Affective modulation of conditioned eyeblinks

Affective states are known to modulate reflexive actions. Aversive states potentiate defensive reflexes while appetitive states diminish them. The present study examined whether the same holds for associatively learned defensive eyeblinks to mild, initially neutral auditory stimuli. First, delay eyeblink conditioning was applied to human participants while they viewed emotionally neutral images. Next, the conditioned eyeblink responses (CRs) of the participants were tested during the viewing of unpleasant, neutral, or pleasant images. The most vigorous CRs were found during the unpleasant images, although they did not differ between neutral and pleasant images. The results add to the motivational priming hypothesis by demonstrating its partial applicability to associatively learned defensive behaviour.     

Emotional modulation of the post-auricular reflex

A large literature now exists on emotional modulation of the startle blink reflex. The current study examined affective modulation of the post-auricular reflex, which can be measured in relation to the same noise probe used to evoke the startle reflex. We recorded the post-auricular reflex during viewing of pictures that varied systematically in emotional valence, content, and intensity. A significant linear valence modulation effect was found, with pleasant pictures potentiating and aversive pictures inhibiting the post-auricular reflex in comparison with neutral pictures. This modulatory effect did not vary as a function of picture content, but it was most robust for highly intense emotional pictures. Implications for the assessment of basic emotional action tendencies are discussed.     

From nociception to pain perception: imaging the spinal and supraspinal pathways

Functional imaging techniques have allowed researchers to look within the brain, and revealed the cortical representation of pain. Initial experiments, performed in the early 1990s, revolutionized pain research, as they demonstrated that pain was not processed in a single cortical area, but in several distributed brain regions. Over the last decade, the roles of these pain centres have been investigated and a clearer picture has emerged of the medial and lateral pain system. In this brief article, we review the imaging literature to date that has allowed these advances to be made, and examine the new frontiers for pain imaging research: imaging the brainstem and other structures involved in the descending control of pain; functional and anatomical connectivity studies of pain processing brain regions; imaging models of neuropathic pain-like states; and going beyond the brain to image spinal function. The ultimate goal of such research is to take these new techniques into the clinic, to investigate and provide new remedies for chronic pain sufferers.     

Cholinergic modulation of tonic immobility and nociception in the NRM of guinea pig

Tonic immobility (TI) is an inborn defensive behavior characterized by a temporary state of profound and reversible motor inhibition elicited by some forms of physical restraint. It is known that endogenous antinociceptive systems are activated during the emission of defensive behaviors including TI. The nucleus raphe magnus (NRM) is related to the modulation of nociceptive and behavioral responses. In the present study, we investigated the role of the cholinergic system of the NRM in the modulation of TI and nociception in guinea pigs. Microinjection of the cholinergic agonist carbachol (0.5 microg/0.2 microl) into the NRM promoted a reduction in the duration of TI episodes and nociception, the latter measured by the vocalization test in guinea pigs. The effect of microinjection of carbachol on TI reduction and antinociception was blocked by the previous microinjection of the cholinergic antagonist atropine (0.5 microg/0.2 microl and 1 microg/0.2 microl, respectively), demonstrating the participation of muscarinic receptors in the modulation of these responses. Microinjection of atropine per se did not interfere with the duration of TI episodes. In summary, the present results demonstrate that cholinergic stimulation of the NRM promoted analgesia and a reduction in the duration of TI in guinea pigs. These data indicate that the NRM possibly contributes to the modulation of defensive and nociceptive behavioral responses, probably by modulating the activity of neurons in the ventral and dorsal horn of the spinal cord, respectively.     

Sex differences in shock motivated behaviors,activity, and discrimination learning of northern grasshopper mice (Onychomys leucogaster)

Sex differences in the behavior of the highly predatory northern grasshopper mouse (Onychomys leucogaster) were investigated in a series of eight experiments. Female mice acquired two-way avoidance behavior more slowly, but passive avoidance more rapidly, than males. Females also buried a shock probe more completely than males and showed more escape behavior during open field testing. There were no sex differences in flinch-jump thresholds or escape from electric shock, general activity levels, or acquisition and reversal of a position discrimination. It is suggested that the sex differences in aversively motivated behavior result from an increased tendency of females to respond defensively to focal sources of aversive stimuli. The enhanced defensiveness of females may be an adaptation to higher levels of pup predation resulting from the large territories required by their predatory specialization and their association with other, more abundant, rodent species.     

