Vocalization Afterdischarge Research Articles

Effect of Chronic Intermittent Exposure to AM Radiofrequency Field on Responses to Various Types of Noxious Stimuli in Growing Rats

There are several reports of altered pain sensation after exposure (from a few minutes to hours in single or repeated doses for 2–3 weeks) to electromagnetic fields (EMF) in adults. The commonly utilized noxious stimulus is radiant heat. The nociceptive responses are known to be influenced by characteristics of stimulus, organism, and environment. We studied the pattern of nociceptive responses to various noxious stimuli in growing rats exposed to radiofrequency field (73.5 MHz amplitude modulated, 16 Hz power density 1.33 mw/cm2, SAR = 0.4 w/kg) for 45 d (2 h/d). Threshold current for stimulation of nociceptive afferents to mediate motor response of tail (TF), vocalization during stimulus (VD), and vocalization after discharge (VA); the withdrawal latency of tail (TFL) and hind paw (HPL) to thermal noxious stimulus and tonic pain responses were recorded in every rat. The TFL was not affected, HPL was decreased (p < 0.01), and the thresholds of TF and VD were not affected, while, that of VA was significantly decreased. The tonic pain rating was decreased (p < 0.01). A decrease in the threshold of VA (p < 0.01) is indicative of an increase in the emotional component of the response to the phasic pain, whereas a decrease in the pain rating indicates analgesia in response to the tonic pain. The results of our study suggest that chronic (45 d), intermittent (2 h/d) amplitude modulated RF field exposure to the peripubertal rat increases the emotional component of phasic pain over a basal eaualgesic state, while late response to tonic pain is decreased. The data suggest that amplitude modulated RF field differentially affects the mechanisms involved in the processing of various noxious stimuli.

Hyperalgesic response in rats fed sucrose from weaning to adulthood:: Role of VMH

The ventromedial nucleus of hypothalamus (VMH) is implicated in food intake, food preference, nociception and its modulation by palatable food. Palatable drink for 5–48 h in adult rat produced hyperalgesia, which is mediated by VMH. The effect of palatable dietary supplement after weaning on the nociceptive response in adult rats has not been reported. Whether or not VMH influences these nociceptive responses is also not known. The present study was therefore undertaken to investigate the effect of VMH lesion on the nociceptive responses in adult rats ingesting (ad libitum) sucrose from weaning. Weanling rats received sucrose solution in addition to drinking water and laboratory pellets (sucrose-fed group), while the control group of rats received laboratory pellets alone. On attaining adulthood, the behavioral responses, namely tail flick latency (TFL), thresholds of tail flick (TF), vocalization during stimulus (SV), and vocalization after discharge (VA) to phasic and formalin pain rating (FP) to tonic noxious stimuli, were noted in pre- and post-VMH lesion states of both groups of rats. In chronic sucrose-fed rats, the TFL was not affected, the thresholds of TF, SV and VA were significantly decreased ( P<.001) and the FP was increased in comparison to the control group, suggesting a hyperalgesic response to chronic sucrose ingestion. After the VMH lesion, in sucrose-fed rats, the thresholds of TF, SV and VA remained unaltered, while the FP was attenuated and TFL decreased. In control rats, VMH lesion produced a hyperalgesic response to both the phasic and tonic noxious stimuli. The data indicate that chronic sucrose feeding and VMH lesion differentially affect the nociceptive responses to the phasic and tonic noxious stimuli. These results suggest that chronic sucrose feeding from weaning to adulthood produces hyperalgesia to both the tonic and phasic noxious stimuli (except TFL), which is probably mediated by VMH.

