• Anesthesia related pain management strategies and 24 hour postoperative outcomes in traumatic tibia fracture patients

      Virts, Elena Victorovna; Storr, Carla L. (2015)
      Background: Pain management Pain management research is uncommon in trauma patients with tibia fracture who undergo surgery within 24 hours of admission. Acute intoxication is a risk factor for orthopedic trauma; however, whether pain management outcome differs between sober and intoxicated patients at admission is unknown. Purpose: Three commonly used anesthesia-related pain management (ARPM) strategies (Benzo, administration of preoperative benzodiazepines within 90 minutes of anesthesia start; Opioid, intraoperative administration opioids by the end of surgery; and Combo, a combination of both strategies) were examined for postoperative outcomes (pain intensity, time to achieve postanesthesia care unit [PACU] discharge criteria, total postoperative opioid consumption, and frequency of postoperative nausea and vomiting [PONV]). The outcomes associated with these ARPM strategies were evaluated according to whether a patient was sober or intoxicated at admission. Methods: A chart review of 206 adult trauma patients admitted for tibia fractures in 2007 though 2009 provided information on personal characteristics and physical status, perioperative pain intensity, administration of analgesics and pharmacological adjuvants, frequencies of PONV, time required to achieve PACU discharge criteria, surgical and injury attributes, and alcohol intoxication on admission. A mixed effects model and linear and logistic regressions were used to examine the relationships between the ARPM strategies and outcomes. Results: Most patients (84%) received an ARPM strategy (Benzo, 30%; Opioid, 21%; Combo, 33%). A majority (83.5%) reported severe pain; one third experienced PONV. Postoperative opioid consumption (range, 3.75 to 336.88 mg of morphine) and time required to achieve PACU discharge criteria (range, 10 to 358 minutes) varied widely. All ARPM strategies were associated with higher pain ratings compared with control patients, without altering the time required to achieve PACU discharge criteria. All ARPM strategies decreased total opioid consumption up to 50%, but this effect was limited to the first four postoperative hours. Combo strategy reduced the occurrence of PONV, but higher pain ratings were reported. Intoxicated patients received the most benefit from Benzo strategy, whereas Opioid strategy was detrimental to them. Conclusion: Benzodiazepines are recommended for orthopedic trauma patients who are intoxicated on admission, whereas a combination strategy is more appropriate for patients prone to PONV.
    • Chronic pain and thalamic abnormalities after traumatic brain injury

      Parihar, Abhishruti; Keller, Asaf (2014)
      Traumatic brain injury (TBI) is an important public health issue in both military and civilian life. Many suffer from cognitive and motor deficits, as well as from excruciating, unrelenting chronic pain (TBI-Pain). TBI-Pain is associated with hypersensitivity to mild tactile and thermal stimulation of the face and scalp, a result of central sensitization, a process by which brain structures undergo maladaptive plasticity, resulting in abnormal activity of brain neurons. Recently central sensitization of the posterior thalamus (PO) has been implicated in chronic pain disorders, spinal cord injury and migraine. We therefore hypothesized that chronic pain after TBI is also associated with abnormal activity of the PO thalamus. Here, we tested this hypothesis using a novel model of blast-TBI with two unique features: (i) blast-TBI was performed in awake, unanesthetized rats, to simulate the human experience and to preclude anesthesia-induced dampening of post-injury increases in excitatory activity that is crucial for the development of central pain; (ii) only the cranium, rather than the entire body, was exposed to a collimated blast wave, with the blast wave striking the posterior cranium in the region of the occipital crest and foramen magnum. Testing for thermal hyperalgesia of the face (distal from direct injury) revealed that blast-TBI rats had a significantly lower tolerance to pain, compared to the control group. Consistent with the behavioral data, single unit electrophysiological recordings from PO showed an increase in the spontaneous and evoked firing rate of neurons from blast-TBI rats, compared to sham. These data support the hypothesis that blast-TBI is associated with hyperalgesia and maladaptive plasticity in the PO thalamus.
    • Chronic Sensory and Affective Craniofacial Pain After Blast-Induced Traumatic Brain Injury and Peripheral Nerve Injury in Rats

