Peripheral and central hyperexcitability: differential signs and symptoms in persistent pain

This target article examines the clinical and experimental evidence for a role of peripheral and central hyperexcitability in persistent pain in four key areas: cutaneous hyperalgesia, referred pain, neuropathic pain, and postoperative pain. Each suggests that persistent pain depends not only on central sensitization, but also on inputs from damaged peripheral tissue. It is instructive to think of central sensitization as comprised of both an initial central sensitization and an ongoing central sensitization driven by inputs from peripheral sources. Each of these factors, initial sensitization, ongoing central sensitization, and inputs from peripheral sources, contributes to the net activity in dorsal horn neurons and thus influences the expression of persistent pain or hyperalgesia. Since each factor, peripheral inputs and central sensitization (initial or ongoing), can contribute to both the initiation and maintenance of persistent pain, therapies should target both peripheral and central sources of pathology.     

The treatment of neuropathic pain

Neuropathic pain is responsible for a significant amount of the morbidity associated with generalized and focal peripheral neuropathies. It is a consequence of alterations in neuronal function, chemistry, and structure that occur secondary to nerve injury. These manifestations of neuronal plasticity occur in the peripheral nerve, spinal cord, and brain. A variety of agents from diverse pharmacologic classes, the so-called adjuvant analgesics, have been used to treat neuropathic pain. These include antidepressants, first- and second-generation anticonvulsants, antiarrhythmic agents, topical agents, N-methyl-D-aspartate receptor antagonists, and opioid analgesics. The use of these adjuvant analgesics, either alone or in combination, should result in the alleviation of neuropathic pain in most patients. Recent advances in the understanding of pain mechanisms at multiple central nervous system levels should pave the way toward more effective treatment modalities.     

Effects of naloxone on hippocampal seizure activity

Although the presence of several types of opiate receptors and ligands has been demonstrated within the hippocampus, little is known about the circumstances in which endogenous opiates may be released. Previous studies have suggested that opiates may be involved in producing seizure activity within the hippocampus, or alternatively, that they may be released by seizure activity within the limbic system to prolong the period of postictal depression and thereby prevent the recurrence of seizures during this period. In this experiment we examined the effect of opiate receptor blockade produced by 20 mg/kg ip naloxone on the duration of afterdischarge produced by high-frequency hippocampal stimulation and on inhibition of subsequent seizure activity in male Sprague-Dawley rats. Contrary to the stated hypotheses, naloxone had no effect on either measure.     

Serotonergic and opiate interactions in the modulation of drug- and environmental-induced analgesia in the neonatal rat pup

Serotonergic and opiate interactions in the modulation of drug- and environmental-induced analgesia were assessed in 6-day-old Sprague-Dawley-derived rat pups using tail-flick testing procedures. In these experiments the serotonergic antagonist metergoline was observed to attenuate both the analgesia induced by the opiate agonist morphine and the analgesia induced by isolation from siblings and the dam, an environmental manipulation which has previously been shown to be associated with increases in opiate activity. In contrast, the opiate antagonist naloxone was observed to be ineffective in blocking not only analgesia induced by the serotonergic agonist quipazine, but also analgesia induced by long-term deprivation from the dam and food, a manipulation that has been previously reported to induce increases in serotonergic utilization. These results suggest that in the neonate, as in the adult, the serotonergic modulation of nociception appears to occur "downstream" from the opiate systems serving to regulate nociception following both drug- and environmental-induced alterations in pain sensitivity. Analgesia induced by long-term deprivation from food and the dam appears to be strongly related to increases in serotonergic activity and relatively unaffected by opiate antagonism, whereas analgesia induced by isolation from siblings and the dam may be related to increases in opiate activity, but modulated by serotonergic systems serving to regulate pain responsivity. Thus alterations in the environment, mediated at least in part by alterations in opiate and serotonergic activity, appear to play an important role in influencing the sensitivity of the neonate to pain stimuli.     

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.     

