Changes In Thermal Thresholds Research Articles

Quantitative Sensory Testing (QST) Estimation of Regional Cutaneous Thermal Sensitivity During Waking State, Neutral Hypnosis, and Temperature Specific Suggestions

This study aimed to determine the effects of neutral hypnosis and hypnotic temperature suggestions in thermal and pain thresholds compared to resting state. Sixteen healthy medium or high hypnotizable volunteers were enrolled. Hypnotizability was assessed with the Hypnotic Induction Profile (HIP); QST was checked in resting state, in neutral hypnosis, after suggestions of heat and cold, and after deinduction. A significant increase in heat threshold was recorded during hypnosis with both cold and heat suggestions compared to neutral hypnosis. HIP induction score showed a linear correlation with changes of temperature thresholds after heat and cold suggestions. Thermal suggestions may result in a significant increase of heat perception thresholds with respect to neutral hypnosis. HIP score is related to thermal threshold changes. QST is a valuable and manageable tool to measure temperature threshold change during hypnosis.

Effects of morphine, butorphanol and levomethadone in different doses on thermal nociceptive thresholds in horses

Various opioids are available for use in equine medicine. Studies directly comparing their analgesic effects and side effects are rare. Therefore, the aim of this study was to compare the antinociceptive effect and the duration of analgesia of two different doses of morphine, butorphanol and levomethadone in horses. Eight adult, healthy horses were used for this randomized, placebo-controlled, blinded cross-over trail. Each horse received placebo (P=0.9% saline) and morphine (M0.1=0.1mg/kg; M0.2=0.2mg/kg), butorphanol (B0.1=0.1mg/kg; B0.2=0.2mg/kg) and levomethadone (L0.1=0.1mg/kg; L0.2=0.2mg/kg) in a low and a high dose and with a wash-out period of 14days. Thermal thresholds were determined by incremental contact heat applied to the skin at the withers. Single stimulations were performed 15 minutes prior and 10, 30, 60, 90, 120, 180, 240, 300, 360, 420, 540 and 1350 minutes after treatment. Threshold values, gastrointestinal auscultation score and horses' behavior were recorded. Data were analyzed with analysis of variance for repeated measurements (p<0.05). In group M0.1, changes in thermal thresholds did not reach significance. Thermal threshold increased significantly in the groups M0.2, B0.1, B0.2, L0.1 and L0.2 for 240, 90, 90, 60 and 300 minutes, respectively. Behavioural changes, increased locomotion and decreased bowel sounds as well as delayed time until defecation were noticed in all groups. Levomethadone induced a dose-dependent increase and prolongation of analgesia, whereas with butorphanol there was no difference between dosages regarding duration and intensity of analgesia. Morphine provided detectable analgesia only in the high dose of 0.2mg/kg. Levomethadone and morphine in the low dose (0.1mg/kg) produced only minor and short lived anti-nociception and further studies are necessary to give a profound dose recommendation for the use of these drugs in horses.

Spinal Cord Injury Induced Hyperalgesia is Associated with Increased Levels of Let-7 Family of MicroRNAs

Title: Spinal cord injury induced hyperalgesia is associated with increased levels of Let-7 family of MicroRNAs. Background: Spinal cord injury (SCI) results in chronic pain syndromes that are often refractory to treatment with opioids, and may represent mu opioid receptor (MOR) dysfunction. MicroRNAs play a role in gene regulation by binding to target mRNA, causing translational repression or mRNA degradation. Let-7 family microRNAs have been shown to target MOR suggesting they may influence the development of pain states and opioid responsiveness. This study sought to determine temporal changes in Let-7 family miRNA and correlate them to the onset of pain behaviors in a rodent model of post-SCI pain. Methods and findings: Thermal thresholds (evoked pain) were assessed in rats before and after intramedullary injection of quisqualic acid (n=18) or sham laminectomy (n=18). Three of the Let-7 family miRNA levels were determined (Let-7a, Lets-7c and Let 7g) using RT-PCR and qRT-PCR on spinal cord segments caudal to lesion at 7, 14 and 21 days after injury. Thermal thresholds were significantly reduced compared to baseline in injured animals at day 21 (mean decrease of 1.9 sec; p=0.02; 95% CI=0.41-3.3). Sham animals showed no significant change in thermal thresholds over time (p=0.77; 95% CI=3.2-4.2). SCI led to a trend in increasing Let-7 family miRNA levels over time. Compared to sham animals, miRNA levels studied increased in injured animals at 14 and 21 days, corresponding to the period during which post-injury pain developed. Conclusions: Our data suggests that increased levels of Let-7 family miRNAs are involved in behavioral responses to SCI. Future work will examine if inhibition of Let-7 family miRNAs alters the behavioral and cellular response to SCI.

