Radiant Heat Stimuli Research Articles

Properties of functionally identified nociceptive and nonnociceptive facial primary afferents and presynaptic excitability changes induced in their brain stem endings by raphe and orofacial stimuli in cats

The activity of 221 single primary afferent units was recorded extracellularly in the trigeminal (V) ganglion of chloralose-anaesthetized cats to examine the receptive field properties of nonnociceptive and nociceptive cutaneous afferents and the effect of conditioning stimulation of the raphe system and orofacial afferents on the antidromic excitability of their brain stem endings in V subnucleus caudalis. In addition to slowly adapting and rapidly adapting low-threshold mechanosensitive afferents, we functionally identified three classes of cutaneous nociceptive afferents: these included A-delta high-threshold mechanoreceptive afferents (A-delta HTMs), C-fiber high-threshold mechanoreceptive afferents (C-HTMs), and C-polymodal nociceptive afferents (CPNs). Most of the CPNs could be activated by light tactile stimuli as well as by heavy pressure and pinch and noxious radiant heat applied to their mechanoreceptive field which usually involved a localized spot (approximately 1 mm in diameter) of skin. In contrast, the C-HTMs and A-delta HTMs could not be activated by radiant heat stimuli although some did show sensitization which was also a feature of the CPNs; they did respond to noxious mechanical stimulation of a localized area of skin. We noted that orofacial conditioning stimulation could produce an increase in antidromic excitability which was considered a reflection of primary afferent depolarization (PAD) in both nociceptive and nonnociceptive afferents innervating the cat's facial skin; nonnoxious mechanical stimuli and electrical stimuli were particularly effective in the low-threshold mechanosensitive afferents and noxious mechanical and high-intensity electrical stimuli were especially effective in the cutanous nociceptive afferents. Raphe conditioning stimulation also was very effective in inducing PAD in these nociceptive afferents; however, the raphe conditioning effects were not limited to these nociceptive afferents since PAD was also frequently demonstrated in the low-threshold mechanosensitive afferents.

Characterization of the effects produced by neurokinins and three agonists selective for neurokinin receptor subtypes in a spinal nociceptive reflex of the rat

In the awake restrained rat the intrathecal (i.th.) administration of 6.5 pmol-40 nmol of substance P (SP), neurokinin A (NKA) or one of two selective NK-1 receptor agonists [Pro 9, Met(O 2) 11]SP, denoted ana 1 and [β-Ala 4, Sar 9, Met(O 2) 11]SP (4–11), denoted ana 2 decreased reaction time (RT) to a noxious radiant heat stimulus in a dose-related manner. The following rank order of potency was observed in relation to this response: ana 1=ana 2 > SP ⪢ NKA. The decrement of tail-flick latency was greatest at 1 min and RT returned to the basal level within 6–11 min post-administration. However, in some rats SP produced a small increase in RT (antinociception) at 6–11 min post-administration. The i.th. administration of neurokinin B (NKB) or a selective NK-3 receptor agonist [β-Asp 4, MePhe 7]NKB (4–10), denoted ana 3 induced an antinociceptive effect which was greatest at 1 min and lasted less than 11 min after NKB or more than 30 min after ana 3 administration. The magnitude of the increase in RT produced by 65 pmol-40 nmol doses of these peptides is ana 3 ⪢ NKB ⪢ SP. The effect of NKB (8.0 nmol) was significantly blocked (P < 0.005) by prior i.th. administration of naloxone (opioid antagonist) but not by idazoxan ( α 2-adrenoceptor antagonist), [Thi 5,8, D-Phe 7]BK (kinin antagonist), or following bilateral adrenalectomy. From these results, we conclude that NKB-induced antinociception is mediated by the spinal release of an opioid and not through a BK or NA mechanism. The results also suggest that the nociceptive and antinociceptive effects of neurokinins are mediated by the activation of NK-1 and NK-3 receptor subtypes respectively, in the rat spinal cord.

