PAIN®

Editorial list (must be on a RH page)

2010-04-01

Respiration-induced hypoalgesia: Additional evidence for pain modulation deficits in fibromyalgia?

Jamie L. Rhudy — 2010-02-01

Fibromyalgia (FM) is a debilitating syndrome associated with widespread musculoskeletal pain and hyperalgesia. While the pathogenesis of FM is currently unknown, several of lines of evidence point to augmented central nervous system processing of pain signals , perhaps stemming from a failure of central modulatory processes in regulating the afferent message .

Pain – Not just a feeling, but a working brain

Jürgen Lorenz — 2010-02-15

What determines pain? The multi-dimensional and, more recently, the anatomical view of pain as derived from brain imaging studies, has attracted many researchers. Melzack and Casey formulated the theory of sensory-discriminative and affective-motivational determinants of pain. However, this paper only loosely linked the cognitive and behavioral consequences of pain to the term “motivational” to indicate the engagement of escape and avoidance behavior during noxious stimulation. Later, Casey and Lorenz revised the concept and included “motivational dominance” as a unique and critical dimension of pain together with “sensory salience” and “affect”. They argued that motivational dominance of pain can be separately identified and measured by interference paradigms. These paradigms are based on the observation that pain and mental tasks compete for attention, the latter intrinsically characterized by its limited resources.

Commentary: A burning question of subgroup analysis in pain trials

Jennifer Gibbs — 2010-02-10

Burning mouth syndrome (BMS) is characterized by continuous superficial pain, often burning in nature. The primary manifestation is in the tongue but BMS may involve other intraoral structures. Several lines of evidence suggest that peripheral and central pain mechanisms contribute to this condition. A contribution of the peripheral nervous system is suggested by the observation of abnormal mucosal innervation in BMS patients with fewer epithelial nerve fibers, and greater numbers of TRPV1 expressing fibers in the epithelium . Alterations of the thermal and gustatory thresholds are also observed in the tongue of BMS patients . Contributions of central nervous system dysfunction are supported by the observation of altered blink reflex in BMS patients compared to normal control patients . Furthermore, studies using PET scan demonstrate lower levels of dopamine in the putamen and decreased striatal FDOPA uptake in the putamen in BMS patients . In this issue of Pain, Grémeau-Richard and colleagues explore the contribution of peripheral afferents to BMS by evaluating the effect of local anesthetic block of the lingual nerve on pain using a double- blind cross-over randomized controlled design .

A cure for back pain?

Nikolai Bogduk — 2010-02-03

In esteemed disciplines of science, such as physics, truth is not defined by a single publication. If a laboratory announces a new discovery, it is standard practice for other laboratories to promptly replicate the study, in order to confirm or refute its observations. The discovery does not become fact until at least one other laboratory confirms the observations, but preferably there should be multiple, independent confirmations. This principle should apply to the results reported by Peng et al. in this issue .

Social interaction in pain: Reinforcing pain behaviors or building intimacy?

Annmarie Cano, Amanda C. de C. Williams — 2009-11-05

To date, pain research has focused almost exclusively on operant models to interpret the function and predict the consequences of pain-related interaction in chronic pain couples. However, evidence suggests that intimacy models of interaction may provide additional and alternative explanations for pain interaction. Specifically, intimacy models conceptualize some verbal expressions of pain-related distress as emotional disclosure, which the partner may validate or invalidate. This review compares and contrasts models of interaction in chronic pain couples, describes limitations of the existing research, and offers directions for future research. Although models of pain empathy suggest that facial expressions and other nonverbal behaviors convey important information concerning pain and other emotions , we focus this review on verbal communications for two reasons. First, it is not known whether nonverbal behavior can be understood using an intimacy framework. Second, others’ interpretations of nonverbal behaviors are affected by accompanying verbal communication .

The effects of slow breathing on affective responses to pain stimuli: An experimental study

