Inhibitory Control System Research Articles

Endogenous kappa-opioid receptor systems inhibit hyperalgesia associated with localized peripheral inflammation

Peripheral inflammation evokes functional and biochemical changes in the periphery and spinal cord which result in central sensitization and hypersensitivity. Inhibitory control systems from the rostral ventromedial medulla (RVM) are also activated. The present study investigates whether endogenous kappa-opioid receptor (KOPr) systems contribute to these neuroadaptations. Inflammation was induced by intraplantar injection of complete Freund’s adjuvant (CFA) into one hindpaw. Mechanical and thermal thresholds were determined using the Von Frey and radiant heat tests, respectively. KOPr gene deletion in mice or systemic administration of the long-acting KOPr antagonist, norbinaltorphimine (norBNI) significantly exacerbated mechanical and thermal hypersensitivity of the ipsilateral, inflamed paw. Thermal and mechanical thresholds of the non-inflamed, contralateral hindpaw were unaffected by CFA treatment. However, gene deletion as well as norBNI treatment resulted in mechanical, but not thermal hypersensitivity of the non-inflamed paw. Similar results were obtained when norBNI was administered intrathecally or into the RVM in rats. These data demonstrate a previously unrecognized role of endogenous KOPr systems in inhibiting hyperalgesia during inflammation. Furthermore, they demonstrate that decreased KOPr activity in either the spinal cord or RVM not only enhances mechanical and thermal hyperalgesia of the inflamed limb but also leads to an unmasking of mechanical hyperalgesia at a site remote from inflammation. The differential effects of KOPr antagonism on mechanical versus thermal thresholds for the non-inflamed paw support the notion that distinct neuroanatomical or neurochemical mechanisms modulate the processing of thermal versus mechanical stimuli.

Effects of The Remote C Fibres Stimulation Induced by Capsaicin on the Blink Reflex in Chronic Migraine

The aim of this study was to test the function of the diffuse noxious inhibitory control system (DNIC) in chronic and episodic migraine, exploring the blink reflex (BR) modifications induced by topical application of capsaicin on the hand. We evaluated 11 migraine without aura (MA) and nine chronic migraine (CM) patients during the not symptomatic phase; they were compared with 14 non-headache subjects (N). The BR was elicited by weak electrical stimuli delivered to the right supraorbital nerve; it was obtained 10 min and 20 min after the application of 1 ml of 3% capsaicin in a cream base (Teofarma) on the skin of the dorsum of the right hand, and 60 min after capsaicin removal. The subjective pain sensation induced by capsaicin was significantly increased in CM with respect to both MA patients and normal subjects; the R2 area was increased in CM patients during capsaicin application, with respect to controls and MA patients, who did not exhibit any reflex alterations. These results may suggest a failure of DNIC and a disturbed control of the trigeminal reflex at the central level, linked with migraine frequency.

Subjective pain perception, spinal nociception and descending inhibition of experimentally induced pain in Parkinson's disease

Patients suffering from Parkinson's disease (PD) complain more often about acute and chronic pain, which can be subdivided into musculoskeletal pain, radicular-neuropathic pain, dystonic pain, central pain and akathisia. Previous studies of experimentally induced pain in PD revealed heterogeneous results. One recent study detected an increased perception of heat-induced pain, which was reversible after dopaminergic treatment. Possibly a reduced dopaminergic descending inhibitory control (DNIC) system contributes to this finding. Therefore, we investigated the DNIC system by using a tonic heat stimulus and a phasic electrical stimulus. In addition to thermal and electrical pain thresholds, we assessed spinal nociception by using the nociceptive flexion reflex (NFR).

ＮＩＣＵ（新生児集中治療室）の光環境における早産児のストレス評価

The purpose of this study is to evaluate the stress of premature infant, who is hospitalized in the various lightingenvironment of neonatal intensive care unit, by measurement of physiological responses. We measured the electrocardiogram (ECG) and motion of when the lighting environment changes from 31.5±18.1 to 761.8±219.9 [lux]. The subjects were 8 premature infantsthat were the mean corrected gestational age at the time of evaluation was from 32 weeks to 39 weeks. As the results, we confirmedthat premature infants were influenced by lighting environment in each week and obtained the suggestion of possibility that prematureinfant's inhibitory control system for lighting stimuli after the mean corrected gestational age at the time of evaluation was from 36 to37 weeks.