Bradykinin analogue blocks bradykinin-induced inhibition of a spinal nociceptive reflex in the rat

In the awake restrained rat the intrathecal (i.th.) administration of 81 pmol to 8.1 nmol of bradykinin (BK) increased reaction time to a noxious radiant heat stimulus. The enhancement of tail-flick latency peaked at 1 min and returned to the basal level 11–16 min after BK administration. Behavioural responses were observed as early as 5 s following peptide administration and lasted for 30–45 s. When BK was given after prior i.th. administration of 6.1 nmol of [Thi 5,8,D-Phe 7]BK, an antagonist of BK at the B 2-receptor, the increase in latency was significantly attenuated. The analogue [Leu 8]BK-(1–8) (10.3 nmol), an antagonist of BK at the B 1-receptor, failed to modify the BK-induced antinociception. The two analogues alone and the fragment BK-(1–8), a potent stimulant of B 1-receptors for BK, failed to alter reaction time and only the B 2-receptor antagonist reduced BK-induced behavioural responses. These results suggest that BK may play a role through the activation of a B 2-receptor type in a spinal sensory pathway subserving pain.

Suppression of C-fibre discharges upon repeated heat stimulation may explain characteristics of concomitant pain sensations : Brain Res., 302 (1984) 203–211

Pain: February 1987 - Volume 28 - Issue 2 - p 271 doi: 10.1016/0304-3959(87)90128-X

A quantitative study on the tail flick test in the rat

Tail flick latency and response temperature were measured in awake rats. Both of these parameters varied with the change in rate of increase of radiant heat stimulus and the are of skin irradiated. The caloric factor applied to the tail before the response occurred was calculated approximately from the time-temperature curves monitored over the tail and the response latencies. The magnitude of the caloric factor over a tentative threshold temperature was the crucial factor for the induction of tail flick response, because it was similar for the various irradiating conditions. It was proposed that analgesic effects in the tail flick test may be expressed using this caloric factor which allows direct comparison of studies in which different base-line latencies are used.

Does neurogenic inflammation alter the sensitivity of unmyelinated nociceptors in the rat?

This study on neurogenic inflammation aimed at comparing the effects of antidromic nerve stimulation and of cutaneous application of mustard oil on the mechanical and thermal sensitivity of cutaneous C-fibres in the rat saphenous nerve. They were tested with von Frey hairs and series of radiant heat stimuli in 5-min intervals before and after one of the above treatments. Antidromic electrical stimulation was effective in evoking a plasma extravasation in the saphenous region as revealed by prior intravenous injection of Evans blue. However, it did not evoke spontaneous activity in the polymodal C-fibres tested nor did it markedly affect their mechanical and thermal excitability in periods of up to 1 h after stimulation. Mustard oil, topically applied to the receptive fields, also evoked localized Evans blue extravasation and strongly affected the C-units. They responded to the application of the irritant with sustained firing; most units showed an increased thermal sensitivity after the treatment. This involved a lowering of the threshold and an increase of the suprathreshold discharge. Even low threshold mechanosensitive C-fibres transiently developed heat sensitivity. In some polymodal units a transient sensitization was followed by a persistent desensitization which abolished their thermal and mechanical sensitivity. Mustard oil application and antidromic nerve stimulation seem to be similar in evoking cutaneous vasodilatation and plasma extravasation but different in inducing nociceptor sensitization.

Hypothalamic inhibition of rat dorsal horn neuronal responses to noxious skin heating

The responses of single lumbar dorsal horn neurons to noxious radiant heat stimuli (42–54°C, 10 sec, 1/2 min) applied to glabrous hind paw skin were recorded in rats anesthetized with sodium pentobarbital. Unit responses to 50 or 52°C stimuli were constant over time and were consistently and powerfully inhibited during bipolar stimulation (three 100 msec trains/sec at 100 Hz, 200 μA) in the medial hypothalamus. Inhibition was also evoked by stimulation in medial and ventrobasal thalamic nuclei, lateral hypothalamus and adjacent cerebral peduncle, and amygdala. Inhibition increased with graded increases in intensity of hypothalamic stimulation, with a mean inhibitory threshold of 71 ± 43 ( S. D.) μA for 13 units. The responses of dorsal horn units to graded increases in the temperature of noxious heat stimuli were inhibited during hypothalamic stimulation, such that slopes of the linear temperature-response functions were reduced with no change in response threshold (mean: approximately 44°C). Inhibition was blocked or reduced in 4 7 units following systemic administration of the 5-hydroxytryptamine (5-HT) antagonist methysergide. The results confirm and extend previous work in the cat and are discussed in relation to analgesic mechanisms.