Differential changes in gingival somatosensory sensitivity after painful electrical tooth stimulation.

We aimed to evaluate the effect of painful tooth stimulation on gingival somatosensory sensitivity of healthy volunteers in a randomized, controlled design. Thirteen healthy volunteers (six women, seven men; 28.4 ± 5.0 years) were included for two experimental sessions of electrical tooth stimulation: painful tooth stimulation and tooth stimulation below the sensory threshold (control). Eight of the human subjects participated in a third session without tooth stimulation. In all sessions, the somatosensory sensitivity of the gingiva adjacent to the stimulated tooth was evaluated with a standardized battery of quantitative sensory tests (QST) before, immediately after and 30 min after tooth stimulation. Painful tooth stimulation evoked significant decreases in warmth and heat pain thresholds (P < 0.001) as well as pressure pain thresholds (increased sensitivity) (P = 0.024) and increases in mechanical detection thresholds (decreased sensitivity) (P < 0.050). Similar thermal threshold changes (P < 0.019) but no mechanical changes were found after tooth stimulation below the sensory threshold (P > 0.086). No QST changes were detected in the session without tooth stimulation (P > 0.060). In conclusion, modest increased gingival sensitivity to warmth, painful heat and pressure stimuli as well as desensitization to non-painful mechanical stimulation were demonstrated after tooth stimulation. This suggests involvement of competing heterotopic facilitatory and inhibitory mechanisms. Furthermore, stimulation below the sensory threshold induced similar thermal sensitization suggesting the possibility of activation of axon-reflex-like mechanisms even at intensities below the perception threshold. These findings may have implications for interpretation of somatosensory results in patients with chronic intraoral pain.

Pharmacokinetic-pharmacodynamic modelling of intravenous buprenorphine in conscious horses

ObjectiveDescribe the pharmacokinetics of buprenorphine and norbuprenorphine in horses and to relate the plasma buprenorphine concentration to the pharmacodynamic effects. Study designSingle phase non-blinded study. AnimalsSix dedicated research horses, aged 3–10 years and weighing 480–515 kg. MethodsThermal and mechanical nociceptive thresholds, heart and respiratory rates and locomotor activity were measured before and 15, 30, 45 & 60 minutes and 2, 4, 6, 8, 12 & 24 hours post-administration of 10 μg kg−1 buprenorphine IV. Intestinal motility was measured 1, 6, 12 & 24 hours after buprenorphine administration. Venous blood samples were obtained before administration of buprenorphine 10 μg kg−1 IV and 1, 2, 4, 6, 10, 15, 30, 45 & 60 minutes, and 2, 4, 6, 8, 12 & 24 hours afterwards. Plasma buprenorphine and norbuprenorphine concentrations were measured using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay with solid-phase extraction. A non-compartmental method was used for analysis of the plasma concentration–time data and plasma buprenorphine concentrations were modelled against two dynamic effects (change in thermal threshold and mechanical threshold) using a simple Emax model. ResultsPlasma buprenorphine concentrations were detectable to 480 minutes in all horses and to 720 minutes in two out of six horses. Norbuprenorphine was not detected. Thermal thresholds increased from 15 minutes post-buprenorphine administration until the 8–12 hour time points. The increase in mechanical threshold ranged from 3.5 to 6.0 Newtons (median: 4.4 N); and was associated with plasma buprenorphine concentrations in the range 0.34–2.45 ng mL−1. Conclusions and clinical relevanceThe suitability of the use of buprenorphine for peri-operative analgesia in the horse is supported by the present study.