      Studlack, Paige Elizabeth; Keller, Asaf; Simard, J. Marc; 0000-0002-3626-1865 (2017)
      Thousands of military members suffer long-term consequences of blast-induced traumatic brain injury (Blast-TBI), including chronic head and face pain. Pain after blast-TBI usually manifests as post-traumatic headaches with a high degree of comorbid mood disorders, suggesting that the affective dimension of pain may burden survivors of blast-TBI. Here, we tested the hypothesis that an innovative model of the unique aspect of blast-TBI over blunt-force TBI, the primary blast injury, directed over the cranium sufficiently modeled long-term conditions of human blast exposure in rats. Rats exposed to cranium-directed primary blast-TBI demonstrated behavioral manifestations of ongoing pain, mechanical hyperalgesia, and cold allodynia three weeks after injury, recapitulating chronic facial pain in patients after blast-TBI. We predicted that maladaptive changes to pain-signaling and -processing nuclei in CNS would induce and maintain pain behavior after blast-TBI. We recorded single units in sensory pain-associated nuclei, the posterior nucleus of the thalamus (PO) and spinal trigeminal nucleus caudalis (SpVc), which have previously been causally associated with pain after spinal cord injury. We observed hyperexcitability at baseline of PO neurons after blast injury in absence of changes to evoked response to cutaneous noxious stimuli. Neuronal hyperexcitability in PO is not associated with persistent gliosis. Affective pain processing through the parabrachial complex (PB) occurs in parallel to information coding the sensory dimension of pain through PO. We assessed central changes to PB neuronal activity in a robust model of post-traumatic pain using the chronic constriction injury of the infraorbital nerve (CCI-ION). PB neurons, weeks to months after injury, are hyper-excitable in chronic pain, as shown by prolonged response after presentation of noxious cutaneous stimulation ("after-discharges"), previously observed to be causally-related to pain due to CCI-ION in SpVc. Further study of PB hyperexcitability in blast-TBI rodent models may elucidate the mechanism underlying blast-TBI-associated affective pain.
    • Influence of Social Observational Learning on Pain Perception

      Raghuraman, Nandini; Colloca, Luana (2018)
      Background: Placebo hypoalgesia is the reduction of pain purely by treatment context. Humans are social beings and learn about their environment by observing others. Research shows observational learning induces placebo hypoalgesia, but its neural underpinnings are not explored. Methods: During EEG acquisitions, twenty-six healthy participants observed a demonstrator experiencing pain on two inert creams on the forearm. He showed painful and neutral expression for each. They then received same creams and recorded their pain ratings. Results: We got 11 responders reporting lower pain (Placebo x = 12.8 ± 3.7, (F (1, 10) = 11.812, p = 0.006)) and 10 non-responders who showed opposite trend (Placebo x = -6.9±3.5, (F (1, 9) = 3.85, p = 0.081)). The peak alpha frequencies during eyes closed resting state did not correlate with placebo response. Conclusion: Social learning does induce placebo in certain people, and further EEG task analysis can help generate an electrophysiological marker for placebo.
    • Non-invasive Motor Cortex Neuromodulation Reduces Secondary Hyperalgesia and Enhances Activation of the Descending Pain Inhibitory System

      Meeker, Timothy Joseph; Greenspan, Joel D. (2017)
      Studies have demonstrated analgesic effects of motor cortex (M1) stimulation for several chronic pain disorders such as neuropathic pain and syndromes involving central sensitization. Central sensitization is an important factor in neuropathic pain, clinically manifested as hyperalgesia and allodynia beyond any apparent injury. We predicted M1 transcranial direct current stimulation (tDCS) would mitigate secondary hyperalgesia, with little or no effect on primary hyperalgesia. We used a capsaicin-heat pain (C-HP) model to elicit heat allodynia and secondary mechanical hyperalgesia in pain-free subjects. In an assessor and subject blind randomized sham-controlled trial, we found anodal M tDCS decreased the intensity and area of pinprick hyperalgesia more than cathodal or sham tDCS with a small to moderate effect size. In contrast, we found no difference among treatments on pain ratings during heat allodynia. These findings confirmed our predictions and support the hypothesis that M1-targeted neuromodulation diminishes central sensitization. To elucidate the mechanism driving analgesia, we repeated application of the C-HP model during anodal, cathodal or sham tDCS in an assessor-blind randomized controlled trial while capturing neurophysiological correlates using functional magnetic resonance imaging (fMRI). We hypothesized M1 anodal tDCS would enhance engagement of a descending pain modulatory (DPM) network in response to mechanical pain compared to cathodal or sham tDCS. Anodal tDCS normalized effects of central sensitization on mechanical pain responses in the DPM network. Anodal tDCS disrupted the normal covariation of mechanical pain processing with subjective pain intensity and blunted the effect of sensitization in primary somatosensory cortex. There were treatment associated differences in functional connectivity (FC) within the DPM network. We found M1 to PAG FC was significantly greater during pain after anodal versus cathodal tDCS. Differences in FC between pain and control states for anodal tDCS included disrupted FC between PAG and sensory regions in the parietal lobe as well as the rostral ventral medulla. No disruptions in FC between control and pain state were found after cathodal or sham stimulation. These results support the hypothesis that analgesia via M1 neuromodulation occurs through modulation of activity in the DPM network even at the earliest stages of therapy.
    • Observational Study Evaluating Pain in Endodontic Patients Diagnosed with Depression – A Pilot Study