P.3.a.013 Untreated patients with schizophrenia have a failure of inhibitory control systems during saccadic tasks

P.3.a.013 Untreated patients with schizophrenia have a failure of inhibitory control systems during saccadic tasks

Sympathetic innervation of ciliary muscle and oculomotor function in emmetropic and myopic young adults

Purpose: Evidence exists for an additional inhibitory accommodative control system mediated by the sympathetic branch of the autonomic nervous system (ANS). This work aims to show the relative prevalence of sympathetic inhibition in young emmetropic and myopic adults, and to evaluate the effect of sympathetic facility on accommodative and oculomotor function. Methods: Profiling of ciliary muscle innervation was carried out in 58 young adult subjects (30 emmetropes, 14 early onset myopes, 14 late onset myopes) by examining post-task open-loop accommodation responses, recorded continuously by a modified open-view infrared optometer. Measurements of amplitude of accommodation, tonic accommodation, accommodative lag at near, AC/A ratio, and heterophoria at distance and near were made to establish a profile of oculomotor function. Results: Evidence of sympathetic inhibitory facility in ciliary smooth muscle was observed in 27% of emmetropes, 21% of early-onset myopes and 29% of late-onset myopes. Twenty-six percent of all subjects demonstrated access to sympathetic facility. Closed-loop oculomotor function did not differ significantly between subjects with sympathetic facility, and those with sympathetic deficit. Conclusions: Emmetropic and myopic groups cannot be distinguished in terms of the relative proportions having access to sympathetic inhibition. Presence of sympathetic innervation does not have a significant effect on accommodative function under closed-loop viewing conditions.

The contribution of neuroimaging techniques to the understanding of supraspinal pain circuits: Implications for orofacial pain

The aim of this article was to give an overview of the current knowledge of supraspinal pain mechanisms derived from neuroimaging studies, and to present data related to chronic orofacial pain disorders. The available studies implied that the anterior cingulate cortex plays a role in the emotional-affective component of pain, as well as in pain-related attention and anxiety. The somatosensory cortices may be involved in encoding spatial, temporal, and intensity aspects of noxious input. The insula may mediate both affective and sensory-discriminative aspects of the pain experience. The thalamus appears to be a multifunctional relay system. The prefrontal cortex has been implied in the pain-related attention processing; it does not have intensity encoding properties. Chronic pain conditions were associated with increased activity in the somatosensory cortices, anterior cingulate cortex, and the prefrontal cortex, and with decreased activity in the thalamus. Few neuroimaging studies used experimental stimuli to the trigeminal system or included orofacial pain patients. However, the available studies appeared to be in agreement with those using stimuli to other body parts and those concerning other chronic pain conditions. Overall, the available data suggest that chronic (orofacial) pain states may be related to a dysfunctional brain network and may involve a compromised descending inhibitory control system. The somatosensory cortices, anterior cingulate cortex, thalamus, and prefrontal cortex may play a vital role in the pathophysiology of chronic pain and should be the main focus of future neuroimaging studies in chronic pain patients.

Changes in GABA A receptor subunit expression in the midbrain during the oestrous cycle in Wistar rats

In women, the late luteal phase or “premenstrual” period is commonly associated with psychological disturbances, which include mood changes and increased aggression. The underlying cause is unknown but one possibility is that fluctuations in levels of neuroactive steroids precipitate changes in expression of GABA A receptor subunits that result in functional changes in inhibitory control systems. The present study investigated the levels of expression of α4, β1 and δ GABA A receptor subunits in the periaqueductal gray matter (PAG) in rats and whether plasticity occurs during the oestrous cycle in females. In male rats α4, β1 and δ subunit immunoreactive neurones were present throughout the PAG in similar numbers. In female rats in proestrus, oestrus and early dioestrus, the density of α4, β1 and δ subunit immunoreactive cells was similar to males. However, in late dioestrus, the numbers increased significantly, especially in the dorsolateral PAG, a region which is particularly rich in GABAergic interneurones. These parallel changes may reflect an increase in expression of the α4β1δ GABA A receptor subtype. Recombinant α4β1δ receptors, expressed in Xenopus oocytes, exhibited and EC 50 for GABA an order of magnitude lower (2.02±0.33 μM; mean±S.E.M.) than that found for the most ubiquitous α1β2γ2 GABA A receptor (32.8±2.5 μM). Increased expression of α4β1δ GABA A receptors in the interneurones of the PAG could render the panic circuitry abnormally excitable by disinhibiting the ongoing GABAergic inhibition. Similar changes in neuronal excitability within the PAG in women consequent to falling steroid levels in the late luteal phase of the menstrual cycle could contribute to the development of pre-menstrual dysphoria.

