Electroacupuncture alleviates affective pain in an inflammatory pain rat model

Pain has both sensory–discriminative and emotional–affective dimensions. Previous studies demonstrate that electroacupuncture (EA) alleviates the sensory dimension but do not address the affective. An inflammatory pain rat model, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a conditioned place avoidance (CPA) test to determine whether EA inhibits spontaneous pain‐induced affective response and, if so, to study the possibility that rostral anterior cingulate cortex (rACC) opioids underlie this effect. Male Sprague–Dawley rats (250–275 g, Harlan) were used. The rats showed place aversion (i.e. affective pain) by spending less time in a pain‐paired compartment after conditioning than during a preconditioning test. Systemic non‐analgesic morphine (0.5 and 1.0 mg/kg, i.p.) inhibited the affective reaction, suggesting that the affective dimension is underpinned by mechanisms different from those of the sensory dimension of pain. Morphine at 0.5 and at 1 mg/kg did not induce reward. Rats given EA treatment before pain‐paired conditioning at GB 30 showed no aversion to the pain‐paired compartment, indicating that EA inhibited the affective dimension. EA treatment did not produce reward or aversive effect. Intra‐rACC administration of D‐Phe‐Cys‐Tyr‐D‐Trp‐Orn‐Thr‐Pen‐Thr amide (CTOP), a selective mu opioid receptor antagonist, but not norbinaltorphimine (nor‐BNI), a selective kappa opioid receptor antagonist, blocked EA inhibition of the affective dimension. These data demonstrate that EA activates opioid receptors in the rACC to inhibit pain‐induced affective responses and that EA may be an effective therapy for both the sensory–discriminative and the affective dimensions of pain.     

Social stress exacerbates the aversion to painful experiences in rats exposed to chronic pain: The role of the locus coeruleus

Stressful experiences seem to negatively influence pain perception through as yet unknown mechanisms. As the noradrenergic locus coeruleus (LC) nucleus coordinates many components of the stress response, as well as nociceptive transmission, we evaluated whether the sensory and affective dimension of chronic neuropathic pain worsens in situations of stress due to adaptive changes of LC neurons. Accordingly, male rats were socially isolated for 5 weeks, and in the last 2 weeks, neuropathic pain was induced by chronic constriction injury. In this situation of stress, chronic pain selectively heightened the animal’s aversion to painful experiences (affective pain), as measured in the place escape/avoidance test, although no changes were observed in the sensory dimension of pain. In addition, electrophysiological recordings of LC neurons showed a low tonic but exacerbated nociceptive-evoked activity when the injured paw was stimulated. These changes were accompanied by an increase in tyrosine hydroxylase and gephyrin expression in the LC. Furthermore, intra-LC administration of bicuculline, a γ-aminobutyric acid-A receptor antagonist, attenuated the negative affective effects of pain. These data show that changes in the LC are greater than those expected from the simple summation of each independent factor (pain and stress), revealing mechanisms through which stressors may exacerbate pain perception without affecting the sensorial dimension.     

Differential effects of morphine on the affective and the sensory component of carrageenan-induced nociception in the rat

Pain is generally considered to have a sensory and an affective component. Clinical research has suggested that morphine more potently attenuates the affective component as compared to the sensory component. Because preclinical nociception models typically focus on the sensory component of nociception, and do not assess the affective component, it is unclear whether this potency difference of morphine can also be found in preclinical models. We therefore adapted the place conditioning paradigm to investigate negative affect accompanying carrageenan-induced (0.5% intraplantar) inflammatory nociception in rats. We found that carrageenan produced clear conditioned place aversion (CPA). Morphine (0.01-10mg/kg i.p.) dose-dependently reduced carrageenan-induced CPA with a minimal effective dose (MED) of 0.03mg/kg. Since morphine has a rewarding effect by itself, morphine-induced conditioned place preference (CPP) was also investigated. Morphine induced CPP with a MED of 1mg/kg, suggesting that the rewarding effect of morphine was not responsible for reducing carrageenan-induced CPA. We also demonstrated that morphine reduced carrageenan-induced mechanical nociception as assessed in the Randall Selitto paradigm with a MED of 1mg/kg. It is concluded that the CPA model allows for an assessment of the negative affective component of carrageenan-induced nociception. Moreover, morphine was able to reduce the affective component of nociception at doses that did not affect the sensory component of nociception, and this effect was not due to its rewarding properties. The fact that this finding mirrors the clinical situation validates the use of the CPA model for assessing the affective component of nociception.     

