Thermal Response Thresholds Research Articles

No antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol in male and female rats with persistent inflammatory pain.

Studies have demonstrated antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol (THC) in animals, but whether such synergy occurs against all types of pain and in humans is unclear. Because a majority of chronic pain patients are women, and sex differences in morphine and THC potencies have been observed in rodents, the present study examined sex-specific effects of morphine and THC given alone and in combination, in rats with persistent inflammatory pain. On day 1, baseline mechanical and thermal response thresholds, hindpaw weight-bearing, locomotor activity, and hindpaw thickness were determined. Inflammation was then induced via hindpaw injection of complete Freund's adjuvant (CFA). Three days later, morphine (s.c.), THC (i.p) or a morphine-THC combination (1:1, 3:1 and 1:3 dose ratios) was administered, and behavioral testing was conducted at 30-240 min postinjection. Morphine alone was antiallodynic and antihyperalgesic, with no sex differences, but at some doses increased weight-bearing on the CFA-treated paw more in males than females. THC alone reduced mechanical allodynia with similar potency in both sexes, but reduced thermal hyperalgesia and locomotor activity with greater potency in females than males. All morphine-THC combinations reduced allodynia and hyperalgesia, but isobolographic analysis of mechanical allodynia data showed no significant morphine-THC synergy in either sex. Additionally, whereas morphine alone was antinociceptive at doses that did not suppress locomotion, morphine-THC combinations suppressed locomotion and did not increase weight-bearing on the inflamed paw. These results suggest that THC is unlikely to be a beneficial adjuvant when given in combination with morphine for reducing established inflammatory pain.

Experienced individuals influence the thermoregulatory fanning behaviour in honey bee colonies

The survival of an animal society depends on how individual interactions influence group coordination. Interactions within a group determine coordinated responses to environmental changes. Individuals that are especially influential affect the behavioural responses of other group members. This is exemplified by honey bee worker responses to increasing ambient temperatures by fanning their wings to circulate air through the hive. Groups of workers are more likely to fan than isolated workers, suggesting a coordinated group response. But are some individuals more influential than others in this response? This study tests the hypothesis that an individual influences other group members to perform thermoregulatory fanning behaviour in the western honey bee, Apis mellifera L. We show that groups of young nurse bees placed with fanners are more likely to initiate fanning compared to groups of nurses without fanners. Furthermore, we find that groups with young nurse bees have lower response thresholds than groups of just fanners. Our results suggest that individuals have the capability to influence other individuals to follow their fanning response as temperatures increase, and these social dynamics balance probability of fanning with thermal response thresholds. An influential individual may ultimately affect the ability for a society to efficiently respond to environmental fluctuations.

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats.

BackgroundE‐52862 (S1RA, 4‐[2‐[[5‐methyl‐1‐(2‐naphthalenyl)‐1H‐pyrazol‐3‐yl]oxy]ethyl]‐morpholine), a novel selective sigma 1 receptor (σ1R) antagonist, has demonstrated efficacy in nociceptive and neuropathic pain models. Our aim was to test if σ1R blockade with E‐52862 may modify the signs of neuropathy in Zucker diabetic fatty (ZDF) rats, a type 2 diabetes model.MethodsMechanical and thermal response thresholds were tested on 7‐, 13‐, 14‐ and 15‐week‐old ZDF rats treated with saline or with E‐52862 acutely administered on week 13, followed by sub‐chronic administration (14 days). Axonal peripheral activity (skin–saphenous nerve preparation) and isolated aorta or mesenteric bed reactivity were analysed in 15‐week‐old ZDF rats treated with saline or E‐52862 and in LEAN rats.ResultsZucker diabetic fatty rats showed significantly decreased thermal withdrawal latency and threshold to mechanical stimulation on week 13 compared to week 7 (prediabetes) and with LEAN animals; single‐dose and sub‐chronic E‐52862 administration restored both parameters to those recorded on week 7. Regarding axonal peripheral activity, E‐52862 treatment increased the mean mechanical threshold (77.3 ± 21 mN vs. 19.6 ± 1.5 mN, saline group) and reduced the response evoked by mechanical increasing stimulation (86.4 ± 36.5 vs. 352.8 ± 41.4 spikes) or by repeated mechanical supra‐threshold steps (39.4 ± 1.4 vs. 83.5 ± 0.9). E‐52862 treatment also restored contractile response to phenylephrine in aorta and mesenteric bed.ConclusionsE‐52862 administration reverses neuropathic (behavioural and electrophysiological) and vascular signs in the ZDF rat.SignificanceBlockade of σ1R avoids the development of diabetic neuropathy in rats, and may represent a potentially useful therapeutic approach to peripheral neuropathies in diabetic patients.What does this study add? This study presents evidences for the potential usefulness of sigma receptor blockade on diabetic neuropathy in rats.The methodology includes behavioural evidences, electrophysiological data and vascular‐isolated models.