Chronic sweet intake lowers pain thresholds without changing brain mu- or delta-opiate receptors

Sprague-Dawley rats drank sweetened (3% dextrose + 0.144% saccharin, w/v) or unflavored water for 18 days and subsequent pain reactivity was assessed using a hot plate. Compared to the rats that consumed unflavored water, the rats that consumed sweet water responded more quickly on the hot plate indicating that their threshold for pain was lowered. Another group of rats given identical exposure to the fluids had their brains prepared for measuring opiate receptor binding using the delta-receptor ligand [3H]D-Ala-D-Leu-enkephalin ([3H]DADLE) and the mu-receptor selective ligand [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol ([ 3H]DAGO). Binding of these opiates to mu- and delta-receptors in the cerebral cortex, striatum, hippocampus, hypothalamus, brain stem, and remaining brain regions was the same for the rats that drank sweet fluids and those that drank unflavored water. These findings suggest that drinking sweet fluids lowers pain thresholds but does not alter mu- and delta-receptors.     

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.     

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.     

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.     

Differentiation of Personality Types Among Opiate Addicts

A wide range of studies indicate that although sociopathic characteristics are predominant in opiate addiction, depressive and psychotic features are also frequently observed. To test the hypothesis that there are really three types of individuals who become addicted to opiates (rather than a single, predominant personality style), fifty-three opiate addicts were given the Loevinger Sentence Completion Test, the Bellak Ego Functions interview, and the Rorschach. Variables derived from these three procedures were submitted to cluster and discriminant function analyses. Three groups of addicts were identified-those primarily with impaired interpersonal relationships and affective lability (42%), those primarily characterized by thought disorder and impaired ego functioning (30%), and a group with diminished ideational and verbal activity (28%). Comparison of the assessment of these three groups with independently defined normal, neurotic, and schizophrenic samples provided support for three opiate-addicted personality types, each respectively characterized as character disordered, borderline psychotic, arid depressed. Although there seems to be a predominance of character-disordered individuals who become addicted to opiates, the data indicate several additional types of opiate addicts with different types of psychopathology who may require different approaches to management and treatment.     

Differentiation of personality types among opiate addicts

A wide range of studies indicate that although sociopathic characteristics are predominant in opiate addiction, depressive and psychotic features are also frequently observed. To test the hypothesis that there are really three types of individuals who become addicted to opiates (rather than a single, predominant personality style), fifty-three opiate addicts were given the Loevinger Sentence Completion Test, the Bellak Ego Functions Interview, and the Rorschach. Variables derived from these three procedures were submitted to cluster and discriminant function analyses. Three groups of addicts were identified--those primarily with impaired interpersonal relationships and affective lability (42%), those primarily characterized by thought disorder and impaired ego functioning (30%), and a group with diminished ideational and verbal activity (28%). Comparison of the assessment of these three groups with independently defined normal, neurotic, and schizophrenic samples provided support for three opiate-addicted personality types, each respectively characterized as character disordered, borderline psychotic, and depressed. Although there seems to be a predominance of character-disordered individuals who become addicted to opiates, the data indicate several additional types of opiate addicts with different types of psychopathology who may require different approaches to management and treatment.     

Neurosteroids for a successful pregnancy

Steroid hormones play a critical role in the initiation and maintenance of pregnancy. In particular, the important role that the progesterone metabolite, and neurosteroid, allopregnanolone, may play in fetal and adolescent development is becoming increasingly evident. Unlike steroid hormones, neurosteroids act at nontraditional targets in the central and peripheral nervous systems, including GABA(A) receptor complexes. This commentary discusses the three works in this issue that elucidate the important role of allopregnanolone in the mechanisms that regulate stress hypo-sensitivity of rodents in late pregnancy, neuroprotective effects in fetal sheep exposed to a hypoxic insult, and the continuing role that prefrontal cortex formation of allopregnanolone may play on the cognitive development of gestationally stressed rat offspring, grown to adolescence. The narrative that these works comprise was facilitated by the 5(th) International Meeting on Steroids and the Nervous System (Torino, Italy), which is organized to update our knowledge on the relationships between steroid hormones synthesized in different organs and the nervous system. Topics covered in this most recent meeting included sex differences in, and hormonal influences on, cannabinoid-regulated biology; steroids and pain; the importance of co-regulatory factors for steroid receptor action in the brain; mechanism and role of estrogen-induced nonclassical signaling in the brain; vitamin D as the forgotten neurosteroid; neurosteroids and GABA(A) receptors; and pathogenic mechanisms mediated by glucocorticoid receptors in psychiatric disorders. The 6(th) International Meeting on Steroids and the Nervous System will be held in Torino, Italy in February 2011.     