LET'S NOT BE IMPULSIVE: COMMENTS ON LUBMAN ET AL. (2004)

In their provocative review, Lubman et al. (2004) propose that dysfunction of inhibitory control systems in the brain is a core feature of the study for substance abuse. There is substantial merit in this concept. Once stated, it appears obvious that an impaired ability to suppress one's behavior would lead to excessive drug use, so it is surprising how little research there has been in this area. But it is precisely because this approach has such a strong intuitive appeal that it is in danger of being tautological, i.e. that the definition becomes the solution. In fact, it is in the definition of the problem wherein lie the greatest challenges to obtaining sound empirical support for this hypothesis. Inhibitory control is the third major paradigm in investigation of the neuronal basis of addiction. The first paradigm was withdrawal and the second was positive reinforcement. Yet each of these paradigms has something that the inhibitory control framework currently lacks: a clearly defined operational definition and experimental implementation (e.g. abstinence signs and symptoms, drug self-administration). Unlike the prior models of addiction, inhibition is both a subject of scientific inquiry and regular part of everyday conversation. To paraphrase William James’ famous comment regarding attention, everyone knows what inhibition is. Unfortunately everyone may have a different meaning for inhibition. Putting aside the connotations of morality and character often conveyed when loss of inhibition is used in everyday speech, the major impediment to the scientific study of inhibitory control at this time is the diversity of competing definitions and approaches. Starting with the title, the authors tend to use terms such as ‘loss of inhibition’, ‘impulsive’ and ‘compulsive’ interchangeably. However, there are reasons to consider that these terms are not identical, but rather may represent anchors on a continuous dimension. If so, then seemingly similar pathological repetition of behavior may be due to entirely different dysfunctions, and therefore may require entirely different treatment approaches. Hollander & Rosen (2000) have proposed that avoidance of harm underlies compulsive behavior whereas during impulsive behavior, harmful consequences are ignored and/or there is excessive attention on positive consequences. Hollander and Rosen's approach provides an entry point for designing studies to determine more precisely what type of dysfunction underlies the loss of control of drug use that characterizes addiction. Beyond issues of definition are the problems of measurement. The construct of impulsivity is a good example. There have been numerous studies using psychometric instruments to study impulsivity as a normal personality factor. Clinical criteria exist for diagnosing pathological aspects of impulsivity. There are also a variety of behavioral, cognitive and even economic tasks that can be used to gauge impulsivity in humans and animals. The problem is that there is not a consistent pattern of agreement across these measures, in that an individual may be considered impulsive by some measures, and not impulsive at all by other measures. Thus, it is becoming increasingly apparent that impulsivity is not a monolithic function. Rather, it is likely that taxonomy of impulsivity will eventually emerge, similar to what has developed for other broad psychological functions such as attention, memory, and emotion. As impulsivity becomes better defined, it is likely that only a subset of processes related to impulsivity will be related to addiction. The problem of specificity also exists at the neurobiological level. The authors cite studies implicating the anterior cingulate and orbitofrontal cortex in both inhibitory control and obsessive-compulsive disorder. However, both the anterior cingulate and orbitofrontal cortex are now known to be heterogeneous neuronal structures, with studies in both animals and humans beginning to delineate the functional differences between sub-regions of the frontal lobe (cf. reviews in Cavada & Schultz 2000). Attending to such regional differentiations may be especially critical when applying these findings to specific aspects of addiction (Kaufman et al. 2003; Fuchs et al. 2004). In summary, there is great merit using dysfunction of inhibitory control as a conceptual framework to guide addiction research. However, the current lack of agreement regarding the definition and measurement of the critical psychological constructs, let alone their neurobiological counterparts, represent significant challenges in conducting research that can be translated into effective methods to prevent and treat drug addiction.

