroundRodent models of orofacial pain typically use methods adapted from manipulations to hind paw; however, limitations of these models include animal restraint and subjective assessments of behavior by the experimenter. In contrast to these methods, assessment of operant responses to painful stimuli has been shown to overcome these limitations and expand the breadth of interpretation of the behavioral responses. In the current study, we used an operant model based on a reward-conflict paradigm to assess nociceptive responses in three strains of mice (SKH1-Hrhr, C57BL/6J, TRPV1 knockout). We previously validated this operant model in rats and hypothesized in this study that wild-type mice would demonstrate a similar thermal stimulus-dependent response and similar operant pain behaviors. Additionally, we evaluated the effects on operant behaviors of mice manipulated genetically (e.g., TRPV1 k.o.) or pharmacologically with resiniferatoxin (RTX), a lesioning agent for TRPV1-expressing neurons. During the reward-conflict task, mice accessed a sweetened milk reward solution by voluntarily position their face against a neutral or heated thermode (37–55°C).ResultsAs the temperature of the thermal stimulus became noxiously hot, reward licking events in SKH1-Hrhr and C57BL/6J mice declined while licking events in TRPV1 k.o. mice were insensitive to noxious heat within the activation range of TRPV1 (37–52°C). All three strains displayed nocifensive behaviors at 55°C, as indicated by a significant decrease in reward licking events. Induction of neurogenic inflammation by topical application of capsaicin reduced licking events in SKH1-Hrhr mice, and morphine rescued this response. Again, these results parallel what we previously documented using rats in this operant system. Following intracisternal treatment with RTX, C57BL/6J mice demonstrated a block of noxious heat at both 48 and 55°C. RTX-treated TRPV1 k.o. mice and all vehicle-treated mice displayed similar reward licking events as compared to the pre-treatment baseline levels. Both TRPV1 k.o. and RTX-treated C57BL/6J had complete abolishment of eye-wipe responses following corneal application of capsaicin.ConclusionTaken together, these results indicate the benefits of using the operant test system to investigate pain sensitivity in mice. This ability provides an essential step in the development of new treatments for patients suffering from orofacial pain disorders.

Characteristics of sensitization associated with chronic pain conditions

Objectives:To describe and understand varieties and characteristics of sensitization contributing to hyperalgesia in participants with chronic pain conditions. Methods:Thermal stimulation was delivered to the face, forearm, and calf of pain-free participants and individuals with irritable bowel syndrome, temporomandibular pain disorder (TMD), and fibromyalgia syndrome (FM). Three-second contacts by a preheated thermode occurred at 30-second intervals in ascending and then in descending series (0.7°C steps). Results:Thermal pain ratings during ascending series were greater at each site in individuals diagnosed with chronic pain. Intense pain at the time of testing further enhanced the ratings at all sites, but mild or moderate clinical pain did not have this effect. Thermal pain in all participants was greater during descending series compared with the ascending series of arm and leg stimulation. The hypersensitivity during the descending series was comparable in pain-free, FM and TMD participants but was increased in duration for arm or leg stimulation of FM participants. Discussion:The widespread sensitization for irritable bowel syndrome and TMD participants does not rely on mechanisms of spatial and temporal summation often invoked to explain widespread hyperalgesia associated with chronic pain. Increased sensitivity during descending series of stimulation of an arm or leg but not the face indicates a propensity for sensitization of nociceptive input to the spinal cord. Abnormally prolonged sensitization for FM participants reveals a unique influence of widespread chronic pain referred to deep somatic tissues.

Psychophysical demonstration of bidirectional pain modulation (sensitization and desensitization) by ascending or descending progressions of thermal stimulus intensity.

A psychophysical method of response-dependent stimulation presented ascending and descending series of thermal stimulus intensities that maintained an average rating (setpoint) of mild pain (20 on a scale of 0-100) or moderate pain (35). Subjects were presented with alternating series of thermal stimuli that increased until ratings reached or exceeded the setpoint, then decreased until ratings equaled or were less than the setpoint, then increased, etc. Plots of pain intensity ratings differed substantially for series of ascending and descending stimulus intensities. After an ascending series, pain ratings during a descending series were higher than predicted, and after a descending series, pain ratings during an ascending series were lower than predicted. Thus, the nervous system detects and discriminates between ascending and descending trends in stimulus intensity and alters the magnitude of pain sensations in the direction of the trend of increasing or decreasing stimulus intensity. Ascending (sensitizing) trend effects may increase the magnitude of pathological pain in the absence of treatment, and descending (desensitizing) trend effects likely would enhance the efficacy of procedures that reduce pain sensitivity.