Effects of 14-methoxymetopon, a potent opioid agonist, on the responses to the tail electric stimulation test and plus-maze activity in male rats: neuroendocrine correlates

We have studied the effects of 14-methoxymetopon (HS 198), a potent opioid agonist, on the responses to the tail electric stimulation test and plus-maze activity of adult male rats. The prototype μ agonist morphine was used as the drug of reference. Besides we addressed the effects of HS 198 on the serum corticosterone levels and on serotonergic systems of discrete brain regions. Both drugs were administered subcutaneously. Morphine (5 mg/kg) and HS 198 (30 μg/kg) induced a similar effect on the nociceptive test, with both drugs significantly increasing the threshold for the vocalization afterdischarge, which is related to the emotional component of pain. In the plus-maze, morphine (5 mg/kg) and HS 198 (20 and 30 μg/kg) induced similar increases in the percentages of entries and time in the open arms, two parameters related to the anxiety state of the animals. The results indicate that HS 198 is far more potent than morphine in reducing the emotive/affective component of pain and in inducing an anxiolytic effect. HS 198 (30 μg/kg) also induced parallel increases in the serum corticosterone levels and the hypothalamic serotonin content. A possible correlation between the anxiolytic action of the drug and its effect on the hypothalamic serotonergic system is suggested.

Ventromedial hypothalamic mediation of sucrose feeding induced pain modulation

Electrophysiological and behavioural studies suggest a modulatory role of ventromedial nucleus of the hypothalamus (VMH) in nociceptive behaviour. Lesion of the VMH produces hyperalgesia and a greater preference for sucrose solution. Hyperalgesia is also produced by sucrose feeding. To explore specifically the contribution of glucoreceptor neurons of the VMH in the mediation of sucrose-fed hyperalgesia, 2-deoxy- d-glucose (2-DG, antimetabolite of glucose) was slowly albeit continuously infused (1 μl/h for 7 days by microinfusion pumps) into the VMH of adult male rats. Simultaneously, the rats underwent tests for their nociceptive responses in control and sucrose-fed states. The tests for nociception, namely, tail flick latency (TFL), thresholds of tail flick (TF), vocalization during stimulus (SV), vocalization after discharge (VA) were recorded at 0500 h. The tests were repeated after 6, 12, and 48 h in 1 M saline (control group) and 2-DG (experimental group) microinfused rats. Rats were presented with sucrose (20%) solution for 48 h at 0500 h ad libitum in addition to food pellets and tap water. Infusion of 2-DG per se in the VMH led to hypoalgesia (in threshold of TF, SV, VA) while feeding sucrose for 6–12 h per se led to hyperalgesia (in TFL, threshold of SV and VA). Sucrose feeding to 2-DG rats, however, attenuated the hypoalgesia of 2-DG as well as the hyperalgesia of sucrose feeding. The results suggest that the VMH glucoreceptor neurons probably modulate sucrose mediated phasic pain responses.

Chronic naltrindole administration does not modify the inhibitory effect of morphine on vocalization responses in the tail electric stimulation test in rats

To address the existence of possible functional interactions between δ- and μ- receptors in relation to the affective component of pain, we have studied the effects of functional blockade of δ-receptors by a chronic treatment with naltrindole (1 mg/kg, 8 consecutive days) on antinociceptive responses to morphine (2 and 5 mg/kg) in the tail electric stimulation test, in adult male rats. The thresholds for the motor response (tail withdrawal), vocalization during stimulus and vocalization afterdischarge were assessed. These responses are considered to be integrated at spinal, medulla oblongata and diencephalon-rhinencephalon levels, respectively. The results show that the vocalization during stimulus and the vocalization afterdischarge were significantly affected by morphine in a dose dependent manner, the latter response being the most sensitive to the effects of the μ-opioid agonist. However, no significant effect was observed on motor responses at the doses used in this study. Chronic naltrindole treatment did not modify the inhibitory effect of morphine on the vocalization responses. Since the vocalization afterdischarge is related to the affective component of pain, the data suggest that the δ-opioid receptor is not involved in the supraspinal mechanisms at which these responses are organized and that there is not a μ- δ interaction in the modulation of the affective responses to noxious electrical stimulation.

Neonatal treatment with 5-HT antiserum alters 5-HT metabolism and function in adult rats

Adult rats were studied for serotonin and its metabolite in basal ganglia, nociceptive responses to electric current and tremor induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) to assess the effects of a single systemic injection of serotonin antiserum given at 1 day old. Antiserum-treated animals showed no overt behavioural abnormalities, but tremor induced by 5-MeODMT was augmented. Basal nociceptive thresholds for tail withdrawal and vocalization were unaffected, whereas vocalization after-discharge was significantly reduced. Significantly decreased serotonin levels and increased turnover were found in nucleus caudatus putamen, nucleus accumbens and tuberculum olfactorium of adult rats treated as neonates with serotonin antiserum. These results demonstrate long-lasting functional alterations and neurochemical suppression of the central serotoninergic system following neonatal administration of serotonin antiserum.