Affective associative learning modifies the sensory perception of nociceptive stimuli without participant's awareness

The present experiment examined the possibility to change the sensory and/or the affective perception of thermal stimuli by an emotional associative learning procedure known to operate without participants' awareness (evaluative conditioning). In a mixed design, an aversive conditioning procedure was compared between subjects to an appetitive conditioning procedure. Both groups were also compared within-subject to a control condition (neutral conditioning). The aversive conditioning was induced by associating non-painful and painful thermal stimuli - delivered on the right forearm - with unpleasant slides. The appetitive conditioning consisted in an association between thermal stimuli - also delivered on the right forearm - and pleasant slides. The control condition consisted in an association between thermal stimuli - delivered for all participants on the left forearm - and neutral slides. The effects of the conditioning procedures on the sensory and affective dimensions were evaluated with visual analogue scale (VAS)-intensity and VAS-unpleasantness. Startle reflex was used as a physiological index of emotional valence disposition. Results confirmed that no participants were aware of the conditioning procedure. After unpleasant slides (aversive conditioning), non-painful and painful thermal stimuli were judged more intense and more unpleasant than when preceded by neutral slides (control condition) or pleasant slides (appetitive conditioning). Despite a strong correlation between the intensity and the unpleasantness scales, effects were weaker for the affective scale and, became statistically non-significant when VAS-intensity was used as covariate. This experiment shows that it is possible to modify the perception of intensity of thermal stimuli by a non-conscious learning procedure based on the transfer of the valence of the unconditioned stimuli (pleasant or unpleasant slides) towards the conditioned stimuli (non-painful and painful thermal stimuli). These results plead for a conception of pain as a conscious output of complex informational processes all of which are not accessible to participants' awareness. Mechanisms by which affective input may influence sensory experience and clinical implications of the present study are discussed.     

Dissociation of rewarding,anti‐aversive and anti‐nociceptive effects of different classes of anti‐nociceptives in the rat

It was previously shown that morphine more potently reduces the affective as compared to the sensory component of nociception, and this effect is independent of morphine's rewarding properties. Here we investigated whether this finding can be generalized to other classes of anti‐nociceptive drugs. The effect of oxycodone (0–10 mg/kg, i.p.), tramadol (0–10 mg/kg, i.p.), ibuprofen (0–300 mg/kg, i.p.) and pregabalin (0–31.6 mg/kg, i.p.) on negative affect and mechanical hypersensitivity accompanying carrageenan‐induced (0.5% intraplantar) inflammatory nociception was assessed using conditioned place aversion (CPA) and Randall Selitto paw pressure test, respectively. The rewarding effect of these drugs was assessed using conditioned place preference (CPP). All four anti‐nociceptive drugs dose‐dependently reduced carrageenan‐induced CPA and mechanical hypersensitivity. Furthermore all drugs induced CPP, except for ibuprofen. Similar to morphine, oxycodone and tramadol showed a large dissociation of anti‐aversive versus anti‐nociceptive potency, i.e. 10 times more potent against the affective versus the sensory component of nociception. Oxycodone and tramadol were 30 and 10 times more potent to produce CPP in animals under normal versus painful conditions. Ibuprofen and pregabalin also showed a dissociation of anti‐aversive and anti‐nociceptive potency, but less pronounced (i.e. three times more potent against the affective component). However, pregabalin showed no dissociation between rewarding potency under normal versus painful conditions. Taken together, these data suggest that the dissociation of rewarding potency in animals under normal versus painful conditions is limited to drugs with an opioid mechanism of action, while the dissociation of anti‐aversive and anti‐nociceptive potency applies to anti‐nociceptive drugs with different mechanisms of action.     