      Mannan, Saurabh; Greenspan, Joel D. (2019)
      TITLE: Observational Study Evaluating Pain in Endodontic Patients Diagnosed with Depression – A Pilot Study Saurabh Mannan, Master of Science 2019 Thesis Directed By: Joel Greenspan, PhD AIM: To evaluate the role of depression in endodontic post-procedural pain METHODOLOGY: This prospective observational study enrolled 42 patients that explored the correlation between patient’s level of depression and pain perception following non-surgical root canal treatment (NSRCT). The Hospital Anxiety and Depression Scale (HADS) assessed the patient’s level of anxiety/depression pre-and postoperatively. The patient used a visual analog scale (VAS) to record their pain intensity and feelings of unpleasantness with their dental experience immediately following their NSRCT. Pain diaries recorded pain intensity post-operatively at the 2nd, 4th, and 7th day. A cohort of endodontic patients who were not diagnosed with depression served as controls. RESULT: A total of 41 patients were included, 30 non-depressed patients and 11 patients diagnosed with depression by their physicians. Two patients did not return the pain dairy. Therefore, data from 29 non-depressed patients and ten depressed patients were available for analysis. This study showed that the diagnosis of depression was significantly associated with both higher immediate post-operative pain and immediate sensations of unpleasantness. Furthermore, HADS ≥ 8 was found to be a significant predictor of greater post-operative pain at day two. CONCLUSIONS: Within the limitations of this study, either a diagnosis of depression or signs of anxiety or depression are a positive predictor of greater post-operative pain.
    • Pain, coping, and depression following burn injury

      Ulmer, Janice Fitzgerald; Gift, Audrey G. (1991)
      Pain, coping, and depression were examined in a convenience sample of 32 burn injured men and women. Subjects were interviewed 3 times at approximately weekly intervals. The first and third interviews focused on coping, the second interview focused on how burn pain is described and rated by burn injured subjects and their care providers. Three criterion variables, pain intensity, pain distress, and depression were used to measure coping outcome. Five variables, severity of injury, surgical intensity, baseline depression, duration of pain, and level of analgesic drug were predicted to influence coping. Although the burn wound was identified as the source of worst pain, when subjects were asked to rate wound, donor, and skin graft pain using the short form McGill Pain Questionnaire (MPQ-SF), no significant differences were found. Average pain intensity, average pain distress, and level of depression decreased significantly over time. Pain with routine activity and pain worst continued to be rated moderate to severe by most patients at the third interview. No changes were noted in coping strategy use when coping was measured using the Coping Strategies Questionnaire. Subjects' perceptions of their ability to control pain increased significantly over the three measurement sessions. Subjects' perceptions of their ability to decrease their pain increased but did not achieve significance. Significant correlations between predictor and criterion variables were found for severity of injury, duration of pain, level of analgesic drug, baseline depression, and perceptions of ability to control and decrease pain. Significant correlations were also found between the criterion variables and beliefs related to personal control and the tendency to catastrophize. A significant positive correlation was found between care provider estimates of pain distress today and the average self-reported pain distress score. Care provider estimates of pain intensity today did not correlate with the average self-reported pain intensity score. When t-test comparisons were made between care provider and patient ratings no significant differences were found.
    • A Phase 3, Multi-Center, Randomized, Double-Blind, Parallel-Groups Clinical Trial Comparing the Efficacy and Safety of Intranasally Administered Kovacaine Mist to Placebo for Anesthetizing Maxillary Teeth in Adults

