Drug and environmentally induced manipulations of the opiate and serotonergic systems alter nociception in neonatal rat pups

The influence of drug- and environmentally induced alterations in serotonergic and opiate activity on pain sensitivity was assessed in 6-day-old Sprague-Dawley-derived rat pups using tail flick-testing procedures. The opiate agonist morphine was observed to induce tail flick analgesia that was blocked by concurrent administration of the opiate antagonist naloxone. Similarly, the serotonergic agonist quipazine induced analgesia that was blocked by pretreatment with the serotonergic antagonist metergoline. Naloxone alone did not alter tail flick responsivity in non-isolated, nondeprived neonates, suggesting that the opiate system may not exert a significant tonic inhibition of pain sensitivity in neonates. In contrast, the serotonergic system may exert some tonic analgesic influence at this age, given that metergoline was observed to induce slight hyperalgesia in nondeprived, non-isolated neonates. Twenty four hours of food and maternal deprivation, shown previously to increase brain serotonin and 5-hydroxyindole acetic acid and their ratio in neonates (L. P. Spear & F. M. Scalzo, 1984, Developmental Brain Research, in press) was observed to induce tail flick analgesia, an effect blocked by metergoline. Isolation from siblings and the dam and nest for 30 min also induced tail flick analgesia; this analgesia was blocked by treatment with naloxone prior to testing. Together, these experiments support the suggestion that the serotonergic and opiate systems may regulate pain sensitivity even in neonatal rat pups, with agonist- or environmentally precipitated increases in serotonergic or opiate activity inducing significant analgesia during the early postnatal period.     

Perceived self-efficacy in coping with cognitive stressors and opioid activation

This experiment tested the hypothesis that perceived self-inefficacy in exercising control over cognitive stressors activates endogenous opioid systems. Subjects performed mathematical operations under conditions in which they could exercise full control over the cognitive task demands or in which the cognitive demands strained or exceeded their cognitive capabilities. Subjects with induced high perceived self-efficacy exhibited little stress, whereas those with induced low perceived self-efficacy experienced a high level of stress and autonomic arousal. Subjects were then administered either an inert saline solution or naloxone, an opiate antagonist that blocks the analgesic effects of endogenous opiates, whereupon their level of pain tolerance was measured. The self-efficacious nonstressed subjects gave no evidence of opioid activation. The self-inefficacious stressed subjects were able to withstand increasing amounts of pain stimulation under saline conditions. However, when endogenous opioid mechanisms that control pain were blocked by naloxone, the subjects were unable to bear much pain stimulation. This pattern of changes suggests that the stress-induced analgesia found under the saline condition was mediated by endogenous opioid mechanisms and counteracted by the opiate antagonist.     

Conditioned fear-induced opiate analgesia on the Formalin test: Evidence for two aversive motivational systems

Fear, conditioned to apparatus cues associated with electric shock, was measured by recording freezing. Pain reactivity was simultaneously measured by recording the paw-licking and paw-lifting response to Formalin injected into a paw. Stimuli associated with shock produced freezing and inhibited the responses to Formalin; whereas various control stimuli did neither. These results indicate that one of the responses to fear is analgesia. The opiate antagonist naltrexone reversed this analgesia, suggesting that the analgesia has an opiate nature. The results were interpreted in terms of a two-aversive-motivational-systems model. One system, the pain system, is instigated by tissue-damaging stimuli and produces recuperative behavior that functions to promote healing. The other system, the fear system, is triggered by conditioned fear stimuli. It produces species-specific defensive reactions and also inhibits the pain system via analgesia.     

Hippocampal EEG and Unit Activity Responses to Modulation of Serotonergic Median Raphe Neurons in the Freely Behaving Rat

Hippocampal EEG, GABAergic interneurons, and principal cells were recorded simultaneously as rats foraged within one of three environments both before and after modulation of serotonergic inputs to the hippocampus. Median raphe microinjections of the 5-HT1a receptor agonist 8-OH-DPAT were made to produce inhibition of serotonergic neurons in this region. Such microinjections produced behavioral arousal and increases in the amplitude of hippocampal EEG theta. Consistent with the pattern of serotonergic innervation of the hippocampus, the GABAergic interneuron population was affected differentially by the microinjections. Principal cells were generally unaffected by the manipulation and maintained robust spatial firing correlates within the foraging environment. The results provide basic data on the relationship between serotonergic median raphe neurons and hippocampal activity in a behaving animal. The data suggest that behavioral responses to manipulation of the serotonergic system are mediated by brain regions other than the hippocampus or are mediated through changes in the activity of hippocampal interneurons.     

