Attention effects on vicarious modulation of nociception and pain

The observation of others’ facial expressions of pain has been shown to facilitate the observer’s nociceptive responses and to increase pain perception. We investigated how this vicarious facilitation effect is modulated by directing the observer’s attention toward the meaning of pain expression or the facial movements. In separate trials, participants were instructed to assess the “intensity of the pain expression”(meaning) or to “discriminate the facial movements” in the upper vs lower part of the face shown in 1-second dynamic clips displaying mild, moderate, or strong pain expressions or a neutral control. In 50% of the trials, participants received a painful electrical stimulation to the sural nerve immediately after the presentation of the expression. Low-level nociceptive reactivity was measured with the RIII-response, and pain perception was assessed using pain ratings. Pain induced by the electrical stimulation increased after viewing stronger pain expressions in both tasks, but the RIII-response showed this vicarious facilitation effect only in the movement discrimination task at the strongest expression intensity. These findings are consistent with the notion that vicarious processes facilitate self-pain and may prime automatic nociceptive responses. However, this priming effect is influenced by top-down attentional processes. These results provide another case of dissociation between reflexive and perceptual processes, consistent with the involvement of partly separate brain networks in the regulation of cortical and lower-level nociceptive responses. Combined with previous results, these findings suggest that vicarious pain facilitation is an automatic process that may be diminished by top-down attentional processes directed at the meaning of the expression.     

Influence of estrous cycle and gonadal hormone depletion on nociception and opioid antinociception in female rats of four strains.

Evidence suggests that gonadal hormones can modulate sensitivity to nociceptive stimuli and opioid antinociception. However, cross-study comparisons addressing the nature of this modulation have been complicated by a number of methodologic factors, including the use of different rodent strains and opioids. The present study examined the influence of estrous cycle and gonadal hormone depletion (ovariectomy) on thermal nociception and opioid antinociception in female F344, Lewis, Long Evans, and Wistar rats. Estrous cycle-dependent differences in nociceptive sensitivity were not observed in any of the strains. Ovariectomy decreased nociceptive sensitivity relative to their intact female counterparts. In normal cycling females, morphine and buprenorphine were generally most potent in metestrus and proestrus and least potent in estrus. The magnitude of these differences was consistently larger with buprenorphine. Ovariectomy increased the antinociceptive potency of morphine and buprenorphine, with this effect also being larger with buprenorphine. These data suggest that in adult females of a number of rat strains, estrous cycle and gonadal hormone depletion modulate the antinociceptive potency of opioids, with the magnitude of this effect being dependent on the type of opioid. In contrast, depletion of gonadal hormones, but not estrous cycle, modulates thermal nociceptive sensitivity in adult female rats. PERSPECTIVE: Gonadal hormones influence opioid antinociception, and this effect is apparent across different genetic backgrounds. These results suggest that the phase of the menstrual cycle might alter the effectiveness of certain opioids administered to relieve pain in women.     

Gonadal hormones do not account for sexual dimorphism in vagal modulation of nociception in the rat

Subdiaphragmatic vagotomy produces a decrease in mechanical nociceptive threshold that is greater in male rats and an enhancement of bradykinin hyperalgesia that is greater in female rats. To examine the role of gonadal hormones in these sex differences, we evaluated the effect of gonadectomy, with or without gonadal hormone replacement, on vagal modulation of nociceptive threshold and bradykinin hyperalgesia by using the Randall-Selitto paw withdrawal test. Gonadectomy (before sexual maturation) plus vagotomy decreased nociceptive threshold in male rats more than either lesion alone, whereas neither lesion nor in combination had an effect on nociceptive threshold in female rats. Testosterone or dihydrotestosterone replacement in gonadectomized plus vagotomized males and 17β-estradiol in females did not significantly alter nociceptive threshold compared to vagotomy plus gonadectomy, respectively. Combined vagotomy and gonadectomy unexpectedly almost completely abolished bradykinin hyperalgesia, whereas gonadectomy alone had no effect on bradykinin hyperalgesia in both sexes. Testosterone replacement in vagotomized males and 17β-estradiol in vagotomized females reversed the effect of gonadectomy. Dihydrotestosterone replacement in vagotomized males also reversed the effect of gonadectomy on bradykinin hyperalgesia, although to a lesser degree than testosterone. We conclude that although gonadal hormones and other gonadal-dependent mechanisms influence nociception, they do not account for sexual dimorphism in vagal modulation of mechanical nociceptive threshold or bradykinin hyperalgesia.     