A developmental study on stress-induced antinociception measured by the tail electric stimulation test

The possible influence of weaning on the development of different neural mechanisms involved in stress-induced antinociception (SIA) was studied. Male Wistar albino rats were used for studies on adult and pre- and postweanling rats of 20 and 25 days of age, respectively. Animals were stressed by warm-water (20C) swimming for 3-min periods. Antinociception wasd assessed by the tail electric stimulation test. The thresholds for the motor response (tail withdrawal) (TW), vocalization during stimulus (V), and vocalization afterdischarge (VAD) were recorded. These responses are considered to be integrated at spinal, medulla oblongata, and diencephalon-rhinencephalon levels, respectively. In 20-day-old neonates, swimming stress only induced significant increases in the VAD thresholds that were not significantly reveresed by naloxone (NAL) (1 mg/kg). Twenty-five-day-old rats showed increased thresholds for the three nociceptive responses after stress, the effects on TW and V being antagonized by NAL. Adult rats subjected to stress showed increased thresholds for the three responses, an effect that was antagonized by NAL in all cases. These results suggest that the weaning period might be critical for the development of the mechanisms mediating SIA. Besides, a different involvement of opioid systems throughout development, particularly in relation to the affective/emotional component of pain, is also suggested.

Study of the relationship between δ-receptor agonist D-Ala 2-Ser(OBZ) 5 and pain threshold

In the rat, morphine and the opioid peptide [D-Ala2]-metenkephalinamide (D-ALA) increased the reaction time in the tail-flick test as well as the threshold for vocalization and vocalization afterdischarge after electrical stimulation of the tail. The analgesic effect of either opiate was potentiated by selective inhibition of brain type B MAO with deprenyl or pargyline and antagonized by selective inhibition of the A form of the enzyme with chlorgyline. β-Phenylethylamine (PEA), a specific substrate of brain type B MAO, also potentiated the opiate analgesia, and the enhancement was especially marked after combined treatments with deprenyl and PEA. The effect of PEA appeared to be preferentially related to the affective component of the pain response (threshold for vocalization afterdischarge). A more general role of PEA in brain function as a neuromodulator of the opiate receptor is proposed.

Pain-induced vocalization in the rat and its modification by pharmacological agents

Vocalization was induced in rats by electrical stimulation of the tail (pain-induced vocalization), and its components were characterized in terms of latency, duration, frequency spectrum and energy. Noxious stimuli at threshold elicit a single vocalization component (V 1). Increases in stimulus intensity produce additional discrete vocalization components (V 2−V n) with successively longer latencies, termed the vocalization afterdischarge (AD). The AD components are acoustically similar to each other but differ significantly from the V 1 component. The duration, the specific acoustic measures and the sound energy of both V 1 and AD components are positively correlated with intensity of the stimulus. The dependence of the V 1 and AD components on the affective state of the rat was evaluated by comparing the acoustic characteristics of both components to those of stress-induced vocalizations, and by studying the effects of the anxiolytic drug diazepam and physical restraint on the threshold of V 1 and AD. The AD components were markedly more dependent on the effective state of the rat then was the V 1 component. A moderately low dose of morphine (3.0 mg/kg) also preferentially affected the AD component, suggesting that a significant portion of the action of morphine on pain-induced vocalization is mediated through its action on the affective state of the rat.