Alex J. Zautra, Robert Fasman, Mary C. Davis, Arthur D. (Bud) Craig — 2010-01-15

Abstract: This study examined whether breathing rate affected self-reported pain and emotion following thermal pain stimuli in women with fibromyalgia syndrome (FM: n=27) or age-matched healthy control women (HC: n=25). FM and HC were exposed to low and moderate thermal pain pulses during paced breathing at their normal rate and one-half their normal rate. Thermal pain pulses were presented in four blocks of four trials. Each block included exposure to both mild and moderate pain trials, and periods of both normal and slow paced breathing. Pain intensity and unpleasantness were recorded immediately following each pain trial, and positive and negative affect were assessed at the end of each block of trials. Compared to normal breathing, slow breathing reduced ratings of pain intensity and unpleasantness, particularly for moderately versus mildly painful thermal stimuli. The effects of slow breathing on pain ratings were less reliable for FM patients than for HCs. Slow versus normal breathing decreased negative affect ratings following thermal pain pulses for both groups, and increased positive affect reports, but only for healthy controls with high trait negative affect. Participants who reported higher levels of trait positive affect prior to the experiment showed greater decreases in negative affect as a result of slow versus normal breathing. These experimental findings provide support for prior reports on the benefits of yogic breathing and mindful Zen meditation for pain and depressed affect. However, chronic pain patients may require more guidance to obtain therapeutic benefit from reduced breathing rates.

Performance-dependent inhibition of pain by an executive working memory task

Jason Buhle, Tor D. Wager — 2010-02-03

Abstract: It is widely assumed that distraction reduces pain. Similarly, it is assumed that pain distracts from concurrent, unrelated cognitive processing, reducing performance on difficult tasks. Taken together, these assumptions suggest pain processing and cognitive function engage an overlapping set of domain-general, capacity-limited mental resources. However, experimental tests of this proposal have yielded mixed results, leading to alternative proposals that challenge the common model of a bidirectional relationship between concurrent pain and task performance. We tested these contrasting positions using a novel concurrent pain and executive working memory paradigm. Both task difficulty and nociceptive stimulus intensity were individually calibrated for each participant. Participants reported less pain during the working memory task than a visually matched control condition. Conversely, increasing levels of heat incrementally reduced task performance. Path analyses showed that variations in pain completely mediated this effect, and that even within a given heat level, trial-by-trial fluctuations in pain predicted decrements in performance. In sum, these findings argue that overlapping cognitive resources play a role in both pain processing and executive working memory. Future studies could use this paradigm to understand more precisely which components of executive function or other cognitive resources contribute to the experience of pain.

Effect of lingual nerve block on burning mouth syndrome (stomatodynia): A randomized crossover trial

2010-01-18

Abstract: Burning mouth syndrome (stomatodynia) is associated with changes of a neuropathic nature the main location of which, peripheral or central, remains unknown. A randomised, double-blind crossover design was used to investigate the effects of lingual nerve block on spontaneous burning pain and a possible correlation with the effects of topical clonazepam, the patient’s response to a psychological questionnaire, and the taste and heat thresholds. The spontaneous burning was measured with a visual analogue scale (VAS) just before and 15min after injection. The decreases in VAS score after lidocaine or saline injection were not significantly different (2.7±3.9 and 2.0±2.6, respectively; n=20). However, two groups of patients could be identified: in a “peripheral group” (n=10) the VAS decrease due to lingual nerve injection was 4.3±3.1cm after lidocaine and 0.9±0.3cm after saline (p=0.02). In a “central group” (n=7), there were an increase in pain intensity score (−0.8±2.6cm) after lidocaine and a decrease (1.5±3.0cm) after saline (p=0.15). An increase in the hospital anxiety and depression (HAD) score and a decreased taste sensitivity and heat pain threshold of painful oral area were seen in patients compared with age-and-sex-matched controls (p<0.05). Topical clonazepam treatment tended to be more effective (p=0.07) and HAD score lower (p<0.03) in the peripheral than in the central group. These results suggest that the neuropathic disorder associated with stomatodynia may be predominantly peripheral, central or mixed depending on the individual. Topical application of clonazepam and HAD may serve as indicators of which mechanism is dominating.

Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain

2010-02-18

Abstract: Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for α4β2 or for α7 nAChRs were then tested in the formalin and complete Freund’s adjuvant models of pain. Nonselective nAChR agonists ABT-594 and varenicline were effective analgesics. By contrast, the selective α4β2 agonist ispronicline and a novel α4β2-selective potentiator did not appear to produce analgesia in either model. α7-selective agonists reduced the pain-related endpoint, but the effect could be ascribed to nonspecific reduction of movement rather than to analgesia. Neither selective nor nonselective α7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by α4β2 and only minimally by α7 subtypes. Taken with previous studies, the results suggest that agonism of α4β2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia.

Graded back pain revisited – Do latent variable models change our understanding of severe back pain in the general population?