Spinal Sufentanil Effects on Spinal Pain-transmission Neurons in Cats

The ability of sufentanil to suppress noxiously evoked activity of wide dynamic range (WDR) neurons was studied in decerebrate, spinal-cord-transected cats. Sufentanil, 2.5 micrograms (n = 7) or 5.0 micrograms (n = 7), when administered spinally, produced a significant, dose-dependent suppression of noxiously evoked (51 degrees C radiant heat stimulus) activity of WDR neurons in the dorsal horn of the spinal cord. Spontaneous recovery from sufentanil suppression was not seen for up to 2 h. Reversal following intravenous naloxone, 0.12 mg, although present, was not as complete as that seen following other spinal opiates. Intravenous sufentanil, 5.0 micrograms/kg (n = 4), produced significant but short-lasting depression of noxiously evoked WDR neuron activity. A comparison of the results of this study with data from a previous fentanyl study suggests that sufentanil may be more appropriate than fentanyl for spinal or epidural administration because of a possible longer duration of action. However, the lesser degree of naloxone reversal seen in this study may suggest that, clinically, reversal of sufentanil effects may be more difficult.

Pain reactions in pregnant women

Reactions to radiant heat stimuli were measured in pregnant women and in a control group of non-pregnant women matched in age. Receiver operating characteristic curve parameters were computed for each of the stages of pregnancy from the 6th month until the postpartum period. When painful stimuli were used, a group by stage of pregnancy interaction was found in the analysis on the response criterion for reporting pain. Pregnant women were found to be significantly more willing to label radiant heat stimuli as painful during the last 2 weeks of pregnancy than during any of the other stages of pregnancy. The control women tested during the same time sequence as the pregnant women showed stable response criteria across the 6 month testing period. There were no group or stage of pregnancy effects evident when the discrimination accuracy measures were analyzed; nor were any effects found with responses to thermal stimuli. The results suggest that the changes in pain reaction associated with pregnancy are based on non-sensory factors that influence the subject's willingness to report pain.

Suppression of C-fibre discharges upon repeated heat stimulation may explain characteristics of concomitant pain sensations

Nociceptors with unmyelinated axons were recorded from the superficial radial nerves of 7 volunteers. A sequence of uniform radiant heat stimuli of 18 s duration, starting from an individually adjusted adapting temperature were used to raise the skin surface temperature by 6°C to a painful level (41–43 °C). These stimuli followed each other at 3 different interstimulus intervals of 35 s, 70 s and 105 s, occurring in a random order. The subjects were asked to track the time course of the stimulus-evoked sensation by manipulating the length of a light bar. Adaptation and stimulus temperatures were chosen to induce sensations of heat and/or pain. All nociceptors studied responded to these stimuli with a phasic response of 3–5 s duration, often followed by a low frequency tonic discharge, lasting as long as the stimulus. No discharges were seen in interstimulus periods. Discharge rates during the phasic responses were linearly related to interval duration, whereas tonic discharges were not influenced by the preceding interval. In parallel readings of pain responses were lower up to the 10th second of the stimulus after short rather than after long intervals. These results indicate that the suppression of C-fibre nociceptor discharges during repetitive stimulation may explain concomitant reductions in the magnitude of human pain sensations.

Functional organization of trigeminal subnucleus interpolaris: nociceptive and innocuous afferent inputs, projections to thalamus, cerebellum, and spinal cord, and descending modulation from periaqueductal gray.