The Antinociceptive and Antihyperalgesic Effects of Topical Propofol on Dorsal Horn Neurons in the Rat

Propofol (2,6-diisopropylphenol) is an IV anesthetic used for general anesthesia. Recent evidence suggests that propofol-anesthetized patients experience less postoperative pain, and that propofol has analgesic properties when applied topically. We presently investigated the antinociceptive effects of topical propofol using behavioral and single-unit electrophysiological methods in rats. In behavioral experiments with rats, we assessed the effect of topical hindpaw application of propofol (1%-25%) on heat and mechanically evoked paw withdrawals. In electrophysiological experiments, we recorded from lumbar dorsal horn wide dynamic range (WDR)-type neurons in pentobarbital-anesthetized rats. We assessed the effect of topical application of propofol to the ipsilateral hindpaw on neuronal responses elicited by noxious heat, cold, and mechanical stimuli. We additionally tested whether propofol blocks heat sensitization of paw withdrawals and WDR neuronal responses induced by topical application of allyl isothiocyanate (AITC; mustard oil). Topical application of propofol (1%-25%) significantly increased the mean latency of the thermally evoked hindpaw withdrawal reflex on the treated (but not opposite) side in a concentration-dependent manner, with no effect on mechanically evoked hindpaw withdrawal thresholds. Propofol also prevented shortening of paw withdrawal latency induced by AITC. In electrophysiological experiments, topical application of 10% and 25% propofol, but not 1% propofol or vehicle (10% intralipid), to the ipsilateral hindpaw significantly attenuated the magnitude of responses of WDR neurons to noxious heating of glabrous hindpaw skin with no significant change in thermal thresholds. Maximal suppression of noxious heat-evoked responses was achieved 15 minutes after application followed by recovery to the pre-propofol baseline by 30 minutes. Responses to skin cooling or graded mechanical stimuli were not significantly affected by any concentration of propofol. Topical application of AITC enhanced the noxious heat-evoked response of dorsal horn neurons. This enhancement of heat-evoked responses was attenuated when 10% propofol was applied topically after application of AITC. The results indicate that topical propofol inhibits responses of WDR neurons to noxious heat consistent with analgesia, and reduced AITC sensitization of WDR neurons consistent with an antihyperalgesic effect. These results are consistent with clinical studies demonstrating reduced postoperative pain in surgical patients anesthetized with propofol. The mechanism of analgesic action of topical propofol is not clear, but may involve desensitization of TRPV1 or TRPA1 receptors expressed in peripheral nociceptive nerve endings, engagement of endocannabinoids, or activation of peripheral γ-aminobutyric acid A receptors.

Docetaxel‐induced peripheral neuropathy: protective effects of dihydroprogesterone and progesterone in an experimental model

Peripheral neurotoxicity is a frequent complication limiting docetaxel chemotherapy in patients with cancer. We developed an experimental model that closely mimics the course of neuropathy in patients, aiming to investigate both the mechanisms of neurotoxicity at biochemical, functional and morphological levels and the potential neuroprotective role of neuroactive steroids. We demonstrated that treatment with dihydroprogesterone (DHP) or progesterone (P) counteracts docetaxel-induced neuropathy, preventing nerve conduction and thermal threshold changes, and degeneration of skin nerves in the foodpad. Neuroactive steroids also counteract the changes in gene expression of several myelin proteins and calcitonin gene-related peptide induced by docetaxel in sciatic nerve and lumbar spinal cord, respectively. Most nerve abnormalities observed during the treatment with docetaxel spontaneously recovered after drug withdrawal, similarly to what occurs in patients. However, results of midterm follow-up experiments indicated that animals cotreated with DHP or P have a faster recovery of the neuropathy compared with docetaxel-treated rats. Our study confirmed that neuroactive steroids exert a protective effect on peripheral nerves at different levels, suggesting that they might represent a new therapeutic frontier for patients with chemotherapy-induced neuropathy.