Naloxone and cold-water swim analgesia: Parametric considerations and individual differences

The role of endogenous opioids in the mediation of stress-induced analgesia has been studied using the opiate antagonist naloxone to reduce or eliminate the response. While the analgesic responses following some stressors are reduced by naloxone, other stressors, like cold-water swims, are altered minimally. However, in the case of inescapable foot shock analgesia, the temporal, numerical, and spatial arrangement of the shocks are critical parameters in determining whether naloxone is capable of altering the analgesic state. In assessing parametric variations of naloxone antagonism of cold-water swim analgesia, five experiments were performed. The first experiment showed that naloxone antagonized the analgesic response following a 3.5-min swim in a 15°C bath, but not in baths of 8°C and 2°C. The second experiment demonstrated dose-dependent antagonism of analgesia induced by 2°C swims for 2.5 and 3.5 min; shorter durations failed to increase thresholds. The third experiment indicated that naloxone decreased 2°C, 3.5-min swim analgesia when the pain test occurred 30 min after stress; longer intervals failed to produce analgesia. The fourth experiment showed that the temporal relationship between injections and swims had little bearing on resultant effects. Finally, since it appeared that naloxone decreased analgesia induced by the 2°C, 3.5-min swim in some animals, but not others, the fifth experiment found that the degree of naloxone antagonism was correlated with the magnitude of the analgesic response induced in individual animals. These results are discussed in terms of opioid and nonopioid mechanisms subserving pain inhibition.     

Programming of the hypothalamo-pituitary-adrenal axis: serotonergic involvement

The ability of the early environment to programme the developing hypothalamo-pituitary-adrenal (HPA) axis has been reported in several animal species. There is considerable evidence that a similar process can occur in the human, and that long-term alterations in HPA function are associated with altered susceptibility to disease in later life. The phenotype of HPA function following early manipulation depends on the timing and intensity of the manipulation as well as the gender of the fetus/neonate. There is considerable interplay between the developing HPA and the reproductive axes and emerging evidence indicates that this interaction is modified by early environmental manipulation. Studies are rapidly unravelling the mechanisms that underlie developmental programming of the HPA axis. In this context, the serotonergic system has been identified as a primary system involved in this process. Understanding the mechanisms involved in neuroendocrine programming will facilitate the development of interventions aimed at reversing or ameliorating the impact of an adverse intrauterine environment.     

Some effects of the opioid antagonist, naloxone, upon the rat's reactions to a heat stressor

Eight experiments examined the apparently paradoxical analgesia that accrues when rats are repeatedly injected with an opiate antagonist, naloxone, and exposed to a heat stressor. Experiments 1 and 2 showed that such pairings came to enhance in a dose-dependent manner the latencies with which rats paw-licked in response to the stressor. Experiment 3 demonstrated that the latencies to paw-lick in saline-treated rats decreased with increases in the intensity of the heat, indicating that naloxone had not provoked long latencies to paw-lick by increasing the functional intensity of the stressor. Experiment 4 documented a role for conditioning processes in recruiting the naloxone-induced analgesia. Experiment 5 showed that the analgesic effect was due to the pairings of the drug and the heat stressor, as a history of exposure to naloxone in a distinctive environment did not render the animals analgesic when challenged with the drug and the stressor. Experiments 6 and 7 provided evidence that the conditioned analgesia that accrued from drug-stressor pairings was non-opioid in nature, as the analgesia was observed in morphine-tolerant rats and was not reversed by an administration of naloxone in advance of exposure to the conditioning context. Experiment 8 demonstrated that the administration of morphine in the context previously associated with naloxone-stressor pairings provoked a superanalgesia. Although analgesic on the paw-lick assay, naloxone-treated subjects did not appear to be insensitive to the heat or impaired motorically, as they persistently reared with short latencies. The results were discussed in terms of the collateral inhibition model of the endogenous pain control system, and some speculations were offered concerning the relation between paw-licking and rearing.     