Influence of pain reduction by transcutaneous electrical nerve stimulation (TENS) on somatosensory functions in patients with painful traumatic peripheral partial nerve injury

Following peripheral nerve injury sensory loss is taken as a sign of denervation. However, based on reports of improved sensitivity following relief of pain it has been suggested that a functional block produced by the activity in the nociceptive system itself may be responsible for at least part of the sensory aberrations. The aim was to examine if pain reduction by high‐frequency TENS influenced somatosensory functions in patients with long‐term unilateral painful traumatic peripheral partial nerve injury. Eighteen patients with spontaneous ongoing pain and a touch sensation in the innervation territory of the injured nervous structure of at least 5 on an intensity 11‐point Likert rating scale compared with contralaterally, participated. Before and following 80 Hz TENS with a stimulus intensity generating non‐painful paresthesiae in the painful areas during 30 min the pain intensity was rated on a numerical rating scale and bedside examination of somatosensory functions (BE) and quantitative sensory testing (QST) were performed in the same areas. Before and following TENS there was no difference in sensory functions between nine patients with ≥50% pain reduction and nine patients with a smaller or no reduction in pain. Compared to baseline, only minor TENS‐induced alterations in somatosensory functions were found at BE in conjunction with decreased sensitivity to light touch at QST (p < 0.01) in both groups alike. In conclusion ≥50% pain reduction by TENS did not alter sensory functions differentially compared to a smaller or no reduction in pain.     

Short-term restoration of facial sensory loss by motor cortex stimulation in peripheral post-traumatic neuropathic pain

We report a case in which motor cortex stimulation (MCS) improved neuropathic facial pain due to peripheral nerve injury and restored tactile and thermal sensory loss. A 66-year-old man developed intractable trigeminal neuropathic pain after trauma of the supraorbital branch of the Vth nerve, associated with tactile and thermal sensory loss in the painful area. MCS was performed using neuronavigation and transdural electric stimulation to localize the upper facial area on the motor cortex. One month after surgery, pain was decreased from 80/100 to 20/100 on visual analogic scale, and sensory discrimination improved in the painful area. Two months after surgery, quantitative sensory testing confirmed the normalization of thermal detection thresholds. This case showed that MCS could restore tactile and thermal sensory loss, resulting from peripheral nerve injury. Although the mechanisms leading to this effect remain unclear, this observation enhanced the hypothesis that MCS acts through modulation of the sensory processing.     

How the number of learning trials affects placebo and nocebo responses

Conditioning procedures are used in many placebo studies because evidence suggests that conditioning-related placebo responses are usually more robust than those induced by verbal suggestions alone. However, it has not been shown whether there is a causal relation between the number of conditioning trials and the resistance to extinction of placebo and nocebo responses. Here we test the effects of either one or four sessions of conditioning on the modulation of both non-painful and painful stimuli delivered to the dorsum of the foot. Placebo and nocebo manipulations were obtained by pairing green or red light to a series of stimuli that were made lower or higher with respect to a yellow light associated with a series of control stimuli. Subjects were told that the lights would indicate a treatment that would reduce or increase non-painful and painful stimuli to the foot. They were randomly assigned to either Group 1 or 2. Group 1 underwent one session of conditioning and Group 2 received four sessions of conditioning. We found that one session of conditioning (Group 1) induced nocebo responses, but not placebo responses in no pain condition. After one session of conditioning, we observed both nocebo and placebo responses to painful stimulation. However, these effects extinguished over time. Conversely, four sessions of conditioning (Group 2) induced robust placebo and nocebo responses to both non-painful and painful stimuli that persisted over the entire experiment. These findings suggest that the strength of learning may be clinically important for producing long-lasting placebo effects.     