Modulation of spinal reflexes by sexual films of increasing intensity

Sexual arousal can be viewed as an emotional state generating sex-specific autonomic and general somatic motor system responses that prepare for sexual action. In the present study modulation of spinal tendious (T) reflexes by sexual films of varying intensity was investigated. T reflexes were expected to increase as a function of increased film intensity. Through use of a between-subjects design, participants were exposed to three erotic films of low, moderate, and high intensity or to three films of moderate intensity. Self-report and genital data confirmed the induction of increasing versus stable levels of sexual arousal. Exposure to the films of increasing intensity resulted in increasing T reflexes. The results indicate that T reflex modulation is sensitive to varying levels of sexual arousal and may be of use in research on behavioral mechanisms underlying appetitive motivation.     

Opioid peptide messenger RNA expression is increased at spinal and supraspinal levels following excitotoxic spinal cord injury

Spinal cord injury in rats is known to cause anatomical, physiological and molecular changes within the spinal cord. These changes may account for behavioral syndromes that appear following spinal cord injury, syndromes believed to be related to the clinical condition of chronic pain. Intraspinal injection of quisqualic acid produces an excitotoxic injury with pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury. In addition, recent studies have demonstrated changes in blood flow, neuronal excitability and gene expression in the brain following excitotoxic injury, indicating that behavioral changes may result from modification of neuronal substrates at supraspinal levels of the neuraxis. Because changes in spinal opioid peptide expression have been demonstrated in models of traumatic spinal cord injury and chronic pain, the present study investigated messenger RNA expression of the opioid peptides, preproenkephalin and preprodynorphin, at spinal and supraspinal levels following excitotoxic spinal cord injury. Male, Long-Evans rats were given three intraspinal injections of quisqualic acid (total 1.2 microl, 125mM). After one, three, five, seven or 10days, animals were killed and quantitative in situ hybridization performed on regions of the spinal cord surrounding the lesion site, as well as whole-brain sections through various levels of the thalamus. Preproenkephalin and preprodynorphin expression was increased in spinal cord areas adjacent to the site of quisqualic injection and in cortical regions associated with nociceptive function, preproenkephalin in the cingulate cortex and preprodynorphin in the parietal cortex, both ipsilaterally and contralaterally at various time-points following injury.These results further our knowledge of the secondary events that occur following spinal cord injury, specifically implicating supraspinal opioid systems in the CNS response to spinal cord injury.     

Modulation of spinal reflexes by aversive and sexually appetitive stimuli

In this study, modulation of spinal tendinous (T) reflexes by sexual stimulation was investigated. T reflexes are augmented in states of appetitive and defensive action and modified by differences in arousal intensity. Reflexes were expected to be facilitated by both pleasant (sexual) and unpleasant (anxiety) stimuli. Subjects were exposed to a sexual, an anxiety-inducing, a sexually threatening, and a neutral film excerpt. Genital arousal, emotional experience, subjective action tendencies, and T reflexes were monitored. Self-report and genital data confirmed the affective states as intended. T reflex amplitude significantly increased during viewing of emotionally arousing film excerpts as compared with a neutral film excerpt. T reflexes were facilitated by the sex stimulus to the same extent as by the anxiety and sexual threat stimuli. The results support the view of sexual arousal as an emotional state, generating sex-specific autonomic and general somatic motor system responses, which prepare the organism for action.     

Attentional set effects on spinal and supraspinal responses to pain

The effects of attentional set on subjective magnitude ratings, spinal reflexes, and somatosensory evoked potentials (SEP) elicited by innocuous and painful sural nerve stimulation were investigated in 24 subjects. Cuing stimuli informed subjects as to whether a visual identification or a somatosensory rating task would follow. Twenty percent of the trials were invalidly cued, where the subjects were expecting a visual stimulus but were given a sural nerve stimulus and vice versa. Subjective magnitude ratings were lower in the invalidly cued condition than the validly cued condition. Attentional set had no effect on innocuous-related spinal or early cortical responses, nor on the spinal nociceptive withdrawal reflex. The pain-related negative difference potential (NDP) and P2 component of the SEP were largest in the invalidly cued condition. These results provide further support for our hypothesis that the NDP is generated in part by the anterior cingulate, and suggest that the anterior cingulate response to pain reflects non-pain-specific cognitive processes (e.g., orienting attention towards important stimuli in the environment and/or response competition) and not some aspect of the pain experience. The effects of attentional set on the pain-related P2 suggests that it might correspond to the P3a event-related potential. If this is the case, the pain-related P2 could serve as a useful index of neural processes involved in the cognitive-evaluative aspect of pain.     