Supraspinal modulation of trigeminal nociception and pain

Objective.— This study examined modulation of trigeminal pain/nociception by 2 supraspinal mechanisms: emotional controls of nociception and diffuse noxious inhibitory controls. Background.— Prior research suggests emotional picture viewing (emotional controls) and tonic noxious stimuli (diffuse noxious inhibitory controls) engage supraspinal mechanisms to modulate pain and nociceptive processes. It is currently unknown, however, whether emotional controls modulate trigeminal pain and nociception. Additionally, the influences of emotional controls and diffuse noxious inhibitory controls have not been compared in the same group of participants. Methods.— Noxious electrodermal stimuli were delivered to the trigeminal nerve using a concentric electrode designed to selectively activate nociceptive fibers. Trigeminal nociception and pain were assessed (34 participants) from the nociceptive blink reflex and pain ratings, respectively. Emotional controls were engaged by presentation of standardized picture stimuli (pleasant, neutral, and unpleasant) shown to reliably evoke pleasure-induced inhibition and displeasure-induced facilitation of pain and nociception. Diffuse noxious inhibitory controls were engaged with a forearm ischemia task. Results.— Trigeminal pain (self-report ratings) and nociception (blinks) were facilitated by unpleasant pictures and inhibited by pleasant pictures. Emotion induction (as assessed from trend analysis) explained 51% of the variance in trigeminal pain and 25% of the variance in trigeminal nociception. Additionally, forearm ischemia inhibited trigeminal pain but not nociception. The baseline vs ischemia comparison explained 17% of the variance in pain report and 0.1% of the variance in blinks. Supraspinal modulation by emotional controls and diffuse noxious inhibitory controls were uncorrelated. Conclusions.— Emotional controls and diffuse noxious inhibitory controls modulated trigeminal pain and emotional controls modulated trigeminal nociception. These procedures can be used to study supraspinal modulation of nociceptive processing in disorders of the trigeminal pain system, including headache.     

Spinal modulation of nociception by music

Numerous studies have demonstrated the capacity of music to modulate pain. However, the neurophysiological mechanisms responsible for this phenomenon remain unknown. In order to assess the involvement of descending modulatory mechanisms in the modulation of pain by music, we evaluated the effects of musical excerpts conveying different emotions (pleasant‐stimulating, pleasant‐relaxing, unpleasant‐stimulating) on the spinally mediated nociceptive flexion reflex (or RIII), as well as on pain ratings and skin conductance responses. The RIII reflex and pain ratings were increased during the listening of unpleasant music compared with pleasant music, suggesting the involvement of descending pain‐modulatory mechanisms in the effects of musical emotions on pain. There were no significant differences between the pleasant‐stimulating and pleasant‐relaxing musical condition, indicating that the arousal of music had little influence on pain processing.     

Gonadal steroid hormone modulation of nociception,morphine antinociception and reproductive indices in male and female rats