Histamine reverses a memory deficit induced in rats by early postnatal maternal deprivation

Early partial maternal deprivation causes long-lasting neurochemical, behavioral and brain structural effects. In rats, it causes a deficit in memory consolidation visible in adult life. Some of these deficits can be reversed by donepezil and galantamine, which suggests that they may result from an impairment of brain cholinergic transmission. One such deficit, representative of all others, is an impairment of memory consolidation, clearly observable in a one-trial inhibitory avoidance task. Recent data suggest a role of brain histaminergic systems in the regulation of behavior, particularly inhibitory avoidance learning. Here we investigate whether histamine itself, its analog SKF-91844, or various receptor-selective histamine agonists and antagonists given into the CA1 region of the hippocampus immediately post-training can affect retention of one-trial inhibitory avoidance in rats submitted to early postnatal maternal deprivation. We found that histamine, SKF-91844 and the H2 receptor agonist, dimaprit enhance consolidation on their own and reverse the consolidation deficit induced by maternal deprivation. The enhancing effect of histamine was blocked by the H2 receptor antagonist, ranitidine, but not by the H1 receptor antagonist pyrilamine or by the H3 antagonist thioperamide given into CA1 at doses known to have other behavioral actions, without altering locomotor and exploratory activity or the anxiety state of the animals. The present results suggest that the memory deficit induced by early postnatal maternal deprivation in rats may in part be due to an impairment of histamine mediated mechanisms in the CA1 region of the rat hippocampus.     

Influence of intracerebroventricular administration of dopaminergic drugs on morphine state-dependent memory in the step-down passive avoidance test

The effects of dopaminergic drugs on morphine state-dependent memory of passive avoidance task were examined in mice. Pre-training administration of morphine (5mg/kg) led to state-dependent learning with impaired memory retrieval on the test day which was reversed by pre-test administration of the same dose of the opiate. The pre-test intracerebroventricular (i.c.v.) administration of the dopamine D1 receptor agonist (SKF38393), dopamine D2 receptor agonist (quinpirole) and dopamine D2 receptor antagonist (sulpiride) not only reversed the effect of pre-training morphine treatment, but also increased this action of the drug. Furthermore, the pre-test i.c.v. administration of dopamine D1 receptor antagonist (SCH23390) prevented the restoration of memory by morphine. In conclusion, the morphine-induced recovery of memory, on the test day, seems to be induced, at least in part, through dopamine receptors.     

Central inhibitory dysfunctions: mechanisms and clinical implications

Injury to the central or peripheral nervous system is often associated with persistent pain. After ischemic injury to the spinal cord, rats develop severe mechanical allodynia-like symptoms, expressed as a pain-like response to innocuous stimuli. In its short-lasting phase the allodynia can be relieved with the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen, which also reverses the hyperexcitability of dorsal horn interneurons to mechanical stimuli. Furthermore, there is a reduction in GABA immunoreactivity in the dorsal horn of allodynic rats. Clinical neuropathic pain of peripheral and central origin often cannot be relieved by opiates at doses that do not cause side effects. The loss of sensitivity to opiates may be associated with the up-regulation of endogenous antiopioid substances, such as the neuropeptide cholecystokinin (CCK). CCK and its receptor (CCK-R) protein is normally not detectable in rat dorsal root ganglion cells. After peripheral nerve section, both CCK and CCK-R are up-regulated in the dorsal root ganglia. Furthermore, CI 988, an antagonist of the CCK-B receptor, chronically coadministered with morphine, reduces autotomy, a behavior that may be a sign of neuropathic pain following peripheral nerve section. Thus, opiate insensitivity may be due to the release of CCK from injured primary afferents. Similarly, in the chronic phase of the spinal ischemic model of central pain, the allodynia-like symptom is not relieved by systemic morphine, but is significantly reversed by the CCK-B antagonist. Consequently, up-regulation of CCK and CCK-R in the CNS may also underlie opiate drug insensitivity following CNS injury. Thus, dysfunction of central inhibition involving GABA and endogenous opioids may be a factor underlying the development of sensory abnormalities and/or pain following injury to neural tissue.     

Analgesic and opioid involvement in the shock-elicited activity and escape deficits produced by inescapable shock

Three experiments examined the involvement of analgesic processes and endogenous opioids in the production of the shuttlebox escape acquisition and unconditioned activity deficits which follow exposure to inescapable shock. Experiment 1 found that the opiate antagonist naltrexone administered before the inescapable shock session interfered with the shuttlebox escape acquisition deficit which would normally follow. Experiment 2 found naltrexone to completely prevent the unconditioned activity deficit. The final experiment revealed that dexamethasone, a synthetic glucocorticoid which abolishes the analgesia produced by inescapable shock, reversed the activity deficit. These results indicate that endogenous opioids may be involved in the production of both the escape acquisition and activity deficits. They also suggest that the analgesia produced by these opioids may participate in the mediation of the activity deficit, even though analgesia is not involved in producing the shuttlebox acquisition deficit.     