Carsten Oliver Schmidt, Heiner Raspe, Thomas Kohlmann — 2010-02-25

Abstract: Back pain severity has extensively been targeted in clinical and epidemiologic studies. However, despite the importance of a valid pain severity grading its adequate conceptualization in the general population has received comparatively little attention. The potentially misleading influence of measurement error remains unclear. Latent variable models allow for a versatile assessment of disease severity and will be applied to propose a model-based grading of back pain. This cross-sectional postal survey was carried out in Germany between 2003 and 2004 to address back pain severity in the general adult population. 8756 subjects, aged 18–75years, provided data on measures of pain intensity and disability. Latent class analysis and confirmatory factor analysis were used to assess and compare categorical and dimensional representations of back pain severity. The results show that beyond differences in their location on a severity continuum, the subjects did not report markedly different pain intensity/disability profiles. Our analyses disconfirmed the presence of a sizeable high pain intensity, low disability subgroup. A comparison of the different latent variable models yielded a usable classification into five severity subtypes. This classification showed statistically significant and clinically important associations to health-related variables. Our results confirm the high burden of back pain in the general population but suggest a different categorization of those with severe back pain. This entails consequences on how to best target this important health problem from a public health perspective.

Hypoalgesia related to elevated resting blood pressure is absent in adolescents and young adults with a history of functional abdominal pain

Stephen Bruehl, Christine M. Dengler-Crish, Craig A. Smith, Lynn S. Walker — 2010-02-01

Abstract: Elevated resting blood pressure (BP) is hypoalgesic in healthy individuals, but this effect is absent in adults with chronic somatic pain. This study tested whether BP-related hypoalgesia is similarly altered in individuals with a history of chronic visceral pain in childhood. Resting BP was assessed in 94 adolescents and young adults with a known history of childhood functional abdominal pain (FAP) and 55 comparable healthy controls. Responses to an acute heat pain stimulus were then evaluated following exposure to two laboratory stressors. A significant participant type×systolic BP (SBP) interaction (p<.005) revealed that elevated resting SBP was associated with significantly higher heat pain threshold (p<.001) in healthy controls, but was unrelated to pain threshold in the FAP group. A similar pattern was observed for heat pain tolerance, with elevated SBP linked to significantly higher pain tolerance (p<.05) in healthy controls, but unrelated to tolerance in the FAP group. Dysfunction in BP-related hypoalgesia associated with FAP was evident regardless of whether childhood FAP had resolved or still persisted at the time of laboratory testing. Subgroup analyses indicated that BP-related hypoalgesia (in healthy controls) and FAP-linked absence of this hypoalgesia was observed only among females. Result suggest that childhood visceral chronic pain may be associated with relatively long-lasting dysfunction in overlapping systems modulating pain and BP that persists even after FAP resolves. Potential implications for later hypertension risk are discussed.

Ventromedial prefrontal neurokinin 1 receptor availability is reduced in chronic pain

2010-02-05

Abstract: Neurokinin 1 (NK1) receptors are involved in pain and anxiety behaviors in animals, but little is known about central alterations in this receptor system in human pain. With positron emission tomography, using a [11]-Carbon labeled NK1 receptor antagonist, we demonstrate attenuated NK1 receptor availability in frontal, insular and cingulate cortex, as well as the hippocampus, amygdala and the periaqueductal gray area in patients with chronic pain. The reduced availability was most pronounced in the ventromedial prefrontal cortex (vmPFC), where attenuations correlated to measures of fear and avoidance of movement. Further, vmPFC NK1 levels also displayed opposing influences in patients as compared to controls on regional cerebral blood flow in the anterior cingulate. We conclude that the central NK1 receptor system is altered in human chronic pain. The results suggest that NK1 receptors in the vmPFC modulate motor inhibition, and contribute to fear and avoidance of movement.

The human vasodilator axon reflex – An exclusively peripheral phenomenon?

Peter Groetzner, Christian Weidner — 2010-02-08

Abstract: The effect of regional anesthesia of the brachial plexus on the size and intensity of the histamine-induced axon reflex flare (neurogenic inflammation) of the forearm and the upper arm was compared to that of the contralateral arm as control in humans. No changes in the axon reflex could be assessed. Thus the lateral spread of the axon reflex flare must be transmitted by peripheral nerve branches not affected by the anesthesia in the axilla. This excludes the existence of physiologically relevant amounts of proximal branchpoints, DRG neurons with multiple peripheral axons or spinal interneurons transmitting action potentials between peripheral C-afferents involved in the axon reflex flare. Mechanoinsensitive C-fibres are known to be activated by histamine and to be responsible for the neuropeptide release in the skin inducing the axon reflex flare. Reports on those proximal connections can therefore obviously not extend to mechanoinsensitive C-fibres and do not explain the origin of neurogenic inflammation in humans without prior sensitization.