A New Thermal Stimulation Method for Human Psychophysical Studies: Pain Intensity Clamping

A method for testing changes in pain sensitivity of human subjects over the course of prolonged thermal stimulation is introduced. It uses a Peltier-device-based thermode to generate a thermal contact stimulus, an electronic visual analog scale to continuously record the pain intensity and a system that controls selected stimulus parameters (temperature or pulse timing) as a function of the pain intensity rating. The stimulus parameter that is modulated to clamp pain intensity near a desired setpoint serves as the response variable and is used to infer pain sensitivity. Advantages of the method are that it automatically finds the stimulus magnitude that elicits predetermined pain intensity, regardless of how sensitive or insensitive the subject is, and it allows prolonged stimulation, because it does not allow pain intensity to escalate to unacceptable levels due to progressive sensitization. The subject is blinded regarding experimental effects because average pain intensity remains constant regardless of sensitization or pharmacological interventions.

Relationships between Irritable Bowel Syndrome Pain, Skin Temperature Indices of Autonomic Dysregulation, and Sensitivity to Thermal Cutaneous Stimulation

This study evaluated relationships between irritable bowel syndrome (IBS) pain, sympathetic dysregulation, and thermal pain sensitivity. Eight female patients with diarrhea-predominant IBS and ten healthy female controls were tested for sensitivity to thermal stimulation of the left palm. A new method of response-dependent thermal stimulation was used to maintain pain intensity at a predetermined level (35%) by adjusting thermal stimulus intensity as a function of pain ratings. Clinical pain levels were assessed prior to each testing session. Skin temperatures were recorded before and after pain sensitivity testing. The temperature of palmar skin dropped (1.5°C) when the corresponding location on the opposite hand of control subjects was subjected to prolonged thermal stimulation, but this response was absent for IBS pain patients. The patients also required significantly lower stimulus temperatures than controls to maintain a 35% pain rating. Baseline skin temperatures of patients were significantly correlated with thermode temperatures required to maintain 35% pain ratings. IBS pain intensity was not significantly correlated with skin temperature or pain sensitivity. The method of response-dependent stimulation revealed thermal hyperalgesia and increased sympathetic tone for chronic pain patients, relative to controls. Similarly, a significant correlation between resting skin temperatures and thermal pain sensitivity for IBS but not control subjects indicates that tonic sympathetic activation and a thermal hyperalgesia were generated by the chronic presence of visceral pain. However, lack of a significant relationship between sympathetic tone and ratings of IBS pain casts doubt on propositions that the magnitude of IBS pain is determined by psychological stress.

Extreme Thermal Sensitivity and Pain-Induced Sensitization in a Fibromyalgia Patient

During the course of a psychophysical study of fibromyalgia syndrome (FMS), one of the subjects with a long history of headache and facial pain displayed an extraordinarily severe thermal allodynia. Her stimulus-response function for ratings of cutaneous heat pain revealed a sensitivity clearly beyond that of normal controls and most FMS subjects. Specially designed psychophysical methods showed that heat sensitivity sometimes increased dramatically within a series of stimuli. Prior exposure to moderate heat pain served as a trigger for allodynic ratings of series of normally neutral thermal stimulation. These observations document a case of breakthrough pain sensitivity with implications for mechanisms of FMS pain.

The Effect of Topical Local Anesthetics on Thermal Pain Sensitivity in Patients with Irritable Bowel Syndrome

Generalized hypersensitivity that extends into somatic areas is common in patients with irritable bowel syndrome (IBS). The sensitized state, particularly assessed by experimental methods, is known to persist even during remissions of clinical pain. It was hypothesized that disease-related nociceptive activity in the gut maintains a systemic-sensitized state. The present study evaluated responses to prolonged thermal stimuli maintained at constant temperature or constant pain intensity during stimulation. The effect of topically applied rectal lidocaine on heat sensitivity was also evaluated. The question is whether silencing potential intestinal neural activity (which may not always lead to a conscious pain experience) with lidocaine attenuates sensitization of somatic areas. Tests were also performed where lidocaine was applied orally to control for systemic or placebo effects of the drug. The IBS subjects exhibited a greater sensitivity to somatic heat stimuli compared to controls; however, lidocaine had no discernible effect on sensitization in this sample of IBS patients, where most of the individuals did not have clinical pain on the day of testing.