The medial amygdala: Serotonergic inhibition of shock-lnduced aggression and pain sensitivity in rats

Two aspects of the amygdaloid complex (corticomedial and basolateral) were examined with reference to serotonergic inhibition of shock-induced aggression. Fighting was significantly depressed by serotonergic stimulation (5-HT, 10 μg bilateral) in the corticomedial amygdala while serotonergic blockade (methysergide, 5 μg bilateral) in this region increased levels of fighting. No consistent effects were obtained with serotonergic manipulation of the basolateral amygdala. Further investigation revealed that the state of serotonergic activity in medial amygdaloid sites was associated with concomitant alterations in the animals' sensitivity to footshock. Results are discussed in relation to a) a general inhibitory role of serotonin in behavioural mechanisms and b) a dopaminergic-serotonergic balance for behavioural arousal involving medial amygdaloid nuclei.     

口腔疾病诊治中的人文关怀

随着现代医学模式的转变,在口腔科疾病的诊治过程中,根据从儿童到老年不同年龄阶段患者的心理特点,给予更多的人文关怀。主要表现在：牙病治疗的无痛、无菌,良好的医患沟通,优质的服务等几方面。     

Injection of 5,7-dihydroxytryptamine into the B3 raphe region of neonatal rat pups induces hyperalgesia but only slight alterations in ingestion-related behaviors.

The effects of intrabrainstem injections of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the B3 raphe region (nucleus raphe magnus and nucleus reticularis paragigantocellularis) on early ingestive behavior and nociception were assessed in Sprague-Dawley rat pups during the first postnatal week. Lesions resulted in a marked depletion of serotonin (5HT) in hindbrain without influencing 5HT levels in forebrain. Pretreatment with desipramine (DMI) resulted in a sparing of noradrenergic neurons from neurotoxic effects. The B3 lesion resulted in significant hyperalgesia as reflected by decreased latencies in tail flick testing. Although nipple attachment latencies in suckling tests were slightly increased by the lesion, no notable effects on mouthing or other ingestive-related behaviors were observed in testing conducted in an independent ingestion paradigm. These results suggest that whereas B3 serotonergic neurons may be functioning in an adult-typical manner to regulate analgesia during the early postnatal period, this raphe region may play only a slight role in the modulation of ingestion-related behaviors early in life.     

Effects of morphine and naloxone upon the reactions of rats to a heat stressor

Five experiments used rats to examine the conditioned hypoalgesia induced by exposure to a heated floor. Experiments 1 and 2 demonstrated that this hypoalgesia is mediated by non-opioid mechanisms of pain control, as evidenced by insensitivity to the opioid antagonist naloxone and by the absence of cross-tolerance with the opioid agonist morphine. Although non-opioid in nature, the acquisition of conditioned hypoalgesia was facilitated by naloxone and impaired by morphine (Experiments 3 and 4). These effects did not appear to be due to an opioid regulation of pain. (1) Pairing morphine with the heated floor attenuated acquisition in drug-tolerant rats. (2) This attenuation by morphine was removed when naloxone was given after exposure to the heated floor. (3) Conditioning was facilitated when naloxone was given after exposure to the heated floor (Experiment 5). The results were discussed in terms of an opioid regulation of (a) surprise, (b) arousal of an aversive motivational system, and (c) the affective component of pain.     

Aggressive behavior inhibition by serotonin and quipazine injected into the amygdala in the rat

The effects on aggressive behavior, open-field activity, and pain threshold of bilateral microinjections of serotonin (20 micrograms) and quipazine (20 micrograms), the direct serotonergic receptor agonist, into the cortico-medial amygdala were investigated in Wistar rats. Both drugs significantly prolonged the attack latency in isolated killer rats (predatory aggression model), and suppressed the incidence of aggressive postures/attacks in shock-induced fighting test (affective aggression). The only difference in the open-field behavior was the lower number of central square entries in drug-treated compared to saline-injected rats. None of the substances produced any significant change in jump threshold. It is concluded that stimulation of serotonin receptors within the amygdala produces inhibition of affective and muricidal behavior in isolated rats. The effect does not seem to be dependent on changes in general activity and pain sensitivity.     