The effect of pituitary removal on pain regulation in the rat

The effects of hypophysectomy (HX) on pain regulation in basal and in various stressful situations were investigated in the rat. Pain sensitivity was assessed by measuring the thresholds of 3 nociceptive reactions (tail withdrawal, vocalization, vocalization afterdischarge) following electrical stimulation of the tail. The completeness of HX and the integrity of hypothalamus were verified in each HX rat. (1) Baseline pain thresholds were lower in HX rats than in sham-operated animals; (2) naloxone (Nx) hyperalgesia was only slightly altered by HX; (3) different types of stress induced different types of changes in nociception i.e. analgesia or hyperalgesia. The influence of HX varied according to the stress: it increased hyperalgesia, reduced analgesia, or had no effect at all. These results indicate that in the rat: (i) the pituitary participates in the regulation of basal pain sensitivity, probably through analgesic factors; (ii) Nx hyperalgesia results essentially from an antagonism of endogenous opioids originating in the CNS and not in the pituitary; and (iii) the pain regulatory processes engaged in adaptation to stressful stimuli involve the CNS and the pituitary in variable proportions depending upon the nature of the stress.

Analgesic activity of substance P in rats: Apparent mediation by met-enkephalin release

The intracerebroventricular administration of Substance P (SP) produced a marked and short-lasting increase in the threshold for vocalization and vocalization afterdischarge in the rat after electrical stimulation of the tail. This effect was blocked by naloxone and potentiated by bacitracin, a peptidase inhibitor. The analgesic effect of SP was also blocked by the concomitant intraventricular injection of the specific antibody against the opioid peptide metenkephalin but not by the antibody against β-endorphin. Anti-met-enkephalin did not block other pharmacological actions of SP. The results suggest that SP produces an analgesic effect in rats by releasing met-enkephalin at supra-spinal levels involved in pain control. The undecapeptide Substance P (SP) produces analgesia in rodents after systemic or intracerebral administration (1–5). The analgesia has been generally observed after the administration of relatively low doses of the peptide and appears to be naloxone reversible. Since SP does not bind to opiate receptors of rat brain (6, 7) and lacks any direct action on the opiate receptors of the mouse vas deferens (2), it has been hypothesized that SP produces analgesia via the release of endogeneous opioid peptides (2, 3). Another suggested possibility is the metabolism of SP to a compound that binds to opiate receptors (8). The present study was planned to explore the above mentioned possibilities. If SP induces analgesia by releasing opioid peptides such as enkephalins or β-endorphin, the effect should be prevented by concomitant administration of specific antibodies to these opioid peptides. Alternatively, if SP requires metabolism to an active compound as a prerequisite to induce analgesia, peptidase inhibition should prevent or delay the analgesic activity of the undecapeptide.

Intrinsic analgesic activity of human beta lipotropin in rats: Comparison with other opioid peptides

The intracerebroventricular administration of human beta lipotropin (β h-LPH) prepared from pituitary extracts increased the threshold for vocalization and vocalization afterdischarge in the rat after electrical stimulation of the tail. This effect was of quick onset, of longer duration than that of other opioid peptides, and was naloxone-reversible. On a molar basis, β h-LPH was a more potent analgesic than met-enkephalin but much less potent than the synthetic pentapeptide analogue (D-Ala 2)-metenkephalinaroide or human β-endorphin. Bacitracin, a peptidase inhibitor, markedly potentiated and prolonged the analgesia elicited by any of the peptides used. Furthermore, the analgesia induced by β h-LPH was blocked by the concomitant intraventricular injection of its specific antibody but not by the antibodies against met-enkephalin or human β-endorphin. These findings suggest that the analgesic effect of β h-LPH depends on the intact 91 amino acid peptide and not on any of its biodegradation products.

Influence of local anesthetics and dissociative anesthetic ketamine on vocalization induced by electrical stimulation of sciatic nerve in rabbits