In view of continuing uncertainties concerning the organization, afferent inputs, and projection sites of neurons in the subnucleus interpolaris of the trigeminal (V) spinal tract nucleus, the characteristics of 222 single neurons in and adjacent to the subnucleus were examined electrophysiologically in adult cats anesthetized with chloralose. Neurons were tested for orthodromic responsiveness to a variety of stimuli that included nonnoxious tactile stimuli, noxious mechanical and radiant-heat stimuli, and graded electrical stimulation of the skin, mucosa, tooth pulp, and masseter nerve. Antidromic activation techniques were also used to determine if the functionally identified neurons projected directly to the contralateral posterior thalamus, ipsilateral cerebellum, or cervical spinal cord. In addition, the periaqueductal gray matter (PAG) was stimulated to test for conditioning influences from the PAG on orthodromic responses to noxious and nonnoxious oral-facial stimuli. Interpolaris neurons were somatotopically arranged in subnucleus interpolaris in a pattern conforming in general to the medially facing, inverted-head representation characteristic of other parts of the V brain stem sensory nuclear complex. On the basis of their responsiveness to cutaneous stimuli, the neurons could be functionally classified as either cutaneous nociceptive or low-threshold mechanoreceptive (LTM) neurons. The LTM neurons constituted the major neuron type, accounting for over 75% of our neuron sample. Most of them had a localized mechanoreceptive field of less than 100 mm2 in area that was restricted to one V division, and they had skin-evoked response latencies indicative of afferent input predominantly from A-beta cutaneous afferents. A population of nociceptive neurons was also encountered in the lateral, marginal region of interpolaris and at its medial or ventral border with the reticular formation. These neurons were of two types: nociceptive-specific (NS) neurons, which did not respond to nonnoxious stimuli but which required noxious stimuli for their activation; and wide dynamic range ( WDR ) neurons, which responded to both noxious and nonnoxious stimuli applied to the facial skin. Most had an ipsilateral receptive field that was greater than 100 mm2 in area and that often involved two or three V divisions. Their properties generally conformed to those previously described for nociceptive neurons in the medullary dorsal horn (V subnucleus caudalis) and spinal cord dorsal horn. Interpolaris neurons of all classes (LTM, WDR , and NS) were found to have direct axonal projections to the thalamus, cerebellum, and spinal cord.(ABSTRACT TRUNCATED AT 400 WORDS)

Spinally administered epinephrine suppresses noxiously evoked activity of WDR neurons in the dorsal horn of the spinal cord.

This study was designed to determine if spinally administered epinephrine is capable of suppressing noxiously evoked activity of wide dynamic range (WDR) neurons in the dorsal horn of the spinal cord. Extracellular activity was recorded from single WDR neurons in the dorsal horn of decerebrate, spinal cord-transected (T-12) cats. Activity was evoked by the presentation of a noxious radiant heat stimulus (51 degrees C) to the cells' receptive fields on the hind paws. Evoked activity was monitored both before and after the spinal administration of either 50 micrograms (n = 6) or 100 micrograms (n = 6) epinephrine. Both doses of epinephrine produced a significant suppression of noxiously evoked activity, which was dose-dependent. In addition, the 100-microgram dose produced a suppression that was of longer duration than that seen following the 50-microgram dose. Recovery from suppression was recorded following both the 50- and 100-microgram dose. These results indicate that spinally administered epinephrine is capable of suppressing noxiously evoked activity of WDR neurons in the dorsal horn of the spinal cord. Since WDR neurons have been identified as cells of origin for the spinothalamic tract, such an action may block the central transmission of afferent pain information. This may be a mechanism by which spinally administered epinephrine enhances the duration or intensity of spinal anesthesia produced by local anesthetics and may also explain spinal analgesia resulting from the spinal administration of adrenergic agonists. Interactions between spinally administered epinephrine and spinally administered opioids also were studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Naloxone does not consistently affect inhibition of spinal nociceptive transmission produced by medial diencephalic stimulation in the cat

In cats anesthetized with sodium pentobarbital and artificially ventilated with 70% N 2O, the response of single lumbar dorsal horn units to noxious radiant heat stimuli (50°C, 10 sec) applied to glabrous footpad skin were recorded with microelectrodes. Unit heat-evoked responses were markedly suppressed by electrical stimulation (100 msec pulse trains at 100 Hz, 3/sec, 50–300 μA) at sites in the medial basal diencephalic periventricular gray, lateral hypothalamic area, preoptic area, and posterior basal telencephalon. Inhibition of dorsal horn unit responses produced by brain stimulation was not consistently affected following systemic administration of the opiate antagonist naloxone (0.5–1 mg/kg i.v.), indicating that the endogenous opioid peptides are not primarily involved in the mediation of this descending inhibition under the experimental conditions.