Classical conditioning and pain: Conditioned analgesia and hyperalgesia

This article reviews situations in which stimuli produce an increase or a decrease in nociceptive responses through basic associative processes and provides an associative account of such changes. Specifically, the literature suggests that cues associated with stress can produce conditioned analgesia or conditioned hyperalgesia, depending on the properties of the conditioned stimulus (e.g., contextual cues and audiovisual cues vs. gustatory and olfactory cues, respectively) and the proprieties of the unconditioned stimulus (e.g., appetitive, aversive, or analgesic, respectively). When such cues are associated with reducers of exogenous pain (e.g., opiates), they typically increase sensitivity to pain. Overall, the evidence concerning conditioned stress-induced analgesia, conditioned hyperalagesia, conditioned tolerance to morphine, and conditioned reduction of morphine analgesia suggests that selective associations between stimuli underlie changes in pain sensitivity.     

Neuropsychological Consequences of Opiate Use

Approximately 3.7 million individuals have used heroin and other opiate substances in their lifetime. Despite increasing knowledge of the effects of heroin, it remains the most abused opiate and use among adults has recently increased. The empirical literature examining the neurocognitive effects of acute and chronic opioid use remains limited; however, findings to date suggest that the use of opiates has both acute and long-term effects on cognitive performance. Neuropsychological data indicate deficits in attention, concentration, recall, visuospatial skills and psychomotor speed with both acute and chronic opioid use. The long-term effects of opiate use appear to have the greatest impact on executive functions, including the ability to shift cognitive set and inhibit inappropriate response tendencies. Factors that contribute to addiction and recovery are also discussed, as it is difficult to disentangle the effects of opiate use on cognitive performance from other factors that may affect neurobehavioral measures.     

中枢胆碱能系统对吗啡成瘾的影响研究现状

介绍了中枢胆碱能系统对吗啡成瘾的影响及其机制。研究结果表明,吗啡成瘾过程中伏隔核等脑区细胞间乙酰胆碱水平发生了改变;去除伏隔核等脑区胆碱能细胞强化了吗啡成瘾行为;胆碱能激动剂和抑制剂都能干预吗啡成瘾、但机制可能不同——前者可能通过与多巴胺能交互作用来实现,后者可能通过干扰记忆或者加速吗啡代谢而发挥作用;胆碱能受体对吗啡成瘾也具有重要影响     

Social influences on behaviour and neuroendocrine responsiveness of talapoin monkeys

The social organisation of a group of primates and in particular its aggressive interactions have profound but predictable effects on sexual behaviour. Dominant individuals have prerogative over sexual interactions, but since moving into a social group itself entails changes in endocrine state, one cannot ignore the fact that these endocrine changes may in some way reinforce the nature of the social hierarchy. In paticular, this paper considers how a monkeys endocrine profile may vary according to its social status and how endocrine profiles change in different rank. Most important is the finding that behavioural experiences in the social group may have repercussions for an animals ability to cope with changing circumstances, depending upon whether that individual was of high or low social status. Recent studies using the opiate receptor blocker, naltrexone, suggest that the endogenous opiates may provide a common neural link between the behavioural consequences of social subordination and some of the endocrine changes which accompany this.     

Perceived self-efficacy and pain control: opioid and nonopioid mechanisms

In this experiment, we tested for opioid and nonopioid mechanisms of pain control through cognitive means and the relation of opioid involvement to perceived coping efficacy. Subjects were taught cognitive methods of pain control, were administered a placebo, or received no intervention. Their pain tolerance was then measured at periodic intervals after they were administered either a saline solution or naloxone, an opiate antagonist that blocks the effects of endogenous opiates. Training in cognitive control strengthened perceived self-efficacy both to withstand and to reduce pain; placebo medication enhanced perceived efficacy to withstand pain but not reductive efficacy; and neither form of perceived self-efficacy changed without any intervention. Regardless of condition, the stronger the perceived self-efficacy to withstand pain, the longer subjects endured mounting pain stimulation. The findings provide evidence that attenuation of the impact of pain stimulation through cognitive control is mediated by both opioid and nonopioid mechanisms. Cognitive copers administered naloxone were less able to tolerate pain stimulation than were their saline counterparts. The stronger the perceived self-efficacy to reduce pain, the greater was the opioid activation. Cognitive copers were also able to achieve some increase in pain tolerance even when opioid mechanisms were blocked by naloxone, which is in keeping with a nonopioid component in cognitive pain control. We found suggestive evidence that placebo medication may also activate some opioid involvement. Because placebos do not impart pain reduction skills, it was perceived self-efficacy to endure pain that predicted degree of opioid activation.     