Long‐term depression of pain‐related cerebral activation in healthy man: An fMRI study

Electrical low‐frequency stimulation (LFS) of cutaneous afferents reliably induces long‐term depression (LTD) of nociception and pain in man. In this study LFS effects on cerebral activation were investigated by functional magnetic resonance imaging (fMRI). In 17 healthy volunteers, nociceptive fibers of right hand dorsum were electrically stimulated via a concentric electrode. Test stimulation sessions consisted of three alternating stimulation periods and rest periods. They were performed before (Pre) and after (Post) conditioning LFS (1200 stimuli, 1 Hz) or 20 min break (Control). Volunteers rated sensory and affective pain perception. Before LFS, test stimulation produced activation in bilateral primary and secondary somatosensory cortex (S1, S2), insula, anterior cingulate cortex (ACC), superior temporal cortex (STG), prefrontal cortex and right inferior parietal lobule (IPL). After LFS, exclusively right IPL was activated. Contrast between Pre and Post LFS indicated significant activity decrease in bilateral S1, S2, and ACC and right insula, IPL, and STG. Pre Control and Pre LFS were not different. Activity in Control experiments remained unchanged. Sensory and affective pain rating solely decreased after LFS. Subsequent regression analysis showed significant correlation between pain relief and increased activity after LFS in ACC, anterior insula, striatum, frontal and temporal cortex. The study revealed LTD of pain‐related cerebral activation, involving sensory, affective, cognitive, and attentional processes. Positive correlation between pain relief and increased brain activation after LFS may indicate involvement of endogenous pain control mechanisms in LTD. These experiments may help to judge the potency of LTD for future chronic pain treatment.     

Sensory and affective dimensions of phasic pain are indistinguishable in the self-report and psychophysiology of normal laboratory subjects.

This study evaluated the discriminant validity of subjects differentially scaling the sensory and affective dimensions of pain. It sought to determine (1) whether subjects can differentially scale sensory and affective aspects of phasic laboratory pain in the absence of task demand bias that fosters apparent differential scaling; (2) whether psychophysiologic responses to painful stimuli can predict pain report (PR); and (3) whether such responses contribute more to affective than to sensory judgments. Fifty-six men and 44 women repeatedly experienced varied painful electrical fingertip stimuli at low, medium, and high intensities. On half of the trial blocks, subjects made sensory judgments; on the remainder they made affective judgments. Response measures included PR, pupil dilation, heart rate, respiration rate, skin conductance response (SCR), and late near field evoked potentials. Subjects did not rate the stimuli differently when making sensory versus affective judgments. The psychophysiologic variables, principally the SCR, accounted for 44% of the variance in the PR. Psychophysiologic response patterns did not differentiate affective and sensory judgment conditions. Noteworthy sources of individual differences included baseline PR levels and the linear effects of SCR on PR.     

Sensory,Affective, and Catastrophizing Reactions to Multiple Stimulus Modalities: Results from the Oklahoma Study of Native American Pain Risk

Native Americans (NAs) have a higher prevalence of chronic pain than any other U.S. racial/ethnic group; however, little is known about the mechanisms for this pain disparity. This study used quantitative sensory testing to assess pain experience in healthy, pain-free adults (n = 137 NAs (87 female), n = 145 non-Hispanic whites (NHW; 68 female)) after painful electric, heat, cold, ischemic, and pressure stimuli. After each stimulus, ratings of pain intensity, sensory pain, affective pain, pain-related anxiety, and situation-specific pain catastrophizing were assessed. The results suggested that NAs reported greater sensory pain in response to suprathreshold electric and heat stimuli, greater pain-related anxiety to heat and ischemic stimuli, and more catastrophic thoughts in response to electric and heat stimuli. Sex differences were also noted; however, with the exception of catastrophic thoughts to cold, these finding were not moderated by race/ethnicity. Together, findings suggest NAs experience heightened sensory, anxiety, and catastrophizing reactions to painful stimuli. This could place NAs at risk for future chronic pain and could ultimately lead to a vicious cycle that maintains pain (eg, pain → anxiety/catastrophizing → pain).PerspectiveNAs experienced heightened sensory, anxiety, and catastrophizing reactions in response to multiple pain stimuli. Given the potential for anxiety and catastrophic thoughts to amplify pain, this characteristic may place them at risk for pain disorders and could lead to a vicious cycle that maintains pain.     