      Sabti, Mohammad Y.; Gordon, Sharon M. (2014)
      Problem: Fear of a painful dental injection and subsequent avoidance behavior are significant barriers to regular visits to the dentist. An anesthetic procedure that would avoid the discomfort of a local anesthetic injection thus obviating fear and anxiety about receiving a "shot," would greatly benefit dental patients. Methods: The study employed a multi-center, randomized, double-blind, placebo-controlled, parallel-groups design to assess the safety and efficacy of Kovacaine Mist delivered intranasally for inducing pulpal anesthesia of maxillary teeth sufficient to allow completion of the Study Dental Procedure. A total of 36 subjects, randomized 2:1 (Kovacaine Mist: Placebo) were enrolled. Results: Kovacaine Mist was significantly superior to placebo (p<0.0001) with respect to the proportion of subjects who did not require rescue by injection of local anesthetic to complete the Study Dental Procedure. Conclusions: Based of the results of this clinical trial, a nasal anesthetic, such as kovacaine mist, could potentially be used as a safe and effective alternative to maxillary infiltration for anesthetizing maxillary premolars and anteriors to achieve pulpal anesthesia.
    • Racial/ethnic differences in experimental pain sensitivity and associated factors - Cardiovascular responsiveness and psychological status

      Kim, Hee Jun; Dorsey, Susan Grace (2016)
      Background Racial/ethnic disparities related to pain in the US have been reported that racial/ethnic minorities have greater levels of chronic pain and receive lower quality of care. Underlying mechanisms to explain the racial/ethnic differences in pain is unclear. Enhanced experimental pain sensitivity is suggested to be associated with ethnic differences in clinical pain. Purpose To examine racial/ethnic differences in experimental pain sensitivity, and evaluate contribution of cardiovascular responsiveness and psychological status to racial/ethnic differences in experimental pain sensitivity. Methods The baseline data of TMD-free 3,159 individuals - non-Hispanic white (NHW): 1,637, African-American (AA): 1,012, Asian: 299, and Hispanic: 211 - from the OPPERA prospective cohort study were used. Quantitative sensory testing measures for pressure, mechanical cutaneous, and heat pain were used. Cardiovascular responsiveness measures (e.g., BP, HR, HR/MAP ratio, and heart rate variability) and psychological status (depression, anxiety, stress, coping, and catastrophizing) were included in the analyses. Structural equation modeling with maximum likelihood estimation method was used for mediation analyses. Putative mediators that showed significant racial/ethnic differences were entered into the final models simultaneously with age, gender, BMI, study site, education and income level as covariates. Results Racial/ethnic minorities showed higher pain sensitivity, including heat pain tolerance, heat pain rating (HPR), heat pain aftersensation (HPA), mechanical cutaneous pain ratings and aftersensation (MCPRAS), and mechanical cutaneous pain temporal summation (MCPTS), compared to NHWs. Catastrophizing significantly mediated the associations between ethnicity and pain sensitivity (heat pain tolerance, HPR, HPA, MCPRAS, and MCPTS) for both AAs and Asians, compared to NHWs. Coping negatively mediated the association between race/ethnicity and heat pain tolerance, HPR, and MCPTS in both AAs and Asians, compared to NHWs. HR/MAP ratio showed a significant negative mediating effect on the association between race/ethnicity (AAs vs. NHWs) and heat pain tolerance. Negative emotion mediated the associations between race/ethnicity (Asians vs. NHWs) and mechanical cutaneous pain threshold, HPR, and MCPRAS. Conclusion The identified mediators should be considered in pain management programs to implement better strategies to reduce clinical pain, especially for AAs and Asians in the US. Further clinical research is required to increase our understanding of the suggested mechanisms.
    • The relationship of pain characteristics, type of cancer, and opioid consumption to quality of life, psychological distress, and pain outcomes