A role for peripheral somatostatin receptors in counter-irritation-induced analgesia

Our hypothesis is that peripheral somatostatin (SRIF) has a role in counter-irritation-induced analgesia. Our paradigm involves the reduction of nociceptive behaviors produced by primary noxious stimuli (formalin or complete Freund's adjuvant [CFA] in the rat hind paw) by a counter-irritating stimulus (capsaicin [CAP] in the tail or muzzle). Activation of peripheral SRIF receptors is key since an SRIF receptor antagonist cyclo-somatostatin (c-SOM) and SRIF antibodies in the hind paw attenuate the counter-irritation-induced analgesia of both formalin and more persistent CFA nociception. Specificity of c-SOM is shown by reversal of its effects with octreotide, a SRIF analog. Injection of formalin in one hind paw and c-SOM in the other does not reduce the counter-irritation analgesia demonstrating local action of the c-SOM. Approximately 33% of peripheral sensory axons contain SRIF, which could release the peptide to activate SRIF receptors on cutaneous axons. Intraplantar naloxone has no effect on the counter-irritation analgesia indicating that SRIF is not activating opioid receptors. These results indicate that in addition to the classic central descending noxious inhibitory control systems that underlie counter-irritation-induced analgesia, there is a peripheral contribution arising from activation of SRIF receptors. Identifying a peripheral contribution of SRIF to mechanisms of counter-irritation analgesia offers opportunities for peripheral therapy.

The contribution of the lateral posterior and anteroventral thalamic nuclei on spontaneous recurrent seizures in the pilocarpine model of epilepsy.

The pilocarpine model of epilepsy in rats is characterised by the occurrence of spontaneous seizures (SRSs) during the chronic period that recur 2-3 times per week during the whole animal life. In a previous study on brain metabolism during the chronic period of the pilocarpine model it was possible to observe that, among several brain structures, the lateral posterior thalamic nuclei (LP) showed a strikingly increased metabolism. Some evidences suggest that the LP can participate in an inhibitory control system involved in the propagation of the seizures. The aim of the present study was to verify the role of LP in the expression and frequency of spontaneous seizures observed in the pilocarpine model. Ten adult male rats presenting SRSs were monitored for behavioural events by video system one month before and one month after LP ibotenic acid lesion. Another group of chronic epileptic rats (n=10) had the anteroventral thalamic nuclei (AV) lesioned by ibotenic acid. After the surgical procedure, the animals were sacrified and the brains were processed for histological analysis by the Nissl method. The LP group seizure frequency was 3.1+/-1.9 before ibotenic acid injection and showed an increase (16.3+/-7.2 per week) after LP lesion. No changes in SRSs frequency were observed in the AV group after ibotenic lesion in these nuclei. These results seem to suggest that LP play a role in the seizure circuitry inhibiting the expression of spontaneous seizures in the pilocarpine model.

The pain inhibiting pain effect: an electrophysiological study in humans

This study examines the counterirritation phenomenon of experimental pain in human subjects. Phasic pain induced by intracutaneous electrical stimuli was simultaneously applied with tonic pain induced by ischemic muscle work. Pain ratings, spontaneous EEG and evoked potentials were measured. We found a significant reduction of phasic pain ratings during and 10 min after tonic pain. The late somatosensory evoked potentials as neurophysiological correlates of phasic pain sensation were attenuated until 20 min after tonic pain offset. The extent of phasic pain relief due to concomitant tonic pain was small but significant, comparable to the effect of a regular systemic dose of a narco-analgesic drug in this experimental pain model. On the other hand, no modulations in the late components of the auditory evoked potential and the power spectrum of the spontaneous EEG were observed. These variables reflect the attention and vigilance of the subject and are well-known to be affected by opioids. The only exception was an increase of beta power, which might reflect hyperarousal during tonic pain. These results support the suggestion, that the analgesic effect of heterotopic noxious stimulation in humans is based on the activation of a specific inhibitory pain control system. Systemic release of endogenous opioids is unlikely to be involved, because the typical effects of opioids on the EEG were not observed.