Assessing supraspinal modulation of pain perception in individuals at risk for hypertension

In this study we tested the hypothesis that hypoalgesia in individuals at risk for hypertension is related to enhanced activation of supraspinal pain modulation systems. Supraspinal inhibition of pain signals was assessed using a diffuse noxious inhibitory control paradigm, in which a noxious conditioning stimulus was used to suppress pain in response to a noxious test stimulus applied to a remote area of the body. Specifically, the nociceptive flexion reflex (NFR) was assessed in 113 healthy young adults before, during, and after exposure to forearm tourniquet ischemia. Consistent with previous evidence of hypoalgesia in individuals at risk for hypertension, offspring of hypertensive individuals exhibited significantly higher NFR thresholds than offspring of normotensive persons. Although NFR activity was significantly decreased in all participants during concomitant application of forearm ischemia, the degree of attenuation of NFR activity was not significantly different as a function of risk for hypertension.     

Examining emotional modulation of pain and spinal nociception in Native Americans: A preliminary investigation

Pain problems are more prevalent in Native Americans than in any other group in the U.S., and this might result from group differences in pain modulation. This study was designed to examine emotional modulation of pain and spinal nociception in healthy, pain-free Native Americans (n = 21) relative to non-Hispanic Whites (n = 20). To assess emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception), participants underwent a well-validated emotional picture-viewing paradigm during which suprathreshold pain stimuli were delivered to the ankle. Compared to Whites, Native Americans reported less pleasure to erotic pictures and failed to show corrugator reactivity to mutilation pictures. Unlike Whites, Native Americans only evidenced pain inhibition in response to erotica, but no pain facilitation (disinhibition) to mutilation pictures. Emotional modulation of NFR was similar in both groups. These preliminary findings suggest that Native Americans failed to disinhibit pain, perhaps due to over-activation of pain inhibitory mechanisms. Chronic over-activation of this system could ultimately exhaust it, thus putting Native Americans at future risk for chronic pain.     

Sex-specific modulation of spinal nociception by alpha2-adrenoceptors: differential regulation by estrogen and testosterone

Sex-related differences in antinociception produced by the activation of alpha(2)-adrenoceptors (alpha(2)-ARs) have been reported, however, the precise role of gonadal steroids is still unknown. Hence, we hypothesized that estrogen and testosterone modulate antinociceptive effects of clonidine (an alpha(2)-AR agonist) on N-methyl-D-aspartate- (NMDA) and heat-induced spinal nociception. We also investigated whether estrogen or testosterone alters the expression of alpha(2A)-adrenoceptors in the spinal cord. Sprague-Dawley (SD) rats were implanted with PE10 cannulae in the intrathecal space of the lumbosacral spinal cord and divided into male, proestrous and diestrous female, ovariectomized (OVX), estradiol-treated OVX (OVX+E), castrated male (GDX), testosterone (GDX+T) and estradiol-treated castrated male (GDX+E) groups. Clonidine dose-dependently inhibited NMDA-induced scratching behavior in the male and OVX groups but to a significantly lesser extent in the OVX+E group. It also increased the tail withdrawal latency in the male, OVX, diestrous and GDX+T groups but not in the OVX+E, proestrous, GDX and GDX+E groups. Levels of alpha(2A)-AR mRNA were significantly higher in the OVX, estradiol-treated OVX, GDX and GDX+E animals. In contrast, alpha(2A)-AR protein levels were higher in estradiol-treated OVX, GDX, GDX+T and GDX+E animals as compared with the male. Indeed, no correlations were observed between changes in the mRNA or protein levels of alpha(2A)-AR and behavioral observations. These results support our hypothesis that sex-related differences in alpha(2)-AR-mediated modulation of spinal nociception are gonadal hormone-dependent: estrogen attenuates antinociceptive effects in females whereas testosterone is required for the expression of antinociception in males. In addition, results also revealed that the mechanism of action of gonadal hormones may not involve a global alternation in expression of alpha(2A)-AR in the spinal cord. Estrogen-induced attenuation of alpha(2)-AR-mediated inhibition of nociception could contribute to the higher prevalence of pain syndromes in women.     