Reference values for quantitative sensory testing in children and adolescents: Developmental and gender differences of somatosensory perception

2010-02-08

Abstract: The Quantitative Sensory Testing (QST) protocol of the German research network on neuropathic pain (DFNS) encompassing all somatosensory modalities assesses the functioning of different nerve fibers and of central pathways. The aim of our study was: (1) to explore, whether this QST protocol is feasible for children, (2) to detect distribution properties of QST data and the impact of body site, age and gender and (3) to establish reference values for QST in children and adolescents. The QST protocol of the DFNS with modification of instructions and pain rating was used in 176 children aged 6.12–16.12years for six body sites. QST was feasible for children over 5years of age. ANOVAs revealed developmental, gender and body site differences of somatosensory functions similar to adults. The face was more sensitive than the hand and/or foot. Younger children (6–8years) were generally less sensitive to all thermal and mechanical detection stimuli but more sensitive to all pain stimuli than older (9–12years) children, whereas there were little differences between older children and adolescents (13–17years). Girls were more sensitive to thermal detection and pain stimuli, but not to mechanical detection and pain stimuli. Reference values differ from adults, but distribution properties (range, variance, and side differences) were similar and plausible for statistical factors. Our results demonstrate that the full QST protocol is feasible and valid for children over 5years of age with their own reference values.

Alteration of GABAergic and glycinergic mechanisms by lidocaine injection in the rostral ventromedial medulla of neuropathic rats

2010-02-16

Abstract: Attenuation of neuropathic manifestations in experimental animals, by lidocaine injection in the rostral ventro-medial medulla (RVM), has been traditionally attributed to selective block of a descending pain facilitatory system. However, the presence of descending fibers carrying this effect and the selective action of lidocaine on the facilitatory neurons, have not been supported by convincing experimental evidence. The present study aimed to investigate the mechanisms underlying the hypoalgesic action of lidocaine injection in the brainstem. Several groups of rats were subjected to mononeuropathy on their left hind paws, according to the model of spared nerve injury, and were subsequently implanted with guide cannulae in the RVM. After recovery, rats received injections of lidocaine, GABA and glycine agonists or antagonists and their effects were assessed on behavioral tests of allodynia and hyperalgesia. Injections of lidocaine at doses ranging between 0.05% and 2% produced attenuation at high doses and no effects or increasing hyperalgesia at low doses. GABA and glycine agonists increased neuropathic manifestations while their antagonists elicited the opposite effects. A combined injection of GABA agonist or glycine with lidocaine (0.5%) prevented the inhibitory effects of lidocaine injection alone. Our results are in line with the abundant documentation on the alteration of the function of inhibitory neurons by lidocaine and reveal a possible action of the injected high doses on the GABAergic and glycinergic neurons in the RVM. The resulting block of the inhibitory tone exerted by these neurons can lead to a release of the descending pain inhibitory systems.

NMDA-receptor activation and nitroxidative regulation of the glutamatergic pathway during nociceptive processing

2010-02-19

Abstract: The role of peroxynitrite (PN) as a mediator of nociceptive signaling is emerging. We recently reported that the development of central sensitization that follows the intraplantar injection of carrageenan in rats is associated with spinal PN synthesis. We now demonstrate that a significant pathway through which spinal PN modulates central sensitization is post-translational tyrosine nitration of key proteins involved in the glutamatergic pathway, namely glutamate transporter GLT-1 and glutamine synthetase (GS). We also reveal that spinal activation of the N-methyl-d-aspartate (NMDA) receptor provides a source of PN in this setting. Intraplantar injection of carrageenan led to the development of thermal hyperalgesia as well as nitration of GLT-1 and GS in dorsal horn tissues. Pretreatment with the PN decomposition catalyst FeTM-4-PyP5+ [Fe(III)5,10,15,20-tetrakis(N-methylpyridinium-4-yl)porphyrin] or the NMDA receptor antagonist MK-801 blocked the development of hyperalgesia. Carrageenan-induced hyperalgesia was also associated with nitration and inactivation of spinal mitochondrial superoxide dismutase (MnSOD) known to provide a critical source of PN during central sensitization. Nitration of GLT-1 and GS contributes to central sensitization by enhancing glutamatergic neurotransmission. Our results support the critical role of nitroxidative stress in the development of hyperalgesia and suggest that post-translational nitration of enzymes and transporters linked to glutamatergic neurotransmission represent a novel mechanism of central sensitization.