The effects of stimulus intensity and age on visual‐evoked potentials (VEPs) in normal children

In this study, we explored the effects of flash intensity and age on visual-evoked potentials (VEPs) in a sample of 85 children aged 8-15 years. Results of previous studies are discrepant regarding the extent to which children show an evoked potential augmenting tendency at vertex, which has been reported to be a characteristic of an immature inhibitory control system. In the present study, VEPs to light flashes of four different intensities were recorded at Cz. The results confirmed that P1N1 and N1P2 at Cz were positively related to increases in stimulus intensity, whereas N1 was not related reliably to intensity. This difference between peak-peak and baseline-peak amplitude findings at Cz relative to evoked potential augmenting and reducing may help to explain discrepant results among earlier studies. Developmental changes were found for our sample of children that were independent of stimulus intensity: N1 amplitude increased significantly with age, whereas N1 latency showed a small (nonsignificant) age-related decrease.

Spinal bicuculline produces hypersensitivity of dorsal horn neurons: effects of excitatory amino acid antagonists

In this study, we sought to characterize the effects of focal GABA A receptor antagonism on spontaneous and evoked activity in dorsal horn neurons of the α-chloralose anesthetized cat. Bicuculline (0.5, 1.0 mM) applied near the neurons through a transparenchymal dialysis fiber resulted in increased evoked activity in nociceptive dorsal horn neurons. Hair deflection was the stimulus most affected, followed by both low and high threshold tonic mechanical stimulation of the receptive field. In addition, neurons displayed increased background discharge and a subpopulation developed an increased afterdischarge to noxious mechanical stimulation. This is in contrast to our previous work with glycine receptor antagonism where only the evoked response to hair follicle activation was significantly enhanced. Subsequent co-administration of an NMDA receptor antagonist (AP-7, 2.0 mM) was without any apparent effect on either basal or bicuculline-enhanced responses. Co-administration of a non-NMDA excitatory amino acid receptor antagonist (CNQX, 1.0 mM) with the bicuculline non-selectively blocked both low and high threshold mechanical input. The inability of AP-7 to reverse the bicuculline-associated hyperreactivity also contrasts with the AP-7 reversal of the strychnine-associated hyperreactivity. These results point out that, while GABA and glycine are frequently co-localized in cells of the spinal dorsal horn and both appear to mediate tonic inhibitory control systems, they are not at all equivalent and are subject to different modulatory pharmacologies. Removal of each influence may model a different component of neuropathic pain.

Modulated expression of c‐Fos in the spinal cord following noxious thermal stimulation of monoarthritic rats

Peripheral noxious stimulation evokes functional and biochemical changes in the spinal cord which results in central sensitization and hyperalgesia, but at the same time also induces the activation of inhibitory control systems. The purpose of the present study was to investigate whether the adaptive changes induced by ongoing peripheral inflammation influence the spinal cord expression of c-Fos (a commonly used marker of neuronal activity) following an additional acute noxious stimulus. Therefore, the spinal expression of c-Fos was immunohistochemically investigated following noxious thermal stimulation of a rat monoarthritic hindpaw at various time points (1, 4, 8, 21 days) after induction of monoarthritis. Compared to normal rats, c-Fos expression following ipsilateral noxious thermal stimulation of monoarthritic rats was strongly modified in the deep laminae of the dorsal horn depending on the time course of inflammation. At 1 day of monoarthritis, an enhanced ipsilateral expression (135% and 208% of normal rats in laminae III–VI and VII, respectively) and at 3 weeks a reduced expression (38% and 23% of normal rats in laminae III–VI and VII, respectively) was detected. The amount of c-Fos-positive neurons in the ipsilateral superficial laminae I and II was unchanged at all time points investigated. To assess excitability changes on the contralateral side at an early stage of inflammation, a group of monoarthritic rats received a contralateral noxious stimulus at day 1 of monoarthritis. This resulted in a potentiated expression of c-Fos ipsilateral to the acute noxious stimulus (i.e., contralateral to the monoarthritic hindpaw) restricted to lamina II (137% of normal rats) of the dorsal horn. The data showed that changes in c-Fos expression depended on the time point of noxious heat stimulation (NHS) of monoarthritic rats, and differed in the ipsi- and contralateral side of the spinal cord. In addition to a possible habituation of c-Fos expression, it may be speculated that the time course-dependent changes reflect laminae-specific modulations of excitatory and inhibitory mechanisms during monoarthritis. Further studies are necessary in order to provide more insights into the contribution of these mechanisms on noxious stimulus-evoked c-Fos expression. J. Neurosci. Res. 53:203–213, 1998. © 1998 Wiley-Liss, Inc.

Modulated expression of c-Fos in the spinal cord following noxious thermal stimulation of monoarthritic rats.