The purpose of this study was to examine how gonadal steroid hormones modulate basal nociception and morphine antinociception relative to regulating reproduction in the adult rat. Male and female Sprague-Dawley rats were either gonadectomized (GDX) or sham-gonadectomized (sham); GDX males were implanted subcutaneously with capsules containing testosterone (T), estradiol (E2), dihydrotestosterone (DHT), E2 and DHT, or nothing (0). GDX females received E2, T, or empty (0) capsules immediately after surgery, and vehicle or progesterone (P4) injections at 4-day intervals. Basal nociception and morphine antinociception were tested 28 days after surgery on 50 degrees C and 54 degrees C hotplate tests, and reproductive behavior and physiology were assessed shortly thereafter. There were no significant differences in baseline hotplate latencies among the male treatment groups, but morphine was significantly more potent in sham and GDX+T males than in GDX+0 males. The ability of T to increase morphine's potency was approximated by its major metabolites E2 and DHT, given together but not alone. Baseline hotplate latencies were higher in sham females tested during diestrus than in those tested during estrus. Morphine was significantly more potent in sham females tested during proestrus and diestrus than in those tested during estrus. Baseline hotplate latencies were significantly higher, and morphine was significantly less potent in GDX+E2, GDX+E2/P4 and GDX+T females than in GDX+0 females. All group differences in basal nociception and morphine antinociception observed on the 50 degrees C hotplate test were smaller and generally non-significant on the 54 degrees C hotplate test. Steroid manipulations produced the expected changes in reproductive behaviors and steroid-sensitive organs. These results demonstrate that in adult rats, gonadal steroid manipulations, that are physiologically relevant, modulate (1) basal nociception in females but not males, and (2) morphine's antinociceptive potency in both males and females.     

Alcohol effects on luteinizing hormone releasing hormone-stimulated anterior pituitary and gonadal hormones in women

Plasma luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, estradiol (E2) and progesterone were measured in 24 normal, adult women before and after i.v. administration of 100 micrograms luteinizing hormone releasing hormone (LHRH; Factrel) and p.o. ingestion of an alcohol (0.694 g of alcohol per kg b.wt.) or placebo solution. Twelve subjects were studied during the early follicular phase of the menstrual cycle and 12 subjects were studied during the midluteal phase of the menstrual cycle. During each menstrual cycle phase, six subjects received placebo solution and six subjects received alcohol solution administered under double-blind conditions. Mean peak blood alcohol levels of 113 to 122 mg/dl were measured 45 to 60 min after initiation of alcohol intake. LHRH stimulated a significant increase in LH after both alcohol (P less than .0001) and placebo (P less than .0001) administration, and this LH increase was equivalent during the follicular and the luteal phases of the menstrual cycle. LHRH also stimulated a significant increase in FSH levels after both alcohol and placebo intake during the follicular and luteal phases of the menstrual cycle (P less than .0001). There were no significant differences in LHRH-stimulated FSH between the alcohol and placebo conditions. Plasma prolactin levels also increased significantly after LHRH administration during the follicular and luteal phases of the menstrual cycle (P less than .0001). There were no significant differences in prolactin response to LHRH administration between the alcohol or placebo conditions during the follicular and luteal phases of the menstrual cycle. Plasma E2 levels did not increase significantly after LHRH administration and placebo alcohol during the follicular phase of the menstrual cycle.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of pain catastrophizing on experimentally induced emotion and emotional modulation of nociception.

Pain catastrophizing is associated with enhanced pain and pain-related outcomes. Unfortunately, the mechanisms underlying the catastrophizing-pain relationship are poorly understood. Given evidence suggesting significant relationships among catastrophizing, emotion, and pain, it is possible that catastrophizing may alter nociception and pain through affective processes. Research has shown that emotionally charged pictures (erotica, neutral, threat/attack scenes) manipulate emotional valence (positive affect vs negative affect) and modulate physiological and subjective nociceptive reactions (pleasure-induced inhibition, displeasure-induced facilitation). Using this methodology, the present study addressed 2 questions: (1) Does pain catastrophizing moderate affective reactions to standard emotional stimuli (eg, augmented negative affect)? and (2) Does pain catastrophizing moderate the relationship between emotion and nociception (eg, augmented displeasure-induced facilitation)? Erotic, neutral, and attack pictures were presented to 53 participants who rated their emotional responses. During pictures, noxious electric stimulations were delivered to evoke nociceptive reactions (nociceptive flexion reflex, skin conductance response, heart rate acceleration, subjective pain). Results suggest that pain catastrophizing did not moderate emotional reactions to standardized picture stimuli, nor did catastrophizing moderate the influence of emotion on nociceptive reactions. This suggests that catastrophizing does not influence pain indirectly through emotional processes.PerspectivePain catastrophizing is commonly associated with negative emotions and maladaptive responses to pain. The current study provides evidence indicating catastrophizing does not alter pain and nociception indirectly via emotional processes.     