A simple and inexpensive method for determining cold sensitivity and adaptation in mice.

Cold hypersensitivity is a serious clinical problem, affecting a broad subset of patients and causing significant decreases in quality of life. The cold plantar assay allows the objective and inexpensive assessment of cold sensitivity in mice, and can quantify both analgesia and hypersensitivity. Mice are acclimated on a glass plate, and a compressed dry ice pellet is held against the glass surface underneath the hindpaw. The latency to withdrawal from the cooling glass is used as a measure of cold sensitivity. Cold sensation is also important for survival in regions with seasonal temperature shifts, and in order to maintain sensitivity animals must be able to adjust their thermal response thresholds to match the ambient temperature. The Cold Plantar Assay (CPA) also allows the study of adaptation to changes in ambient temperature by testing the cold sensitivity of mice at temperatures ranging from 30 °C to 5 °C. Mice are acclimated as described above, but the glass plate is cooled to the desired starting temperature using aluminum boxes (or aluminum foil packets) filled with hot water, wet ice, or dry ice. The temperature of the plate is measured at the center using a filament T-type thermocouple probe. Once the plate has reached the desired starting temperature, the animals are tested as described above. This assay allows testing of mice at temperatures ranging from innocuous to noxious. The CPA yields unambiguous and consistent behavioral responses in uninjured mice and can be used to quantify both hypersensitivity and analgesia. This protocol describes how to use the CPA to measure cold hypersensitivity, analgesia, and adaptation in mice.

Social context influences the initiation and threshold of thermoregulatory behaviour in honeybees

Interactions between individuals in a society are the basis of effective task allocation. Division of labour plays a critical role in the ecological efficiency of social insect societies. In this study we tested whether social context, specifically the number of workers present, affects thermoregulatory task performance in honeybees, Apis mellifera . We report here that worker bees assayed singly were significantly less likely to initiate fanning behaviour in response to elevated temperature than bees assayed in small groups of three or 10 workers. Bees assayed in groups also showed lower response thresholds than those assayed alone. The likelihood for fanning behaviour varied significantly among behavioural castes, while thermal response thresholds did not. These results suggest that worker task performance depends on the presence of other workers and offer another method by which division of labour in societies is organized. • We tested whether social context (number of workers) affects thermoregulatory task performance in honeybees. • Honeybees were more likely to fan in groups of 3 or 10, compared to when isolated. • As group size increased, the thermal threshold at which bees fanned decreased. • Some behavioural castes were more likely to fan than others. • There were no differences in thermal threshold across behavioural castes.

The Temperature-Sensitive Ion Channel TRPV2 is Endogenously Expressed and Functional in the Primary Sensory Cell Line F-11

In sensory neurons heat is transduced by a subfamily of TRP channels sharing sequence homology with the capsaicin-sensitive vanilloid receptor subtype 1 (TRPV1), but differing in their thermal response thresholds. To identify a neuronal cell line endogenously expressing noxious heat-transducing ion channels, we examined F-11 cells, a hybridoma derived from rat dorsal root ganglia and mouse neuroblastoma. Using RT-PCR, transcripts homologous to TRPV2 and TRPV4, but not to TRPV1 or TRPV3, were found. We isolated a full-length cDNA of 2.4 kb coding for a 757-amino acid protein corresponding to mouse TRPV2, which was further characterized by immunocytochemistry and electrophysiology. Using the whole-cell patch-clamp technique, we observed a heat-evoked increase in outward and inward currents with a threshold of 51.6 ± 0.2°C. The current-voltage relationship stimulated by a temperature of 52°C was characterized by an outward rectification with a reversal potential close to –10 mV. Heat-evoked currents could be inhibited by ruthenium red. There was no activation by stimulation with capsaicin or 2-aminoethoxydiphenyl borate. Our results indicate that F-11 cells express functional noxious heat-sensitive TRPV2 channels. Thus, we propose that F-11 cells represent a valuable in vitro model to characterize the properties of TRPV2 in a native neuronal environment.

A capsaicin-receptor homologue with a high threshold for noxious heat.