Movement related EMGs become more variable during learning of fast accurate movements

Human subjects performed simple flexion and extension movements about the elbow in a visual step-tracking paradigm. Movements were self-terminated. Subjects were instructed to increase movement velocity while maintaining end-point accuracy during practice. The effects of practice on the pattern and variability of EMG activity of the biceps and triceps muscles were studied. Initial movements were performed using reciprocal phasic activation of agonist and antagonist muscles as indicated by surface EMGs. With practice, increases in movement speed were associated with larger agonist and antagonist bursts and an earlier onset of the antagonist burst. Decreased duration of the premovement antagonist silence was also observed during practice. Decreases in variability of movements during practice were not accompanied by equivalent decreases in variability of the associated EMGs. Surprisingly, both agonist and antagonist EMGs were more variable in faster, practiced movements. The combined agonist-antagonist EMG variability depended on both movement speed and trajectory variability. Lower variability in movements in the presence of greater variability in the related EMGs occurred because of linked variations in agonist and antagonist muscle activities. Variations in the first agonist burst were often compensated for by associated variations in the antagonist and late agonist bursts. These linked variations maintained the limb trajectory relatively constant in spite of large variations in the first agonist burst. Modifications to impulse-variability models are therefore needed to explain compensations for variability in accelerative impulses (produced by the first agonist burst) by linked variations in impulses for deceleration (produced by the antagonist and late agonist bursts).     

Variable-interval schedules of timeout from avoidance: effects of chlordiazepoxide, CGS 8216, morphine, and naltrexone.

Rats were trained on concurrent schedules in which pressing one lever postponed shock and pressing the other occasionally (variable-interval schedule) produced a 2-min timeout during which the shock-postponement schedule was suspended and its correlated stimuli were removed. These procedures provided a baseline for studying the effects of drugs on behavior maintained by different sources of negative reinforcement (shock avoidance and timeout from avoidance). Experiment 1 studied a benzodiazepine agonist, chlordiazepoxide, and antagonist, CGS 8216. Chlordiazepoxide (2.5-30 mg/kg) had little effect on avoidance responding except at higher doses, when it reduced responding. By comparison, responding on the timeout lever was increased in 5 of 6 rats. These effects were reversed by CGS 8216 (2.5-5 mg/kg) in the 2 rats tested, but CGS 8216 had no effect by itself. Experiment 2 studied an opiate agonist, morphine, and antagonist, naltrexone, with 3 rats. Morphine's (2.5-20 mg/kg) effects were opposite those of chlordiazepoxide: At doses that either increased or had no effect on avoidance responding, morphine depressed timeout responding. Naltrexone (5 mg/kg) reversed these actions but had no effect by itself.     

Movement Related EMGs Become More Variable During Learning of Fast Accurate Movements

Human subjects performed simple flexion and extension movements about the elbow in a visual step-tracking paradigm. Movements were self-terminated. Subjects were instructed to increase movement velocity while maintaining end-point accuracy during practice. The effects of practice on the pattern and variability of EMG activity of the biceps and triceps muscles were studied. Initial movements were performed using reciprocal phasic activation of agonist and antagonist muscles as indicated by surface EMGs. With practice, increases in movement speed were associated with larger agonist and antagonist bursts and an earlier onset of the antagonist burst. Decreased duration of the premovement antagonist silence was also observed during practice.

Decreases in variability of movements during practice were not accompanied by equivalent decreases in variability of the associated EMGs. Surprisingly, both agonist and antagonist EMGs were more variable in faster, practiced movements. The combined agonist-antagonist EMG variability depended on both movement speed and trajectory variability. Lower variability in movements in the presence of greater variability in the related EMGs occurred because of linked variations in agonist and antagonist muscle activities. Variations in the first agonist burst were often compensated for by associated variations in the antagonist and late agonist bursts. These linked variations maintained the limb trajectory relatively constant in spite of large variations in the first agonist burst. Modifications to impulse-variability models are therefore needed to explain compensations for variability in accelerative impulses (produced by the first agonist burst) by linked variations in impulses for deceleration (produced by the antagonist and late agonist bursts).     

Hypnosis, suggestion, and placebo in the reduction of experimental pain

Two experiments compared placebo and hypnotic analgesia in high and low hypnotizable subjects. Experiment 1 demonstrated that hypnotic and placebo analgesia were equally ineffective in low hypnotizables, but that hypnotic analgesia was much more effective than placebo analgesia in high hypnotizables. Experiment 2 replicated these results, but also included low and high hypnotizables who were given a nonhypnotic suggestion for analgesia. Both the low and high hypnotizables in this group reported greater suggested than placebo analgesia and as much suggested analgesia as high hypnotizable hypnotic subjects. Both experiments found substantial discrepancies between the amount of pain reduction subjects expected from the various treatments and the amount of pain reduction they actually reported following exposure to those treatments. In Experiment 2, subjects in all treatments who reduced reported pain engaged in more cognitive coping and less catastrophizing than those who did not reduce pain. Theoretical implications are discussed.