Affective deficits and pain insensitivity in schizophrenia

Affective deficits have long been considered a prominent feature of schizophrenia and play a central role in recent theory and research on the pathophysiology of this disorder. However, it has recently been argued that current approaches to the conceptualization and assessment of affective flattening in schizophrenia are confounded by the social and neuromotor deficits that are also prevalent in this disorder. Insensitivity to pain in individuals with schizophrenia — a phenomenon that has been reported frequently but never systematically investigated — provides one approach to examining affective flattening unconfounded by social and neuromotor deficits. Two studies are described in which signal detection theory measures of thermal pain sensitivity were examined in patients with schizophrenia, mood disorder, and normal controls; in addition, in the patients with schizophrenia, the relationships between these measures and measures of affective deficits were examined. Patients with schizophrenia had significantly poorer sensory discrimination of painful thermal stimuli than control subjects, but did not differ from controls with respect to their response criterion for reports of pain; patients with mood disorder had a significantly higher (i.e., more stoical) criterion for reports of pain than controls. As predicted, among the patients with schizophrenia, higher response criterion was significantly correlated with greater affective flattening and less intense affective experience (as well as with fewer positive symptoms and poorer premorbid adjustment). The results of these studies suggest that pain insensitivity in schizophrenia may reflect affective as well as sensory abnormalities, and that pain insensitivity in schizophrenia may provide a method for studying affective flattening in this disorder that is relatively independent of the social and neuromotor deficits that confound existing measures of this symptom. Continued examination of the relationship between pain insensitivity and affective deficits in schizophrenia is also important because numerous clinical reports have suggested that pain insensitivity is detrimental to health and can have life-threatening consequences in individuals with this disorder.This research was supported, in part, by research grants from the National Institute of Neurological Disorders and Stroke to Robert H. Dworkin (NS-30714) and W. Crawford Clark (NS-09263, NS-20248).     

Voluntary exercise ameliorates cognitive deficits in morphine dependent rats: the role of hippocampal brain-derived neurotrophic factor

Chronic exposure to opiates impairs spatial learning and memory. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we investigated whether voluntary exercise would ameliorate the cognitive deficits that are induced by morphine dependence. If an effect of exercise was observed, we aimed to investigate the possible role of hippocampal brain-derived neurotrophic factor (BDNF) in the exercise-induced enhancement of learning and memory in morphine-dependent rats. The rats were injected with bi-daily doses (10mg/kg, at 12h intervals) of morphine over a period of 10 days of voluntary exercise. Following these injections, a water maze task was performed twice a day for five consecutive days, followed by a probe trial 2 days later. A specific BDNF inhibitor (TrkB-IgG chimera) was used to block the hippocampal BDNF action during the 10 days of voluntary exercise. We found that voluntary exercise blocked the ability of chronic morphine to impair spatial memory retention. A blockade of the BDNF action blunted the exercise-induced improvement of spatial memory in the dependent rats. Moreover, the voluntary exercise diminished the severity of the rats' dependency on morphine. This study demonstrates that voluntary exercise ameliorates, via a TrkB-mediated mechanism, the cognitive deficits that are induced by chronic morphine. Thus, voluntary exercise might be a potential method to ameliorate some of the deleterious behavioral consequences of the abuse of morphine and other opiates.     

Understanding neuropathic pain

Neuropathic pain is defined as a chronic pain condition that occurs or persists after a primary lesion or dysfunction of the peripheral or central nervous system. Traumatic injury of peripheral nerves also increases the excitability of nociceptors in and around nerve trunks and involves components released from nerve terminals (neurogenic inflammation) and immunological and vascular components from cells resident within or recruited into the affected area. Action potentials generated in nociceptors and injured nerve fibers release excitatory neurotransmitters at their synaptic terminals such as L-glutamate and substance P and trigger cellular events in the central nervous system that extend over different time frames. Short-term alterations of neuronal excitability, reflected for example in rapid changes of neuronal discharge activity, are sensitive to conventional analgesics, and do not commonly involve alterations in activity-dependent gene expression. Novel compounds and new regimens for drug treatment to influence activity-dependent long-term changes in pain transducing and suppressive systems (pain matrix) are emerging.