Peripheral noxious stimulation evokes functional and biochemical changes in the spinal cord which results in central sensitization and hyperalgesia, but at the same time also induces the activation of inhibitory control systems. The purpose of the present study was to investigate whether the adaptive changes induced by ongoing peripheral inflammation influence the spinal cord expression of c-Fos (a commonly used marker of neuronal activity) following an additional acute noxious stimulus. Therefore, the spinal expression of c-Fos was immunohistochemically investigated following noxious thermal stimulation of a rat monoarthritic hindpaw at various time points (1, 4, 8, 21 days) after induction of monoarthritis. Compared to normal rats, c-Fos expression following ipsilateral noxious thermal stimulation of monoarthritic rats was strongly modified in the deep laminae of the dorsal horn depending on the time course of inflammation. At 1 day of monoarthritis, an enhanced ipsilateral expression (135% and 208% of normal rats in laminae III-VI and VII, respectively) and at 3 weeks a reduced expression (38% and 23% of normal rats in laminae III-VI and VII, respectively) was detected. The amount of c-Fos-positive neurons in the ipsilateral superficial laminae I and II was unchanged at all time points investigated. To assess excitability changes on the contralateral side at an early stage of inflammation, a group of monoarthritic rats received a contralateral noxious stimulus at day 1 of monoarthritis. This resulted in a potentiated expression of c-Fos ipsilateral to the acute noxious stimulus (i.e., contralateral to the monoarthritic hindpaw) restricted to lamina II (137% of normal rats) of the dorsal horn. The data showed that changes in c-Fos expression depended on the time point of noxious heat stimulation (NHS) of monoarthritic rats, and differed in the ipsi- and contralateral side of the spinal cord. In addition to a possible habituation of c-Fos expression, it may be speculated that the time course-dependent changes reflect laminae-specific modulations of excitatory and inhibitory mechanisms during monoarthritis. Further studies are necessary in order to provide more insights into the contribution of these mechanisms on noxious stimulus-evoked c-Fos expression.

Inhibition of dopamine re-uptake: significance for nigral dopamine neuron activity.

In the present study the effect of inhibition of the re-uptake of dopamine (DA) was analysed with respect to DA release and to the firing pattern of DA neurons in the substantia nigra (SN). Intravenous administration of GBR 12909 (0.5-8 mg/kg), a specific and potent inhibitor of DA re-uptake, was found to dose-dependently increase the DA concentration both in the SN and in the striatum, as measured by microdialysis. However, the drug failed to significantly affect the firing rate of the nigral DA neurons. In contrast, GBR 12909 dose-dependently induced a regularisation of the firing pattern, concomitant with a reduction in burst activity. An acute hemisection of the brain, which by itself produced a slight regularisation of the firing pattern of the nigral DA neurons without changing the firing rate of the ability of the DA neurons to fire in bursts, was found to prevent the regulatory action of GBR 12909. Pretreatment with the selective GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v., 5 min) did not significantly affect the firing rate, the regularity of the DA neurons, or their ability to fire in bursts. However, CGP 35348 markedly antagonised the ability of GBR 12909 to induce pacemaker-like firing or a decrease in burst activity of the nigral DA neurons. The results of the present study suggest that a striatonigral feedback projection may serve to control the activity of nigral DA neurons not primarily by regulating the firing rate, but, preferably, by modulating the firing pattern of the neurons. In this regard, activation of somatodendritic GABAB-receptors may form the final link in this feedback inhibitory control system.

Inhibition of dopamine re‐uptake: Significance for nigral dopamine neuron activity

In the present study the effect of inhibition of the re-uptake of dopamine (DA) was analysed with respect to DA release and to the firing pattern of DA neurons in the substantia nigra (SN). Intravenous administration of GBR 12909 (0.5–8 mg/kg), a specific and potent inhibitor of DA re-uptake, was found to dose-dependently increase the DA concentration both in the SN and in the striatum, as measured by microdialysis. However, the drug failed to significantly affect the firing rate of the nigral DA neurons. In contrast, GBR 12909 dose-dependently induced a regularisation of the firing pattern, concomitant with a reduction in burst activity. An acute hemisection of the brain, which by itself produced a slight regularisation of the firing pattern of the nigral DA neurons without changing the firing rate or the ability of the DA neurons to fire in bursts, was found to prevent the regulatory action of GBR 12909. Pretreatment with the selective GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v., 5 min) did not significantly affect the firing rate, the regularity of the DA neurons, or their ability to fire in bursts. However, CGP 35348 markedly antagonised the ability of GBR 12909 to induce pacemaker-like firing or a decrease in burst activity of the nigral DA neurons. The results of the present study suggest that a striatonigral feedback projection may serve to control the activity of nigral DA neurons not primarily by regulating the firing rate, but, preferably, by modulating the firing pattern of the neurons. In this regard, activation of somatodendritic GABAB-receptors may form the final link in this feedback inhibitory control system. Synapse 25:215–226, 1997. © 1997 Wiley-Liss, Inc.