The intravenous use of local anesthetics-particularly, lidocaine-as an analgesic, has interested anesthesiologists in recent years. They have reported the value of lidocaine as part of a mixed general anesthetic and as an analgesic for a postoperative pain. The dissociative anesthetic, ketamine, was reported to produce conspicuous analgesia. Therefore, the following experiments were performed to determine the analgesic effects of local anesthetics and ketamine on vocalization after nociceptive stimulation in the rabbit. Vocalization was produced by electrical stimmulation to the sciatic nerve in urethane light-anesthetized rabbits. To analyze the mechanism of production of vocalization, vocalization during stimulation and vocalization afterdischarge was distinguished in this study, because the former was formed through spinal internuncials and the latter through a thalamic sensory relay. Local anesthetics lidocaine, mepivacaine and procaine, when administered intravenously, inhibited vocalization. Vocalization afterdischarge was particularly inhibited more remarkably than vocalization during stimulation. Of the three local anesthetics studied, lidocaine was found to be most effective, followed by mepivacaine and procaine. The ketamine action was similar to that of local anesthetics that is the suppression of vocalization afterdischarge at low doses and both vocalization during stimulation and after discharge at high doses. The duration of action was shorter than that of local anesthetics and the recovery was very faster in comparison with local anesthetics. The studies thus suggest that in addition to the thalamus, a well-known pain receptive site, vacalization afterdischarge in the rabbit, depends upon the integrity of thalamo-neocortical circuits, and furthermore, it was discussed that catecholaminergic, dopaminergic and cholinergic neurones in the central nervous system may be play an important role in the mechanism of vocalization afterdischarge.

Irreversible inhibitors of GABA transaminase induce antinociceptive effects and potentiate morphine

The irreversible inhibitors of GABA-transaminase, γ-acetylenic GABA and γ-vinyl GABA, were examined for antinociceptive actions in rodents. An antinociceptive effect unaccompanied by ataxia was demonstrated in mice on the 52°C hot-plate and in rats in a tail-stimulation procedure and was maximal at 4–6 hr after drug administration, which correlates temporally with reported maximal increases of brain GABA. The antinociceptive effect was antagonized by a subconvulsive dose of bicuculine (0.5 mg/kg, i.p.) in rats, but could not be prevented by naloxone (1 mg/kg, i.p.) in mice. Only the (+)-stereoisomer γ-vinyl GABA, active as a GABA-transaminase inhibitor, was antinociceptive. The effects appear to be causally related to elevated cerebral GABA levels. The profile of these agents in the tail stimulation test in rats suggests a specific antinociceptive effect since vocalization and vocalization after-discharge were similarly affected. The analgesic actions of morphine in mice on the 56°C hot-plate were enhanced 5 hr after the administration of γ-acetylenic GABA or γ-vinyl GABA. The compounds did not alter the naloxone-precipitated morphine withdrawal syndrome in the rat. It is concluded that γ-acetylenic GABA and γ-vinyl GABA can produce distinct antinociceptive effects in rats and mice related to increased brain GABA levels, but which are not opioid-like in nature.

Potentiation of the analgesia induced in rats by morphine or [D-Ala 2]-metenkephalinamide after inhibition of brain type B monoamine oxidase: The role of phenylethylamine

In the rat, morphine and the opioid peptide [D-Ala 2]-metenkephalinamide (D-ALA) increased the reaction time in the tail-flick test as well as the threshold for vocalization and vocalization afterdischarge after electrical stimulation of the tail. The analgesic effect of either opiate was potentiated by selective inhibition of brain type B MAO with deprenyl or pargyline and antagonized by selective inhibition of the A form of the enzyme with chlorgyline. β-Phenylethylamine (PEA), a specific substrate of brain type B MAO, also potentiated the opiate analgesia, and the enhancement was especially marked after combined treatments with deprenyl and PEA. The effect of PEA appeared to be preferentially related to the affective component of the pain response (threshold for vocalization afterdischarge). A more general role of PEA in brain function as a neuromodulator of the opiate receptor is proposed.

62) - Studies on the relationship between the central mechanism of vocalization after-discharge (Va) and dopamine (Da) and noradrenaline (Na) in the rabbit

62) - Studies on the relationship between the central mechanism of vocalization after-discharge (Va) and dopamine (Da) and noradrenaline (Na) in the rabbit

Clonidine antinociceptive activity: effects of drugs influencing central monoaminergic and cholinergic mechanisms in the rat.