      Polomano, Rosemary Carol; Belcher, Anne E. (1995)
      The relationship of pain to quality of life (QOL) outcomes has been studied; yet, for the most part, the presence and magnitude of pain have been the major variables of interest. Little is known about the impact of pain types (somatic, visceral and neuropathic) on QOL. The primary purpose of this study was to evaluate the extent to which physiological source(s) of pain, pain duration, intensity, location(s), number of sites, relief, sensory and affective components, and opioid consumption affect perceptions of QOL and psychological distress. In addition, the association and validity of pain language in predicting physiologic pain were evaluated. A convenience sample (N = 100) of subjects with chronic pain from advanced cancer was recruited for study from three outpatient medical oncology practices. Information was collected on age, sex, tumor type, treatment information, average daily opioid requirement, physiologic source(s) of pain, pain location(s), number of painful sites, and duration of pain. Each subject completed the following measures: (a) a Numeric Pain Rating (NRS) Scale for present pain intensity (PPI) and average worst pain intensity (WPI); (b) pain relief scale (VASPR); (c) the sensory and affective Short Form-McGill Pain Questionnaire (SF-MPQ); (d) The Brief Symptom Inventory (BSI) (psychological distress); and, (e) The Quality of Life Survey (QOLS). Data analyses were conducted using The SSPS-PC Program and the SAS Software System. Multiple regression analysis determined that SF-MPQ affective component, VASPR and age accounted for a significant portion (25.3%) of the variance in the QOLS scores, while WPI, VASPR and age explained 21.3% of the model for psychological distress. Discriminant Analysis, Chi-Square analyses and linear logistic regression evaluated significant associations of pain language to physiological pain categories. No significant differences in the QOLS, BSI and average pain intensity were found for pain location and cancer diagnosis using MANOVA's. ANOVA and Student's t-tests assessed differences among pain types. Subjects with a component of neuropathic pain experienced significantly more psychological distress, (p<.05), average pain (p<.01), greater sensory and affective pain (SF-MPQ) (p<.001), and present pain (p<.01).
    • Switch of GABAA signaling with persistent inflammation

      Zhu, Yi; Gold, Michael S., Ph.D. (2012)
      Following inflammation there is a switch in spinal GABAA signaling from inhibition to excitation such that GABA receptors contribute to inflammatory hyperalgesia. We hypothesized that this switch occurs in primary afferent neurons, as a result of a steady state and/or dynamic depolarizing shift in the reversal potential of GABAA currents (EGABA) which is coupled to an increase in high affinity extrasynaptic GABAA receptors. To test this hypothesis, back labeled, acutely dissociated cutaneous dorsal root ganglion (DRG) neurons from naïve and inflamed rats were studied with a variety of techniques including Ca2+ imaging and patch-clamp electrophysiology. With calcium imaging, GABAA receptor activation was shown to be inhibitory in neurons from naïve animal but was facilitatory or directly exciting in neurons from inflamed rats. Results from gramidicin perforated patch showed that a steady-state depolarizing shift in EGABA was not responsible for this shift in signaling. Rather, the shift appeared to be due to a combination of changes including an increase in GABAA current, a decrease in K+ current, and a depolarizing shift in resting membrane potential. The increase in GABAA current was associated with an increase in both high and low affinity currents which was due to a persistent increase in the relative activity of tyrosine kinase, resulting in part to a decrease in receptor internalization, rather than a change in subunit expression or protein. Dynamic regulation of EGABA was also observed in association with neural activity, but the shift in EGABA was hyperpolarizing, and likely to be due to the activation of a Cl- channel rather than a change in secondary ion transporter activity. Interestingly, inflammation was associated with a decrease in the activity dependent shift in EGABA. Our results indicate that the inflammation-induced switch in GABAA signaling is a complex process that involves the modulation of multiple channels and Cl- equilibrium potential and suggested different approaches to prevent the hyperalgesic effect of GABA.
    • The Contribution of TRPV1 S801 Phosphorylation to Nociception and Inflammatory Pain in Vivo

      Joseph, John; Chung, Man-Kyo (2020)
      Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cation permeable channel activated by painful stimuli, such as capsaicin and noxious heat, and enriched in many primary afferent neurons of the pain pathway. During inflammation, chemical mediators activate protein kinases (such as PKC) that phosphorylate TRPV1 and thereby enhance its function, which results in nociceptor sensitization. And this can result in a lower threshold for pain. However, the causal relationships between TRPV1 phosphorylation and pathological pain remain unexplored. To directly investigate the roles of one specific TRPV1 phosphorylation event in vivo, we genetically altered a major PKC phosphorylation site, mouse TRPV1 S801, to alanine. The TRPV1 expression pattern in sensory neurons of S801A knock-in (KI) mice was comparable to that in wildtype (WT) controls. In sensory neurons from KI mice, following the activation of PKC, the usual increase of capsaicin-induced currents was substantially impaired. Thermal hyperalgesia induced by PMA or burn injury in KI was identical to WT. Thermal hyperalgesia was only marginally attenuated in KI mice duirng inflammation. In contrast, PMA-evoked nocifensive responses and hyperalgesia to capsaicin were significantly attenuated in the hindpaws of KI mice. Ongoing pain from inflamed masseter muscle was also reduced in KI mice, and the pain was further inhibited by the TRPV1 antagonist AMG9810. These results suggest that PKC-mediated phosphorylation of TRPV1 S801 contributes to inflammation-mediated sensitization of TRPV1 to ligand, but not heat, in vivo. Further, this suggests that interference with TRPV1 S801 phosphorylation might represent a potential way to reduce inflammatory pain in the clinic, yet spare basal sensitivity and produce fewer side effects than with a more general TRPV1 inhibition.
    • The Role of Nociceptors in Orthodontic Tooth Movement, Pain, and Alveolar Bone Remodeling