Painful traumatic peripheral partial nerve injury‐sensory dysfunction profiles comparing outcomes of bedside examination and quantitative sensory testing

The primary aim of this retrospective study was to focusing on the relationship between individual outcomes of bedside examination (BE) and quantitative testing of somatosensory functions (QST) in 32 patients with painful traumatic partial nerve injury. In addition, the potential presence of common sensory dysfunction denominators has been probed. Patients with a history of traumatic partial nerve injury and ongoing pain were included if pain was confined to the entire or part of the innervation territory of the severed nerve and a bedside titration of the neuronanatomical borders confirmed sensory aberrations. An in‐depth BE and QST was then performed in the most painful area. Categorization of normal and pathological outcome for both BE and QST was based on time honoured clinical decision‐making using the healthy contralateral corresponding area as control. In patients with normal outcome or quantitative aberrations (i.e. hypo‐ or hyperesthesia) at BE and QST, the same individual outcome of touch sensation was reported by 48% of the patients, for cold in 54% and for warmth in 58%. The most common dysfunction found at both BE and QST was hypoesthesia, however with no common denominators in somatosensory dysfunction. In conclusion, this study demonstrated that not infrequently the individual outcome of BE and the corresponding QST measure differed, most frequently for touch sensibility. This finding is of outmost importance when QST outcomes are used to corroborate results from BE in the diagnostic situation.     

Contributions of the anterior cingulate cortex and amygdala to pain- and fear-conditioned place avoidance in rats

The pain experience includes a sensory-discriminative and an affective-emotional component. The sensory component of pain has been extensively studied, while data about the negative affective component of pain are quite limited. The anterior cingulate cortex (ACC), and amygdala are thought to be key neural substrates underlying emotional responses. Using formalin-induced conditioned place avoidance (F-CPA) and electric foot-shock conditioned place avoidance (S-CPA) models, the present study observed the effects of bilateral excitotoxic (quinolinic acid 200 nmol/microl) lesions of the ACC and amygdala on pain and fear induced negative emotion, as well as on sensory component of pain. In the place-conditioning paradigm, both intraplantar (i.pl.) injection of formalin and electric foot-shock produced conditioned place avoidance. Excitotoxin-induced lesion of either the ACC or amygdala significantly reduced the magnitude of F-CPA. However, the decrease in the magnitude of S-CPA occurred only in the amygdala, but not ACC lesioned animals. Neither ACC nor amygdala lesion significantly changed formalin-induced acute nociceptive behaviors. These results suggest that the amygdala is involved in both pain- and fear-related negative emotion, and the ACC might play a critical role in the expression of pain-related negative emotion.     

Inhibitory effects do not depend on the subjective experience of pain during heterotopic noxious conditioning stimulation (HNCS): a contribution to the psychophysics of pain inhibition.

Heterotopic noxious conditioning stimulation (HNCS) has been thought to give access to the diffuse noxious inhibitory controls (DNIC) in man, which can be activated in wide-dynamic-range neurons by noxious stimulation from remote areas of the body and form the neurophysiological basis of the phenomenon 'pain inhibits pain'. The latter phenomenon suggests that the subjective experience of pain is a prerequisite for an inhibitory action. The necessity of using painful stimuli as conditioning and as test stimuli to produce inhibitory effects was investigated in the present study, using a HNCS paradigm. Twenty young men received conditioning stimuli created by tonic heat at painful and non-painful levels, using either hot water (hand) or thermode (forearm). The test stimuli were phasic heat stimuli (thermode) at painful and non-painful levels applied to the cheek. Only painful but not non-painful heat as conditioning stimulus increased the heat pain threshold and decreased the ability to discriminate between painful heat of different intensities. These two findings are in accord with an inhibitory effect depending on a painful conditioning stimulus. However, the intensity ratings of the test stimuli indicated inhibitory effects of the conditioning stimuli also upon non-painful levels. Furthermore, non-painful heat as conditioning stimulus also appeared to be capable of decreasing the ratings of the test stimuli at painful levels. The latter two findings suggest: (i) that very strong but subjectively still non-painful stimulation can trigger pain inhibitory effects and (ii) that also subjectively non-painful stimuli are affected by inhibitory influences during HNCS.     