Serotonin involvement in descending inhibition of spinal nociceptive transmission produced by stimulation of medial diencephalon and basal forebrain

The responses of single lumbar dorsal horn neurons to noxious radiant heat stimuli (50 degrees C, 10 sec) applied to glabrous footpad skin were recorded in cats anesthetized with sodium pentobarbital and 70% N2O. Responses were markedly reduced during electrical stimulation (100-msec trains at 100 Hz, 3/sec, up to 400 microA) at sites in the medial diencephalic periventricular gray (PVG), preoptic area, and basal forebrain. A role for serotonin (5-hydroxytryptamine, 5-HT) was investigated by determining whether descending inhibition from these areas could be affected by (1) acute systemic administration of the 5-HT antagonist methysergide, or (2) depletion of central 5-HT levels by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA; 500 mg/kg, i.p.). Inhibition produced by stimulation at these sites was reduced or abolished in 22 cases following administration of methysergide (0.2 to 1 mg/kg) to non-pretreated cats. In the PCPA-pretreated cats, stimulation in preoptic or basal forebrain areas inhibited the responses of 26 units to noxious skin heating to varying degrees; PVG stimulation inhibited the responses of 14 of 26 units, while the remainder were unaffected. The mean current threshold for inhibition produced by PVG or preoptic/basal forebrain stimulation was significantly higher, while mean inhibition at 200 microA was significantly lower, in units from PCPA-pretreated cats compared to those from non-pretreated cats. The results indicate that 5-HT may be involved in the mediation of spinal inhibition produced by medial diencephalic and basal forebrain stimulation.

An ROC analysis of pain reactions in dysmenorrheic and nondysmenorrheic women.

Reactions to radiant heat stimuli were measured in dysmenorrheic and nondysmenorrheic women across a 4-week period. (Dysmenorrhea is a condition in which pain accompanies menstruation.) Receiver operating characteristic (ROC) curve parameters were computed for each of the phases of the menstrual cycle. When painful stimuli were used, a group × phase interaction was found in the analysis on the d’e scores. Nondysmenorrheic women were found to vary cyclically in their ability to discriminate painful from nonpainful stimuli, whereas dysmenorrheic women showed consistent pain reactions throughout the whole cycle. Cyclic effects were not apparent in the analyses on the response criteria or in those on reactions to thermal stimuli. The results suggest that women who experience pain with menstruation differ from women who do not differ in their perception of pain across the menstrual cycle. The sensory differences between the groups of women were not characteristic of responses to thermal stimuli and were not accompanied by shifts in willingness to report pain. Biochemical differences between dysmenorrheic and nondysmenorrheic women are believed to be the cause of the differences in pain reactions across phase.

Dose-response suppression of noxiously evoked activity of WDR neurons by spinally administered fentanyl.