Pain-producing heat is detected by several classes of nociceptive sensory neuron that differ in their thermal response thresholds. The cloned capsaicin receptor, also known as the vanilloid receptor subtype 1 (VR1), is a heat-gated ion channel that has been proposed to mediate responses of small-diameter sensory neurons to moderate (43 degrees C) thermal stimuli. VR1 is also activated by protons, indicating that it may participate in the detection of noxious thermal and chemical stimuli in vivo. Here we identify a structurally related receptor, VRL-1, that does not respond to capsaicin, acid or moderate heat. Instead, VRL-1 is activated by high temperatures, with a threshold of approximately 52 degrees C. Within sensory ganglia, VRL-1 is most prominently expressed by a subset of medium- to large-diameter neurons, making it a candidate receptor for transducing high-threshold heat responses in this class of cells. VRL-1 transcripts are not restricted to the sensory nervous system, indicating that this channel may be activated by stimuli other than heat. We propose that responses to noxious heat involve these related, but distinct, ion-channel subtypes that together detect a range of stimulus intensities.

The effect of dynamic exercise on resting cold thermoregulatory responses measured during water immersion

The purpose of this study was to evaluate the effect of exercise on the subsequent post-exercise thresholds for vasoconstriction and shivering measured during water immersion. On 2 separate days, seven subjects (six males and one female) were immersed in water (37.5 degrees C) that was subsequently cooled at a constant rate of approximately 6.5 degrees C x h(-1) until the thresholds for vasoconstriction and shivering were clearly established. Water temperature was then increased to 37.5 degrees C. Subjects remained immersed for approximately 20 min, after which they exited the water, were towel-dried and sat in room air (22 degrees C) until both esophageal temperature and mean skin temperature (Tsk) returned to near-baseline values. Subjects then either performed 15 min of cycle ergometry (at 65% maximal oxygen consumption) followed by 30 min of recovery (Exercise), or remained seated with no exercise for 45 min (Control). Subjects were then cooled again. The core temperature thresholds for both vasoconstriction and shivering increased significantly by 0.2 degrees C Post-Exercise (P < 0.05). Because the Tsk at the onset of vasoconstriction and shivering was different during Pre- and Post-Exercise Cooling, we compensated mathematically for changes in skin temperatures using the established linear cutaneous contribution of skin to the control of vasoconstriction and shivering (20%). The calculated core temperature threshold (at a designated skin temperature of 32.0 degrees C) for vasoconstriction increased significantly from 37.1 (0.3) degrees C to 37.5 ( 0.3) degrees C post-exercise (P < 0.05). Likewise, the shivering threshold increased from 36.2 (0.3) degrees C to 36.5 (0.3) degrees C post-exercise (P < 0.05). In contrast to the post-exercise increase in cold thermal response thresholds, sequential measurements demonstrated a time-dependent similarity in the Pre- and Post-Control thresholds for vasoconstriction and shivering. These data indicate that exercise has a prolonged effect on the post-exercise thresholds for both cold thermoregulatory responses.

Responses of primary afferents and spinal dorsal horn neurons to thermal and mechanical stimuli before and during zymosan-induced inflammation of the rat hindpaw

Intraplantar administration of zymosan produces inflammation and results in behavioral evidence of hyperalgesia to mechanical and thermal stimuli in the rat. In the present studies, responses of primary afferents and spinal dorsal horn neurons to mechanical and thermal stimuli were examined before and during zymosan-induced inflammation of the hindpaw. In tests of responses of primary afferents to mechanical stimuli, group mean mechanical response thresholds of C-mechanonociceptor (CMN) units significantly decreased after zymosan administration. The group mean mechanical response thresholds of low threshold mechanoreceptor (LTM) units, A-mechanoheat (AMH) units, high threshold mechanoreceptor (HTM) units, and C-mechanoheat (CMH) units showed either no change or were increased significantly by intraplantar administration of zymosan. The group mean total discharges evoked during the 10 s mechanical stimulus were significantly increased after zymosan administration in CMN units. The group mean total discharges were either significantly decreased or unchanged in LTM, AMH, HTM, and CMH units. In tests of responses of spinal dorsal horn neurons to mechanical stimuli, the group mean mechanical response threshold of nociceptive specific (NS) units decreased significantly 1 h following administration of zymosan, whereas no significant changes occurred in the mechanical response thresholds of wide dynamic range (WDR) neurons in zymosan-injected rats, WDR neurons in saline-injected rats, or NS neurons in saline-injected rats. The group mean total discharges of only NS neurons were significantly increased during the 10 s mechanical stimulus 3 and 4 h after zymosan administration. In tests of responses of primary afferents to thermal stimuli, intraplantar administration of zymosan resulted in significant decreases in group mean response thresholds of CMH units and significant increases in group mean response thresholds of AMH units. The group mean total discharges of CMH units was either unchanged or significantly increased during thermal stimuli depending on both the time of testing and the temperature of the test stimulus. The group mean total number of discharges of AMH units was significantly decreased during tests of all thermal stimuli. In tests of responses of spinal dorsal horn neurons to thermal stimuli, intraplantar administration of zymosan resulted in significant decreases in thermal response thresholds of both WDR and NS units of zymosan-injected rats, but no changes in WDR and NS units of saline-injected rats. The group mean total discharges evoked by the 15 s thermal stimuli also increased significantly in both WDR and NS units after zymosan administration. Zymosan administration resulted in increased background activity only in CMH units. These increases occurred immediately following the injection and dissipated by the first hourly test period. Significant changes in background discharges of both WDR and NS units occurred at some hourly test intervals following administration of zymosan, but these changes were not consistent with respect to either unit type or modality of the test stimulus. These data suggest that the zymosan-induced hyperalgesia to mechanical stimuli observed in behavioral studies reflects decreases in response thresholds of peripheral CMN units and spinal NS neurons. Hyperalgesia to thermal stimuli reflects decreases in response thresholds of peripheral CMH units, spinal WDR neurons, and spinal NS neurons. These data support the view that different physiological substrates mediate hyperalgesia to either thermal or mechanical stimuli following intraplantar administration of zymosan.