Emotional modulation of pain and spinal nociception in fibromyalgia

Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (eg, depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well-validated affective picture-viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain-free controls (HC). Mutilation, neutral, and erotic pictures were presented in 4 blocks; 2 blocks assessed only physiological-emotional reactions (ie, pleasure/arousal ratings, corrugator electromyography, startle modulation, skin conductance) in the absence of pain, and 2 blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (eg, reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all 3 groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain-to-spinal cord circuitry that modulates spinal nociceptive processes.     

Hypothalamic modulation of nociception and reproduction in cluster headache. I. Therapeutic trials of leuprolide

A slow-release gonadotropin-releasing hormone (Gn-RH) analogue was administered to 30 males suffering from chronic cluster headache (CH) in a placebo-controlled study with the aim of enhancing neurotransmission in the pain-suppressing systems of the hypothalamus through a feedback action involving neuroendocrine functions too. A significant improvement in the severity of the pain occurred together with the expected lowering of the libido and serum levels of testosterone and luteinizing hormone. We postulate that the benefit of the Gn-RH analogue relates to an impairment of neuronal modulation in cluster headache.     

Biphasic modulation of visceral nociception by neurotensin in rat rostral ventromedial medulla.

A potential role for neurotensin in the rostral ventromedial medulla (RVM) in modulation of visceral nociceptive transmission was examined in this study. Microinjection of neurotensin (3-3000 pmol) into the RVM of awake rats produced a dose-dependent inhibition of the visceromotor response (VMR) to noxious colorectal distension (CRD) that lasted 30 to 120 min. Additionally, intra-RVM injection of neurotensin (300 pmol) significantly reduced the slope of the stimulus-response function to graded CRD (20-80 mm Hg), whereas the greatest dose of neurotensin (3000 pmol) completely inhibited the VMR at all intensities of CRD. General motor function was unaffected after intra-RVM injection of neurotensin (3000 pmol). Intra-RVM injection of lesser doses of neurotensin (0.03-0.30 pmol) resulted an enhancement of the VMR to noxious CRD that had a short duration (18-30 min), and produced a leftward shift of the stimulus-response function to graded CRD without a change in the slope of the function. Additionally, intra-RVM injection of the neurotensin-receptor antagonist SR48692 (0.3-300 fmol) in naive animals produced dose-dependent inhibition of VMR to noxious CRD, whereas a lesser dose (0.03 fmol) enhanced the VMR. These data support a role for neurotensin in the RVM in biphasic modulation of visceral nociception. The results obtained with SR48692 suggest that endogenous neurotensin in the RVM modulates VMR to noxious CRD via a prominent interaction with neurotensin receptors that mediate facilitatory influences and a lesser interaction with neurotensin receptors that mediate masked inhibitory influences.     

Effects of pharmacological adrenergic and vagal modulation on fractal heart rate dynamics