Quantified sensory abnormalities in early genetically verified transthyretin amyloid polyneuropathy

Transthyretin amyloid neuropathy of type 1 (Swedish-Portuguese type) is an autosomally inherited progressive disease with a Val30Met mutation, causing generalized sensory-motor polyneuropathy. Quantitative sensory testing (QST) quantifies thermal threshold changes in patients with manifest general polyneuropathy, but its applicability at an early clinical stage of a strict biochemically defined disease has not yet been shown. Thermal QST was performed in 23 patients having a positive Val30Met marker and clinical symptoms of peripheral small-fiber neuropathy but normal electrophysiological findings and compared to a reference group of 43 healthy volunteers, both subdivided into age groups < or =45 and >45 years. Significant differences between patients and controls were found at all test sites in both age groups, except for warm thresholds at the medial lower leg in those >45 years. QST thus demonstrated elevated thermal thresholds before the development of electrophysiological abnormalities, which indicate large-fiber involvement. These findings confirm that QST is a useful method for documentation of developing polyneuropathy.

The Effect of Ting Point (Tendinomuscular Meridians) Electroacupuncture on Thermal Pain: A Model for Studying the Neuronal Mechanism of Acupuncture Analgesia

The aim of this study was to characterize the role of Ting points (TP) in acute pain management and its potential use in functional imaging studies by quantitatively assessing: (1) the change in peripheral thermal thresholds before and after the electroacupuncture (EA); and (2) the corresponding behavioral feedback of thermal pain stimulation and the de qi sensation of EA. The study design was prospective. Healthy subjects were recruited for the study at the University of California, San Diego Medical Center. Thirteen (13) healthy subjects were studied. Baseline thermal thresholds (cold and warm sensations and cold and hot pain) were measured at premarked testing sites along the medial aspects of bilateral lower extremities. Five (5) seconds of hot pain (HP) was delivered to the testing sites and the corresponding pain visual analog scale (VAS) scores were recorded. Thirty (30) seconds of EA was delivered via the SP1 and LR1 on the left lower extremities at 5 Hz via a 6-V square-wave stimulator. The VAS scores of the HP and de qi sensation (tingling) during the EA were recorded. The thermal thresholds and VAS scores for the HP and de qi were obtained immediately and both 30 and 60 minutes after the EA. Adaptation testing was also carried out to assess the change in thermal thresholds and the VAS scores of HP without EA. The warm thresholds of bilateral medial calves significantly increased (p < 0.01) after 30 seconds of EA stimulation. The HP VAS score reduced significantly at the ipsilateral calf during EA in comparison to preacupuncture and postacupuncture (p < 0.01) measurements. No significant change in thermal thresholds was noted in the adaptation paradigm. EA at the TP has an inhibitory effect on the C-fiber afferents. The analgesic benefit observed is most likely A-delta afferent mediated. Further correlation studies in functional imaging may provide defining data for the observed analgesic mechanism.

Changes in thermal threshold response in eight cats after administration of buprenorphine, butorphanol and morphine

Thermal thresholds were measured in eight cats after the intramuscular administration of morphine (0.2 mg/kg), buprenorphine (0.01 mg/kg) or butorphanol (0.2 mg/kg), doses commonly used in clinical practice; 0.9 per...