A pharmacological study of the modulation of neuronal and behavioural nociceptive responses in the rat trigeminal region

Electrical stimulation of the brain, particularly in the periventricular grey areas, caused long-lasting increases in behavioural escape thresholds to heating and mechanical stimuli applied to the facial region of the rat. The brain stimulation selectively suppressed responses to noxious stimuli. Responses to non-noxious stimuli, evoked by low threshold brush, were unaffected. The same animals that were studied in the behavioural tests were then anaesthetized with urethane and the inhibitory effect of the same brain stimulation was studied in single neurones recorded in the caudal trigeminal nucleus. A clear correlation ( r s = 0.63 ) emerged between degree of behavioural antinociception and the amount of inhibition seen in nociceptive neurones. In addition the mean duration of the inhibition (6 min) was similar to the mean duration of the antinociceptive effect (7.3 min). Other classes of non-nociceptive neurones were unaffected by the stimulation. The neurones were also studied using iontophoretically applied monoamine candidates for the inhibitory neurotransmitter, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). The profile of the effects of NA most closely fitted that of the inhibitory neurotransmitter. This profile was expressed in terms of depression and excitation of different classes of neurones, and by the duration of effects. The depressant effects could be antagonized by iontophoretic idazoxan. In addition clonidine induced long-lasting depression of firing. 5-HT was more likely than NA to excite nociceptive neurones and to depress non-nociceptive neurones. Only NA consistently elevated thermal response thresholds in a similar manner to that produced by brain stimulation. These results provide some support for the hypothesis that selective descending inhibition of nociceptive responses in neurones of the rat caudal trigeminal nucleus is mediated by NA, possibly by an action at α 2-adrenoceptors .

Cutaneous sensory afferents recorded from the nervus intramandibularis of Gallus gallus var domesticus.

The responses of single sensory afferent nerve fibres were recorded from small nerve bundles of the intramandibular nerve of the chicken following thermal and mechanical stimulation of the beak. Thermoreceptors, nociceptors and mechanoreceptors were identified and their responses characterized. Of the thermoreceptors identified 11 units were classified as cold receptors, which responded to cooling the receptive field by increasing the discharge rate and had conduction velocities in the range 0.83 to 4.4 m/s. Only one warm unit was identified. Two classes of nociceptors were identified: mechano-thermal (polymodal) nociceptors and high threshold mechanical nociceptors. The discharge characteristics and stimulus-response curves of both types were described. While the mechano-thermal nociceptors were exclusively C-fibres (c.v. 0.4 to 1.86 m/s), the high threshold mechanoreceptors contained both C and A delta fibres (c.v. 1 to 5.5 m/s). Thermal response thresholds for the mechano-thermal units ranged from 41 to 50 degrees C with mechanical thresholds of 2 to over 50 g. Mechanical thresholds for the high threshold units ranged from 5 to over 50 g. The mechanoreceptors were either slowly or rapidly adapting. The pattern of response together with stimulus-response curves were presented for the slowly adapting units. Conduction velocities of the slowly adapting units varied from 0.7 to 20 m/s and mechanical threshold from 0.1 to 2 g. On the basis of their response to a vibrating, and a ramp-and-hold mechanical stimulus, the rapidly adapting units were divided into Herbst and Grandry units with only the Herbst units responding accurately to the vibrating stimulus. Both units had fibres conducting in the 50 m/s range with thresholds in the 0.1 to 10 g range. The results are discussed in relation to the receptors found in other avian species and mammalian peripheral sensory afferents.