NMDA NR2A and NR2B receptors in the rostral anterior cingulate cortex contribute to pain-related aversion in male rats

NMDA receptors, which are implicated in pain processing, are highly expressed in forebrain areas including the anterior cingulate cortex (ACC). The ACC has been implicated in the affective response to noxious stimuli. Using a combination of immunohistochemical staining, Western blot, electrophysiological recording and formalin-induced conditioned place avoidance (F-CPA) rat behavioral model that directly reflects the affective component of pain, the present study examined formalin nociceptive conditioning-induced changes in the expressions of NMDA receptor subunits NR1, NR2A, and NR2B in the rostral ACC (rACC) and its possible functional significance. We found that unilateral intraplantar (i.pl.) injection of dilute formalin with or without contextual conditioning exposure markedly increased the expressions of NMDA receptor subunits NR2A and NR2B but not of NR1 in the bilateral rACC. NMDA-evoked currents in rACC neurons were significantly greater in formalin-injected rats than in naïve or normal saline-injected rats. Selectively blocking either NR2A or NR2B subunit in the rACC abolished the acquisition of F-CPA and formalin nociceptive conditioning-induced Fos expression, but it did not affect formalin acute nociceptive behaviors and non-nociceptive fear stimulus-induced CPA. These results suggest that both NMDA receptor subunits NR2A and NR2B in the rACC are critically involved in pain-related aversion. Thus, a new strategy targeted at NMDA NR2A or NR2B subunit might be raised for the prevention of pain-related emotional disturbance.     

Electrical low‐frequency stimulation induces long‐term depression of sensory and affective components of pain in healthy man

Electrical low‐frequency stimulation (LFS) of nociceptive skin afferents reliably induces long‐term depression (LTD) of pain. Recent experiments have assessed the effects of LTD on pain perception by using a simple one‐dimensional rating scale. The psychophysical study investigated the impact of noxious LFS on the sensory and affective aspects of pain perception by multidimensional rating scales. In 20 healthy volunteers, nociceptive fibers of the left hand dorsum were electrically stimulated by a concentric electrode. Test stimulation series (15 stimuli each, 0.125Hz) were performed before (Pre) and after (Post) a conditioning LFS (1Hz, 20min) or no stimulation period (Control). Pain ratings concerning test stimulation and LFS were obtained by multidimensional assessment including Verbal rating scale of perceived stimulus intensity (VRS‐I) and unpleasantness (VRS‐U) and pain perception scale with sensory (SES‐S) and affective items (SES‐A). After the conditioning LFS, VRS‐I, VRS‐U, SES‐S, and SES‐A decreased as compared to Pre series and Control. During conditioning LFS, ratings decreased. Factor analysis of SES‐S revealed sole reduction of superficial sharp pain perception after conditioning LFS in contrast to Control experiment. Perception of deep rhythmic pain decreased over time. Deep constant pain and superficial heat pain were not affected. Electrical test stimulation via concentric electrode evokes sensory as well as affective pain perception. Both components decrease during noxious, conditioning LFS and remain depressed for at least one hour. Reduction of sharp pain points to Aδ fiber mediated LTD. These results stress the analgesic potency of LTD and its possible impact on future therapy in chronic pain.     

Preterm births: Can neonatal pain alter the development of endogenous gating systems?

Prematurity is known to affect the development of various neurophysiological systems, including the maturation of pain and cardiac circuits. The purpose of this study was to see if numerous painful interventions, experienced soon after birth, affect counterirritation-induced analgesia (triggered using the cold pressor test) later in life. A total of 26 children, between the ages of 7 and 11 participated in the study. Children were divided into three groups, according to their birth status (i.e., term-born, born preterm and exposed to numerous painful interventions, or born preterm and exposed to few painful interventions). Primary outcome measures were heat pain thresholds, heat sensitivity scores, and cardiac reactivity. Results showed that preterm children and term-born children had comparable pain thresholds. Exposure to conditioning cold stimulation significantly increased heart rate and significantly decreased the thermal pain sensitivity of term-born children. These physiological reactions were also observed among preterm children who were only exposed to a few painful interventions at birth. Changes in heart rate and pain sensitivity in response to conditioning cold stimulation were not observed in preterm children that had been exposed to numerous painful procedures during the neonatal period. These results suggest that early pain does not lead to enhanced pain sensitivity when premature babies become children, but that their endogenous pain modulatory mechanisms are not as well developed as those of children not exposed to noxious insult at birth. Greater frequency of painful procedures also dampened the rise in heart rate normally observed when experimental pain is experienced.     