The neuronal response to pain

A great deal of information has been obtained about the normal physiology of pain transmission. This information has been utilised in the development of techniques, such as transcutaneous electrical nerve stimulation and dorsal column stimulation, to relieve pain symptoms. This review will discuss the role of both the peripheral and the central nervous systems in the transmission of noxious stimuli. It will also discuss the neuronal response to pain involving spinal, thalamic and cortical neurons, as well as the descending inhibitory control systems. The response of peripheral and central neurons in pain models such as arthritis and peripheral neuropathy is altered. There is an increase in the neuronal response to peripherally applied stimuli following tissue or nerve injury that involves spinal, thalamic and cortical neurons. Increased activation of the endogenous descending inhibitory systems also occurs in response to injury. Both the peripheral and central nervous systems are ‘plastic', they can be modified and show considerable adaptation to injury. The severity of some diseases and injuries does not allow the body to control associated pain, resulting in chronic pain. Models of chronic pain syndromes are beginning to provide insight into the pathophysiology of injury and disease. Research in this area will hopefully provide better treatments for the chronic pain patient.

β-Cell Memory to Insulin Secretagogues: Characterization of the Time-Dependent Inhibitory Control System in the Isolated Rat Pancreas*

Most secretagogues, in addition to their acute stimulatory effect on insulin release, modify the responsiveness of the islet to subsequent stimulations. According to the nature and duration of the stimulus, the generated islet memory may either amplify [time-dependent potentiation, (TDP)] or diminish [time-dependent inhibition (TDI)] the responsiveness of the beta-cell. This work characterizes the kinetic parameters of TDI in the isolated rat pancreas. When subjected to a low dose (8.3 mmol/liter) glucose stimulus, maximal TDI was observed after 5 min of priming, while at a higher dose (16.7 mmol/liter) shorter exposures were sufficient. Longer periods of stimulation (10-40 min) resulted in the predominance of TDP, thus amplifying the release rate. TDI was not affected by previous generation of TDP; 40-min priming with 16.7 mmol/liter glucose markedly augmented the subsequent insulin responses to a pair of 6.9 mmol/liter stimuli, but the response to the second stimulus was inhibited, as in unprimed pancreas. Stimulation with arginine (5.0 mmol/liter) in the presence of basal (3.3 mmol/liter) glucose activated TDI only, and hence revealed monophasic insulin release. Tolbutamide (100 micrograms/ml), glucagon (5 micrograms/ml), and isobutylmethylxanthine (0.1 mmol/liter) also demonstrated TDI when given as a pair of 10-min stimuli; they all elicited monophasic insulin responses during prolonged stimulation. Arginine was chosen for detailed characterization of TDI because of its potency. Using identical concentrations of arginine for the generation and expression of TDI, a similar degree of inhibition (60-80%) was observed at all doses tested (0.5-5.0 mmol/liter). However, there existed competition between TDI and the acute secretory signal. Thus, TDI generated by 1.0 mmol/liter arginine had a minimal effect on insulin release induced by 2.0-5.0 mmol/liter amino acid, while it was fully inhibitory of the response to 1.0 mmol/liter arginine. Similarly, inhibition of the insulin response to 5.0 mmol/liter arginine was dependent on the dose (0.5-5.0 mmol/liter) of the priming pulse of arginine. The generation of TDI was unaffected by the insulin release rate during priming, since synergistic augmentation (combined arginine-glucose or arginine-isobutylmethylxanthine stimulation) or partial inhibition (arginine plus epinephrine) of the response had no effect on the subsequent expression of TDI. It is concluded that TDI and TDP are two distinct regulatory systems that independently control the rate of insulin release, most probably operating through different mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)