Serotonin transporter gene (5-HTTLPR) polymorphisms are associated with emotional modulation of pain but not emotional modulation of spinal nociception

The short allele of the serotonin transporter gene (5-HTTLPR) is associated with greater negative emotionality. Given that emotion modulates pain, short allele carriers (s-carriers) may also demonstrate altered pain modulation. The present study used a well-validated emotional picture-viewing paradigm to modulate pain and the nociceptive flexion reflex (NFR, a measure of spinal nociception) in 144 healthy genotyped participants. As expected, pain/NFR responses were largest during unpleasant pictures and smallest during pleasant pictures. However, relative to l/l-carriers, s-carriers demonstrated greater pain inhibition during pleasant pictures and greater pain facilitation during unpleasant pictures. Neither emotional modulation of NFR nor NFR threshold was associated with 5-HTTLPR polymorphisms. Results also indicated that men who were s-carriers had a higher pain threshold and tolerance than other participants. Taken together, our results indicate 5-HTTLPR polymorphisms may influence pain modulation at the supraspinal (not spinal) level; however, the influence on pain sensitivity may be sex-specific.     

Habituation and sensitization in the modulation of reflex amplitude.

The interaction of decrement due to repeated presentation of an auditory eliciting stimulus with an ancillary visual stimulus that itself increased reflex amplitude was studied in 4 separate experiments. This interaction produced a multiplicity of complex reflex changes that cannot readily be accounted for by current conceptualizations of the processes of habituation (underlying reflex decrement) and sensitization (underlying reflex increment) that presumably modulate reflex change.     

Assessment of opiate modulation of pain and nociceptive responding in young adults with a parental history of hypertension

This double blind, placebo-controlled study examined the effects of an opiate antagonist, naltrexone, on nociceptive flexion reflex (NFR) thresholds and subjective pain in individuals with and without a parental history of hypertension. Using a repeated measures design, NFR threshold was repeatedly assessed on two testing days after administration of either placebo or naltrexone. Immediately after NFR threshold was determined, participants rated the level of pain experienced during the preceding NFR assessment, and at the end of each session participants’ electrocutaneous pain threshold was assessed. Two primary findings were obtained. First, individuals with a parental history of hypertension exhibited attenuated pain sensitivity. Second, endogenous opioid blockade was associated with increased pain ratings in women but with increased pain threshold in men. In sum, the present study did not support a direct involvement of the endogenous opioid system in the attenuated pain sensitivity observed in individuals at increased risk for hypertension.     

Structure of the embryonic primate spinal cord at the closure of the first reflex arc

Early development of the spinal cord was studied in macaque monkey embryos, using light- and electron microscopy, Golgi impregnation and [³H]thymidine radioautography. All neurons engaged in the first reflex arc are generated before E27 in the 165 day gestation period. The earliest-generated cells differentiate into motoneurons while the commissural and association neurons are generated later. Synaptogenesis starts at E27 in the basal plate, and 2 days later in the alar plate. The first synapses appear as symmetrical junctions situated on the neuronal perikarya and proximal dendrites. Closure of the first spinal reflex arc is established within 2 days and follows an antidromic pattern as related to the physiological spread of nerve impulses: synapses on motoneuronal somata and primary dendrites in the basal plate appear first and are followed by synapses in the alar plate, between dorsal root axon collaterals and somata of borderline (commissural/association) neurons. Commissural axons grow towards the floor plate, cross the midline and proceed caudo-rostrally, while association fibers remain ipsilateral. The first wave of apoptosis (programmed cell death) thins out dense populations of nerve and glial cells by E30. Some of the early-generated borderine cells that form commissural and association interneurons, seem to play the role of transient target cells and die once the definitive axonal pathways are established. Since transient cells form numerous synapses, deprivation from the afferent impulses is not a likely cause of their elimination. The present results indicate that the initial developmental events, including formation of the first reflex arc in the primate spinal cord, occur considerably earlier in respect to birth than in other mammals, but that the schedule of cellular events and cellular mechanisms seem to be the same.On leave from the Department of Clinical Neurology, Albert Szent-Gyorgyi Medical University, Szeged, HungaryFogarty Senior Scientist     

炎症的自主神经调控与临床意义

Enormous progresses have been made in recent years for the involvement of nervous system in particular the vagus nerve in inflammatory responses. The parasympathetic nerve can be activated by “inflammatory reflex“ to inhibit macrophages, via their specific nicotinic receptor α- 7 subunit, and hence to reduce the production of tumor necrosis factor [TNF) that plays a pivotal role in many inflammatory reactions and is a key mediator for septic shock. This cholinergic anti - inflammatory pathway has been utilized, with positive outcomes, by means of either pharmacological or electrical stimulation in animal models against inflammatory responses and septic shock. Monoclonal antibodies against TNF and other pro- inflammatory cytokines have also been developed and used against inflammation experimentally and clinically. Although clinical use of these new treatments have yielded primitive and only limited results, these new research findings and concepts are important for the advance of modem medicine, as well as for better comprehension of some theories and practices in traditional medicine. Future directions are discussed herewith.     