Breakdown of short‐term fractal‐like behaviour of HR indicates an increased risk for adverse cardiovascular events and mortality, but the pathophysiological background for altered fractal HR dynamics is not known. Our aim was to study the effects of pharmacological modulation of autonomic function on fractal correlation properties of heart rate (HR) variability in healthy subjects. Short‐term fractal scaling exponent (α₁) along with spectral components of HR variability were analysed during the following pharmacological interventions in healthy subjects: (i) noradrenaline (NE) infusion (n=22), (ii) NE infusion after phentolamine (PHE) (n=8), (iii) combined NE + adrenaline (EPI) infusion (n=12), (iv) vagal blockade with high dose of atropine (n=10), (v) and vagal activation by low dose of atropine (n=10). Then α₁ decreased progressively during the incremental doses of NE (from 0·85 ± 0·250 to 0.55 ± 0·23, P<0·0001). NE also decreased the average HR (P<0·001) and increased the high frequency spectral power (P<0·001). Vagal blockade with atropine increased the α₁ value (from 0·82 ± 0·22 to 1·24 ± 0·41, P<0·05). Combined NE + EPI infusion and vagal activation with a low dose atropine did not result in any changes in α₁, and α‐adrenergic blockade by PHE did not completely reverse the effects of NE on α₁. Increased levels of circulating NE result in reduction of short‐term correlation properties of HR dynamics. The results suggest that coactivation of cardiac vagal outflow at the time of high levels of a circulating sympathetic transmitter explains the breakdown of fractal‐like behaviour of human HR dynamics.     

Ovarian steroid hormone modulation of the acute effects of cocaine on luteinizing hormone and prolactin levels in ovariectomized rhesus monkeys

Cocaine stimulates significant increases in luteinizing hormone (LH) and decreases prolactin levels in gonadally intact rhesus monkeys, but cocaine did not alter plasma levels of these anterior pituitary hormones in ovariectomized females. These findings suggested that ovarian steroid hormones may contribute to the endocrine effects of acute cocaine administration. To test this hypothesis, the acute effects of cocaine and placebo-cocaine on plasma LH and prolactin levels were examined in five ovariectomized rhesus females during three chronic hormone replacement conditions: 1) estradiol (E2beta) treatment (0.0015-0.006 mg/kg/day i.m.), 2) progesterone treatment (0.32 mg/kg/day i.m.), and 3) combinations of progesterone (0.32 mg/kg/day i.m.) and E2beta (0.002 and 0.004 mg/kg/day i.m.). Cocaine (0.8 mg/kg i.v.) did not alter prolactin or LH in ovariectomized monkeys without ovarian steroid replacement. During chronic estradiol treatment, cocaine produced an estradiol dose-dependent decrease in prolactin. Cocaine also decreased prolactin during treatment with progesterone alone and progesterone + E2beta (0.004 mg/kg/day i.m.). Cocaine stimulated a significant increase in LH during treatment with progesterone alone, but not during treatment with progesterone + E2beta, or three of four estradiol treatment doses. Cocaine pharmacokinetics did not differ as a function of hormone replacement conditions. Together, these data suggest that both E2beta and progesterone modulate cocaine's effects on prolactin, whereas E2beta alone and in combination with progesterone, do not facilitate LH release in response to cocaine in ovariectomized rhesus females.     

Influence of gonadal steroids on rat pituitary growth hormone secretion

Growth hormone (GH) secretion increases at the time of puberty, and both androgens and estrogens increase the GH response to provocative agents. Little is known, however, with regard to the mechanism or site of action of gonadal steroid-stimulated GH secretion. Using monolayer primary cell culture and radioimmunoassay techniques, insulin-like growth factor I (IGF-I), purified and biosynthetic human GH, 17 beta-estradiol (E2), and testosterone (T) effects on GH release from rat anterior pituitary cells were investigated. Media content of rat GH was measured, both basally and after growth hormone releasing factor (GRF) stimulation. IGF-I at 50 nM concentration inhibited basal rGH release but not in GRF-stimulated cells. E2 (10 pM) stimulated basal secretion of rGH, although higher concentrations did not. High concentrations of T (100,000 pM) caused an increase in GRF-stimulated rGH secretion. Neither purified nor biosynthetic hGH pretreatment influenced subsequent rGH release. These results suggest that IGF-I inhibits and E2 (low dose) and T (high dose) augment rGH release in part at the level of the anterior pituitary.     

Gender effects and central opioid analgesia.