Onset and duration of the antinociceptive activity of intravenous fentanyl in cats

Compared to other species, the data on the pharmacodynamic actions of opioids in cats are few. The time to onset and duration of the antinociceptive effect of IV fentanyl (F) was studied in cats using a ramped thermal stimulus. Six young adult cats (four females, two males, mean ± SD weight of 4.7 ± 1.3 kg) were included in the study. On the day before each study, a cephalic catheter was placed, and the hair over the thorax was clipped. A small, lightweight probe was attached by Velcro to an elasticized band that was placed around the shaved thorax. Cats were accustomed to wearing the bands. The probe contained an electrical element and temperature sensor. The probe heated at a rate of 0.85 °C second−1, creating a thermal stimulus. Inflating a blood pressure cuff incorporated into the band, to a constant pressure, ensured constant contact. The sensor output was read on a digital voltmeter. The end point was a distinct skin twitch, jump, or turn to look at the probe, at which time the thermal stimulus was stopped. A safety cut-off was set at 60.5 °C. Three baseline thermal thresholds were recorded from each cat before treatment. Cats received 10 µg kg−1 F, or saline (S) IV in a randomized crossover design; the total volume of all injections was 1.5 mL and the tester was blinded to treatments. Thermal threshold was tested at 5 minutes after treatment, then at 15-minute intervals for 3 hours. Fentanyl produced marked dilation of the pupils and mild euphoria. The baseline threshold for all cats was 41.5 ± 0.95 °C. There was no significant change in thermal thresholds in the S-treated cats whereas the F-treated cats had significantly elevated thresholds for 110 minutes after injection. The maximum effect was seen at 5 minutes (55.3 ± 2.15 °C). The antinociceptive action of F after IV administration in cats has a rapid onset and a dose of 10 µg kg−1 produces a significant effect for 110 minutes.

Physiological correlates associated with cribbing behaviour in horses: changes in thermal threshold, heart rate, plasma beta-endorphin and serotonin.

The aim of the present study was to obtain information on the possible mechanisms underlying cribbing behaviour in horses. To investigate the horse's responsiveness to an external stimulus, a device for telemetric measurement of thermal threshold, using the forelimb withdrawal reflex, was developed and validated. Measurements of thermal threshold took place in cribbing horses (n = 11) before and during cribbing periods. Heart rate was monitored continuously in the same horses. Blood samples were collected before and during cribbing periods as well and in age- and sex-matched control horses (n = 11). beta-endorphin and cortisol were determined in plasma using radioimmunoassay techniques, serotonin was analysed by high performance liquid chromatography. Compared with basal values, thermal threshold was significantly (P = 0.003) lower during cribbing periods. The mean difference was 4.9 degrees C. Heart rate decreased significantly (P = 0.026) and showed a mean reduction of 2.4 beats/min during cribbing. Given the fact that arousal usually is associated with an increase in nociceptive threshold and in heart rate, the decrease in both during cribbing provide evidence that cribbing may reduce stress. Cribbers showed 3 times higher basal beta-endorphin levels than controls (mean 49.5 vs. 16.2 pmol/l, P = 0.006) and there was a trend for lower basal serotonin levels (mean 201.5 vs. 414.3 nmol/l, P = 0.07). These data indicate differences in cribber's endogenous opioid and serotonergic systems.

Rapid sprouting of sympathetic axons in dorsal root ganglia of rats with a chronic constriction injury

We compared the time-course of sympathetic nerve sprouting into the L4–6 dorsal root ganglia (DRG) of adult rats following a chronic constriction injury (CCI) made on the sciatic nerve, or following sciatic nerve transection at the same site. We also tested the rats for changes in threshold for withdrawal from mechanical and thermal stimuli delivered to the hindpaws. We found sympathetic sprouting in DRG by 4 days following CCI, paralleling the decreases in mechanosensory threshold and preceding changes in thermal thresholds. However, with sciatic nerve transection, sympathetic sprouting was not detectable until 14 days after nerve injury. Thus, after CCI, sympathetic sprouting occurs with a sufficiently rapid time-course for it to play a role in the genesis of neuropathic pain. We suggest that the more rapid sprouting seen after CCI than after resection is due to the availability of products of Wallerian degeneration, including nerve growth factor, to both spared and regenerating axons following CCI, but not following resection.