Affective modulation of eyeblink startle with reward and threat

An emotion-modulated acoustic startle paradigm for inducing positive and negative affect was used to address pregoal and postgoal affect. Participants played a computerized lottery task in which they chose digits that could match a subsequently displayed, random set of numbers. In the positive conditions, matches led to monetary rewards. In the negative condition, matches led to an aversive noise blast. In three experiments, we found eyeblink startle magnitude was potentiated just prior to feedback concerning reward outcome, suppressed following the feedback that a monetary reward was won, and potentiated when threatened with an aversive noise. When presented with a 0%, 45%, 90%, or 100% chance of winning, higher probabilities suppressed startle response after feedback whereas the 45% trials did not. These data indicate that postgoal positive affect (winning reward) reliably suppressed the startle response whereas pregoal positive affect did not.     

Contrasting effects of nitric oxide and corticotropin-releasing factor within the dorsal periaqueductal gray on defensive behavior and nociception in mice

The anxiogenic and antinociceptive effects produced by glutamate N-methyl-D-aspartate receptor activation within the dorsal periaqueductal gray (dPAG) matter have been related to nitric oxide (NO) production, since injection of NO synthase (NOS) inhibitors reverses these effects. dPAG corticotropin-releasing factor receptor (CRFr) activation also induces anxiety-like behavior and antinociception, which, in turn, are selectively blocked by local infusion of the CRF type 1 receptor (CRFr1) antagonist, NBI 27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)aminopyridine]. Here, we determined whether i) the blockade of the dPAG by CRFr1 attenuates the anxiogenic/antinociceptive effects induced by local infusion of the NO donor, NOC-9 [6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine], and ii) the anxiogenic/antinociceptive effects induced by intra-dPAG CRF are prevented by local infusion of N^ω-propyl-L-arginine (NPLA), a neuronal NOS inhibitor, in mice. Male Swiss mice (12 weeks old, 25-35 g, N = 8-14/group) were stereotaxically implanted with a 7-mm cannula aimed at the dPAG. Intra-dPAG NOC-9 (75 nmol) produced defensive-like behavior (jumping and running) and antinociception (assessed by the formalin test). Both effects were reversed by prior local infusion of NBI 27914 (2 nmol). Conversely, intra-dPAG NPLA (0.4 nmol) did not modify the anxiogenic/antinociceptive effects of CRF (150 pmol). These results suggest that CRFr1 plays an important role in the defensive behavior and antinociception produced by NO within the dPAG. In contrast, the anxiogenic and antinociceptive effects produced by intra-dPAG CRF are not related to NO synthesis in this limbic midbrain structure.     

M-wave modulation at relative levels of maximal voluntary contraction

Frequency (mean and median power frequency, f and f _m) and amplitude (average rectified and root mean square values, ARV and rms), parameters of the M-wave, and the dorsiflexor force parameters of the anterior tibial muscles were measured in seven healthy human subjects. Intermittent, voluntary contractions at relative intensities (40%, 60%, and 80%) of maximal voluntary contraction (MVC) were performed in conjunction with electrical stimulation. The M-wave parameter changes were measured over the course of the isometric contractions. At higher force levels, M-wave potentiation was observed as increases in both ARV and rms. The ARV augmentation attained levels as high as 206.1 (SD 7.4)% of resting values after both initial and final contractions of 80% MVC, reaching statistical significance (P < 0.01). The f and f _m failed to show a significant difference at any level of contraction. It was surmised that potentiation of the M-wave was the result of an increased contribution of muscle fibre type IIb recruited during higher contraction levels, reflecting the change to larger, deeper innervating motoneurons as the intensity of contraction, as a percentage of MVC, rose. Recruitment of type IIb fibres, which have been reported to have a higher energy potential and frequency content, were thought to reflect changes in the local, excitability threshold of some motor units as the force intensity increased during the intermittent voluntary contractions. It is suggested that the M-wave elicited after contractions has the potential to reflect, to some extent, motor unit recruitment changes resulting from the preceding contractions, and that through comparisons of M-wave amplitude parameters, contributions of varying fibre types over the course of a contraction may be indicated.