Central morphine analgesia is significantly greater in male than in female rats. Since mu and delta opioid receptor subtypes have been implicated in supraspinal analgesia, the present study evaluated whether gender or adult gonadectomy altered (a) analgesia on the tail-flick and jump tests following central administration of the mu-selective agonist, [D-Ala2, Me-Phe4, Gly(ol)5] enkephalin (DAMGO) and the delta-selective agonist, [D-Ser2,Leu5] enkephalin-Thr6 (DSLET) and (b) mu1, mu2 and delta opioid receptor binding. Sham-operated male rats displayed significantly greater magnitudes of peak and total analgesia than sham-operated females on the tail-flick test following DAMGO, but not DSLET. Gender differences were not observed for DAMGO and DSLET analgesia on the jump test. Gonadectomy failed to consistently affect either DAMGO or DSLET analgesia. Regression analyses failed to reflect significant shifts in the dose-response functions for either agonist on either measure. Gender differences were not observed for mu1, mu2, or delta binding in hypothalamus or cortex. These data are compared with analgesic responses sensitive to gender differences.     

The effect of the menstrual cycle on affective modulation of pain and nociception in healthy women

Research indicates pain may be influenced by the menstrual cycle. While the mechanisms underlying these effects are unclear, it is possible that menstrual phase-related changes in endogenous pain modulation contribute. The present study used well-validated methods to study affective modulation of pain and the nociceptive flexion reflex (NFR) in healthy women during two menstrual phases (mid-follicular vs. late-luteal). Women (N = 41) tracked their menstrual phases for three complete cycles and were asked to attend two laboratory testing sessions in the second and third cycles to assess affective modulation of pain and nociception (testing order counterbalanced). Menstrual phase was assessed from daily diaries, luteinizing hormone tests, and basal body temperature. At each session, emotionally charged pictures were presented and suprathreshold electrocutaneous stimulations were delivered during and in between pictures. Subjective and physiological emotional reactions were recorded in response to each picture and pain ratings and NFRs were recorded in response to each suprathreshold stimulus. Results suggested pictures effectively manipulated emotion in both menstrual phases. Moreover, arousing unpleasant pictures enhanced pain and NFR, whereas arousing pleasant pictures inhibited pain and NFR. These modulatory effects were similar in both menstrual phases. Together, these findings suggest that affective engagement of corticospinal mechanisms does not differ across these phases of the menstrual cycle. However, future research is needed to directly assess the relationship between affective modulation of pain/nociception and inter- and intra-individual differences in ovarian hormones and to extend these findings to women who suffer from menstrual cycle-related pain (e.g., premenstrual dysphoric disorder, fibromyalgia).     

Gender differences in ethanol preference and ingestion in rats. The role of the gonadal steroid environment.

An ethanol oral self administration paradigm showed the existence of gender differences in alcohol preference in rats: whereas males and females initiated alcohol drinking at similar rates, females maintained their preference for ethanol over a longer duration. Neonatal estrogenization of females, which effectively confers a male phenotype on a genetically female brain, resulted in patterns of drinking that were similar to those displayed by intact male rats, indicating that gender differences in alcohol drinking patterns may be, at least partially, accounted for by sexual differentiation of the brain. To test whether gonadal steroids also exert activational effects on ethanol-seeking behavior, we also examined the effects of gonadectomy alone, or in combination with gonadal steroid replacement therapy. Castration did not significantly alter ethanol consumption in males, although treatment of castrated rats with dihydrotestosterone resulted in a significant inhibition of this parameter. As compared with the situation in intact female rats, ethanol ingestion was significantly reduced in ovariectomized female rats receiving estradiol (E2) and in ovariectomized female rats receiving combined E2 and progesterone replacement therapy. However, neither ovariectomy nor progesterone replacement in ovariectomized rats resulted in ethanol drinking patterns that were different compared to those observed in intact female controls. Thus, dihydrotestosterone and E2, respectively, appear to exert modulatory influences on the male and female rats' preference for ethanol, but further investigations are necessary to determine to what extent these effects result from activational actions on the brain.