      Elnabawi, Omar; Pae, Eung-Kwon (2018)
      Objective: To determine the effects of selectively ablating transient receptor potential vanilloid 1 (TRPV1)-expressing nociceptors on orthodontic tooth movement, pain, and alveolar bone remodeling. Methods: Resiniferatoxin (RTX) or vehicle was stereotaxically injected into left trigeminal ganglia in adult C57BL/6 mice. After 1 week, orthodontic spring was placed between left maxillary first molar and upper incisors. Pain level was evaluated by measuring mouse grimace scale (MGS) and bite force before and after 1, 3, and 7 days following the procedures. After 12 days, micro-CT was used to quantify tooth movement and analyzing alveolar bone changes. Results: Experimental tooth movement increased MGS scores and decreased bite force. RTX ablation of TRPV1+ nociceptors attenuated MGS scores and relieved the reduction in bite force. The extent of tooth movement was decreased in RTX-treated group, but interradicular alveolar bone volume was not affected. Conclusion: Selective ablation of TRPV1+ nociceptors significantly decreases tooth movement and pain.
    • Trigeminal-rostral ventromedial medulla involvement in contralateral deep tissue orofacial hyperalgesia

      Chai, Bryan Young; Ren, Ke (2013)
      In 2008, the National Institute of Dental and Craniofacial Research indicated that approximately 10 million Americans suffer from temporomandibular joint disorders (TMJD). Orofacial pain disorders not only impair the quality of life, but also seriously inhibit the health of the patient by impairing a person's ability to eat and drink. Reports have shown that patients with myofascial TMJD experience bilateral thermal hypersensitivity in the trigeminal region (Fernandez-de-las-Penas et al 2010). Our previous studies have shown that complete Freund's adjuvant (CFA)-induced masseter muscle inflammation and microinjection of the pro-inflammatory cytokine interleukin-1&beta (IL-1&beta) into the subnucleus interpolaris/subnucleus caudalis transition zone of the spinal trigeminal nucleus (Vi/Vc) induce contralateral orofacial hyperalgesia in rat models. Furthermore, ventral Vi/Vc second order neurons project to the rostral ventromedial medulla (RVM) (Sugiyo et al 2005), a critical site for descending pain modulation, and substance P (SP) and its neurokinin-1 (NK-1) tachykinin receptor in the RVM are involved in descending pain facilitation (LaGraize et al 2010). We hypothesize that the development of bilateral deep tissue orofacial hyperalgesia after unilateral inflammation involves neuron-glial interactions in the ipsilateral Vi/Vc transition zone, the SP/NK-1 receptor signaling in the RVM, and subsequent activation of RVM 5-HT containing neurons terminating in the contralateral Vi/Vc transition zone. The results showed that 1) microinjection of the IL-1 receptor antagonist into the ipsilateral Vi/Vc attenuated the CFA-induced contralateral hyperalgesia, 2) lesions to the ipsilateral Vc did not prevent the development of contralateral hyperalgesia, 3) ibotenic acid lesion of RVM neurons prevented the development of IL-1&beta-induced contralateral hyperalgesia, 4) intra RVM post-treatment injection of the NK-1 receptor antagonists attenuated CFA-induced bilateral hyperalgesia and IL-1&beta-induced bilateral hyperalgesia, 5) serotonin depletion in RVM neurons prior to intra-masseter CFA injection prevented the development of contralateral hyperalgesia, and 6) inhibition of 5-HT3 receptors in the contralateral Vi/Vc attenuated CFA-induced contralateral hyperalgesia. These results suggest that the development of CFA-induced contralateral orofacial hyperalgesia is mediated through descending facilitatory mechanisms involving the Vi/Vc-RVM circuitry.