Sudden amnesia resulting in pain relief: the relationship between memory and pain

Nociceptive pain and its emotional component can result in the development of a "chronic pain memory". This report describes two patients who had long histories of chronic pain and opioid dependence. Both patients experienced sudden memory loss that was followed by significant pain reduction and an eradication of their need for opioid management. Neural centers involved in sensory pain, its affective component, opioid dependence, and memory overlap in the brain and share common pathways. The anterior cingulate cortex, the insular cortex, and the amygdala are examples of regions implicated in both pain and memory. One of the patients in the report experienced multiple seizure episodes, which may have contributed to memory loss and pain relief. The role of electroconvulsive therapy as it relates to amnesia and pain is reviewed. Questions are raised regarding whether therapies that address the memory component of pain may have a role in the treatment of long-term chronic pain patients.     

High-efficacy 5-hydroxytryptamine 1A receptor activation counteracts opioid hyperallodynia and affective conditioning

Pain may become intractable as tolerance develops to opioids and the opioids, paradoxically, induce pain. We examined the hypothesis that the analgesia produced by the novel analgesic and high-efficacy 5-hydroxytryptamine (5-HT)(1A) receptor agonist (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]methyl]piperidin-1-yl]methanone, fumaric acid salt (F 13640) may counteract opioid-induced pain. In studies of the somatosensory quality of pain in infraorbital nerve-injured rats, morphine infusion (5 mg/day) by means of osmotic pumps initially caused analgesia (i.e., decreased the behavioral response to von Frey filament stimulation), followed by hyperallodynia and analgesic tolerance. Infusion of F 13640 (0.63 mg/day) prevented the development of opioid hyperallodynia and reversed opioid hyperallodynia once established. In studies of the affective/motivational quality of pain, F 13640 both prevented and reversed the conditioned place aversion induced by naloxone (0.04 mg/kg i.p.) in morphine-infused rats; F 13640 also prevented and reversed the conditioned place preference induced by morphine injections (7.5 mg/kg i.p.). The data confirm that opioids produce bidirectional hypo- and proalgesic actions, and offer initial evidence that high-efficacy 5-HT(1A) receptor activation counteracts both the sensory and the affective/motivational qualities of opioid-induced pain. The data also indicate that F 13640 may be effective with opioid-resistant pain. It further is suggested that opioid addiction may represent self-therapy of opioid-induced pathological pain.     

Sex differences in endogenous pain modulation by distracting and painful conditioning stimulation

Sex differences in endogenous pain modulation were tested in healthy volunteers (32 men, 30 women). Painful contact heat stimuli were delivered to the right leg alone, and then in combination with various electrical conditioning stimuli delivered to the left forearm. Four conditioning protocols were applied to each subject in separate sessions: mild, non-painful (control); distracting; stressful-yet-non-painful; strongly painful. Thermal stimuli were rated on visual analog scales for pain intensity (INT) and unpleasantness (UNP). Distracting and painful conditioning stimuli significantly reduced heat pain INT and UNP ratings for both sexes, with significantly larger distraction effects on INT ratings for men than women (p=0.004). No sex differences in pain-evoked hypoalgesia were detected (p>0.05). The stress protocol did not consistently reduce heat pain ratings, possibly because the protocol was not sufficiently stressful to activate endogenous modulatory systems. Regression analysis revealed that the magnitude of pain-evoked hypoalgesia was predicted by the perceived distraction (p=0.003) and stress (p=0.04) produced by the painful conditioning stimulation, providing evidence that distraction and stress contribute to pain-evoked hypoalgesia. However, the contribution of stress to pain-evoked hypoalgesia differed by sex (p=0.02), with greater perceived stress associated with greater hypoalgesia in men and the opposite trend in women, suggesting sex differences in the mechanisms underlying pain-evoked hypoalgesia. This study provides indirect evidence that multiple neural mechanisms are involved in endogenous pain modulation and suggests that sex-specific aspects of these systems may contribute to greater pain sensitivity and higher prevalence of many chronic pain conditions among women.