The present study examined the influence of spinally administered fentanyl on the spontaneous and noxiously evoked activity of wide dynamic range (WDR) neurons in the dorsal horn of decerebrate, spinal cord-transected cats. This work was performed in order to evaluate the dose-response relationship, time course, and naloxone reversibility of fentanyl suppression of neurons that are involved with the transmission of information about pain. Extracellular single neuron recordings were obtained from 18 WDR neurons in the lumbar enlargement. These neurons were activated by a radiant heat stimulus on the footpads of the hindpaw. Fentanyl (10, 15, 25 micrograms in 0.5 ml of physiologic saline) was placed on the spinal cord following control studies of each neuron and the effect was observed. In 12 cats, 31 min after fentanyl administration, naloxone (0.1 mg) was administered intravenously, and its effect on the fentanyl suppression was determined. All three doses of fentanyl suppressed both the spontaneous and evoked activity of all the neurons studied. Thirty minutes after fentanyl the mean evoked activity was reduced to 47, 23, and 11% of control values by 10, 15, and 25 micrograms, respectively. The spontaneous activity was reduced to similar levels. Intravenous naloxone (0.1 mg) caused a significant reversal of the fentanyl suppression. The results of the present study indicate that fentanyl causes a naloxone-reversible, dose-dependent suppression of noxiously evoked WDR neuron activity. Such results support the concept that fentanyl is acting through a specific drug-receptor interaction. The onset of neuronal suppression occurred more rapidly, and the duration of the suppression was longer following fentanyl than that seen following spinal morphine. The onset and duration of this suppression correlates well with human clinical data, providing further evidence that alterations of WDR neuronal activity may be important in the production of spinal opioid analgesia.

Substance P reduces tail-flick latency: Implications for chronic pain syndromes

In the awake restrained rat the intrathecal administration of substance P or the partial substance P homologue eledoisin-related peptide (ERP) reduced reaction time to a noxious radiant heat stimulus and, at high doses, produced additional behavioural responses suggesting that the animals had reacted to what they perceived as a painful stimulus. The reduction in tail-flick latency was observed as early as 30 sec following peptide administration peaked at 1 min and persisted for 5–10 min, after which an overshoot of the response (i.e., an increase in reaction time) was observed. The responses varied in their magnitude with the amount of peptide given, substance P being approximately 4 times more potent on a molar basis than ERP. Intrathecal administration of an equal volume of vehicle (artificial cerebrospinal fluid) had no effect on tail-flick latency and failed to produce any of the other behavioural changes. The following interpretations are made. The decrease in tail-flick latency suggests that pain threshold was decreased, and the dramatic behavioural effects seen at high doses suggest that an excess of substance P in the spinal cord is capable of producing a painful sensation. The rapid onset of the response suggests rapid penetration of substance P and ERP to the appropriate receptors, and the rapid decay of the response suggests rapid removal. Taken together, these results are consistent with the earlier suggestion that substance P plays a role as an excitatory agent in sensory pathways subserving pain. It is proposed that some conditions of chronic pain in man may therefore be due to an overabundant amount of substance P. This is complementary to a second proposal that other cases of chronic pain may be due to a supersensitivity of substance P receptors. The former is more likely to be associated with organic disorders, the latter with nerve damage, e.g. with causalgia, the neuralgias and perhaps some cases of phantom limb pain.

Diurnal variation in excitation of dorsal horn units by naloxone in the spinal cat suggests a circulating opioid factor

Naloxone was administered in intravenous doses of 0.1–0.6 mg/kg in the spinal cat while recording extracellular spike activity from single, nociceptive dorsal horn units in lumbar segments 5–7 in the spinal transected cat. It was found that while naloxone increased on-going activity and excitatory responses to noxious radiant heat stimuli when it was administered during the day and early evening (12:30–20:00h) there was no observable effect when it was administered during the early hours of the morning (01:20–02:20 h). The one case in which early morning administration provoked an ‘excitation’ was in a cat without a regular rhythm. Units tested were in Rexed's laminae I, III, IV and V. These results suggest that an endogenous opioid factor is released into the circulation in amounts which vary on a diurnal cycle and that this factor crosses the blood-brain barrier at the spinal level to exert an inhibitory effect on transmission specifically in nociceptive pathways at the spinal level.

Signal detection and threshold measures for chronic back pain patients, chronic illness patients, and cohort controls to radiant heat stimuli.

Signal detection and threshold measures for chronic back pain patients, chronic illness patients, and cohort controls to radiant heat stimuli.

Signal detection and threshold measures for chronic back pain patients, chronic illness patients, and cohort controls to radiant heat stimuli.

Signal detection and threshold measures for chronic back pain patients, chronic illness patients, and cohort controls to radiant heat stimuli.