Clonidine is able to increase the threshold for vocalisation during stimulation and the threshold for vocalisation after withdrawal of stimulus (vocalisation afterdischarge). These effects of clonidine were investigated after treatment of rats with drugs influencing central monoaminergic and cholinergic mechanisms. Chlorpromazine, atropine and p-chlorophenylalanine increased the activity of clonidine at both thresholds while phenoxybenzamine and reserpine pretreatment increased the activity at the thresholds for vocalisation only. Yohimbine decreased clonidine activity at both thresholds while 5-HTP and alpha-methyl-p-tyrosine decreased the effects at the threshold for vocalisation afterdischarge. Naloxone did not change the activity of clonidine at either pain response studied. It is concluded from the present findings that influence from several neuronal systems modulate the antinociceptive action of clonidine. The inhibition of the medullary nociceptive response after clonidine might be connected to a decreased activity of noradrenergic neurons. Endogenous noradrenaline seems to be of minor importance in mediating this effect. It is moreover shown that decreased cholinergic receptor activity enhances clonidine antinociceptive action on both medullary and diencephalic-rhinencephalic pain responses. The possible involvement of serotonin these functional responses after clonidine is also discussed.

Enhancement of apomorphine-induced inhibition of vocalisation afterdischarge response by theophylline

Apomorphine has been shown to increase, dose-dependently, the threshold for the vocalisation afterdischarge (VA), this effect of apomorphine being abolished by pimozide and potentiated by theophylline. A combined treatment with theophylline and L-Dopa elevated the VA threshold as well. The results also indicate that the pharmacological response after theophylline can be modulated by dopamine receptor interactions.

Antinociceptive action of oxotremorine and regional turnover of rat brain noradrenaline, dopamine and 5-HT

In the rat, oxotremorine increases the threshold for vocalisation after-discharge (affective component of pain reactions) dose dependently at subtremor doses (30-67 mug/kg s.c.). Doses of 225-506 mug/kg were needed to elevate the thresholds for vocalisation and motor response. 1-Tryptophan, PCPA, alpha-methyl-p-tyrosine, 1-Dopa, pimozide and LSD-25 did not affect the antinociceptive activity of oxotremorine, while phenocybenzamine slightly increased the threshold for vocalisation. Oxotremorine did not change the endogenous brain concentrations of noradrenaline and dopamine or 5-HT but decreased that of 5-HIAA in all brain regions at the time of maximal analgesia. The decrease of 5-HIAA was still present after pretreatment with probenecid. After inhibition of tyrosine hydroxylase, oxotremorine accelerated the depletion of dopamine in telencephalic cortex during maximal antinociceptive activity and of noradrenaline in all brain regions at a time when this activity had vanished. Atropine significantly antagonized the analgesic activity of oxotremorine. It is concluded that oxotremorine antinociceptive activity in the rat is related to a cholinergic compoent, while a monoaminergic component is not directly involved.

Morphine-induced inhibition of different pain responses in relation to the regional turnover of rat brain noradrenaline and dopamine

The influence of morphine on different pain reactions integrated at different levels of the central nervous system was studied in rats together with the determination of the turnover rate of noradrenaline and dopamine in discrete areas of the brain. Morphine was found to increase the thresholds for vocalisation and vocalisation afterdischarge leaving the threshold for motor response unaffected. The effect of morphine on the threshold for vocalisation was found to be antagonized by naloxone and yohimbine and increased by α-methyl-p-tyrosine, FLA 63, phenoxybenzamine, chlorpromazine and pimozide. The effects on the threshold for vocalisation afterdischarge were antagonized by naloxone, and reduced by α-methyl-p-tyrosine, pimozide and chlorpromazine and were enhanced by phenoxybenzamine and yohimbine. Atropine did not change the morphine effect on either threshold. Morphine (5 mg/kg s.c.) was found to increase the turnover rate of dopamine in the telencephalic cortex and the diencephalons-mesencephalon-striatum and that of noradrenaline in the medulla oblongata-pons region. Both increases were antagonized by naloxone. The ability of morphine to increase the threshold for vocalisation afterdischarge (proposed to reflect the emotional component of pain reactions) is suggested to be closely related to the increased turnover of dopamine in limbic structures of the brain, most probably by an increased release of this transmitter. The effect of morphine on the threshold for vocalisation remains to be evaluated but a decreased activity of noradrenaline and dopamine neurotransmission was found to increase the morphine effect on this threshold.