Cellular basis for opioid potentiation in the rostral ventromedial medulla of rats with persistent inflammatory nociception

Liang Zhang, Donna L. Hammond — 2010-02-22

Abstract: Direct inhibition of pain facilitatory neurons in the rostral ventromedial medulla (RVM) is one mechanism by which mu opioid receptor (MOPr) agonists are proposed to produce antinociception. The antinociceptive and anti-hyperalgesic effects of the MOPr agonist DAMGO are enhanced after intraplantar injection of complete Freund’s adjuvant (CFA). This study therefore examined whether CFA treatment similarly enhanced the ability of DAMGO to induce outward currents in spinally projecting RVM neurons. It further examined whether the electrophysiological properties of RVM neurons are altered by CFA treatment. Whole-cell patch clamp recordings were made from three types of serotonergic as well as non-serotonergic spinally projecting RVM neurons obtained from control rats and rats 4h or four days after CFA. Persistent, but not acute inflammatory nociception increased the percentage of Type 2 non-serotonergic neurons that responded to DAMGO from 17% to 57% and the percentage of Type 3 serotonergic neurons that responded to DAMGO from 5% to 55%. These same two populations of RVM neurons exhibited significant differences in their passive membrane properties or spontaneous discharge rate. The outward currents produced by the GABAB receptor agonist baclofen were not enhanced, suggesting that the enhancement does not reflect global changes in levels of Gi/o or activity of G-protein regulated inwardly rectifying potassium channels. These results provide a cellular basis for the enhanced anti-hyperalgesic and antinociceptive effects of MOPr agonists under conditions of persistent inflammatory nociception. These results also provide intriguing, albeit indirect, evidence for two different populations of pain facilitatory neurons in the RVM.

Low-dose amitriptyline for treatment of persistent arm pain due to repetitive use

2010-02-22

Abstract: Amitriptyline is sometimes used to treat arm pain related to repetitive use, but rigorous evidence of its benefit is lacking. This randomized controlled trial investigated whether amitriptyline provided greater pain relief or improved arm function than a placebo pill in adults with arm pain associated with repetitive use that had persisted for at least 3months. Participants (N=118) were randomly assigned to receive 25mg of amitriptyline or a placebo pill for 6weeks. The primary outcome was intensity of pain (10-point numerical rating scale) and secondary outcomes were arm symptoms, arm function, grip strength, mood, and sleep. Assessments were done at baseline, 3 and 6weeks of treatment, and 1month after the treatment ended. Changes in arm pain were not statistically significant. However, the amitriptyline group improved more than the placebo group in arm function (p=0.023) and sense of well being (p=0.034). In a longitudinal analysis, the amitriptyline group’s arm function score improved 0.45 points per week faster than placebo after adjusting for subject characteristics (p=0.015). At the treatment’s midpoint, the amitriptyline group reported more “troublesome side-effects” than the placebo group (52.5% vs. 27.1%, p=0.005), but this difference decreased by the end of the treatment (30.5% vs. 22.0%, p=0.30). The most frequent side effect was drowsiness. In conclusion, this study found that low-dose amitriptyline did not significantly decrease arm pain among these participants but did significantly improve arm function and well being. Future research is needed to explore the effects of higher doses and longer duration of treatment.

A randomized placebo-controlled trial of intradiscal methylene blue injection for the treatment of chronic discogenic low back pain

Baogan Peng, Xiaodong Pang, Ye Wu, Changcheng Zhao, Xinghua Song — 2010-02-19

Abstract: A preliminary report of clinical study revealed that chronic discogenic low back pain could be treated by intradiscal methylene blue (MB) injection. We investigated the effect of intradiscal MB injection for the treatment of chronic discogenic low back pain in a randomized placebo-controlled trial. We recruited 136 patients who were found potentially eligible after clinical examination and 72 became eligible after discography. All the patients had discogenic low back pain lasting longer than 6months, with no comorbidity. Thirty-six were allocated to intradiscal MB injection and 36 to placebo treatment. The principal criteria to judge the effectiveness included alleviation of pain, assessed by a 101-point numerical rating scale (NRS-101), and improvement in disability, as assessed with the Oswestry Disability Index (ODI) for functional recovery. At the 24-month follow-up, both the groups differed substantially with respect to the primary outcomes. The patients in MB injection group showed a mean reduction in pain measured by NRS of 52.50, a mean reduction in Oswestry disability scores of 35.58, and satisfaction rates of 91.6%, compared with 0.70%, 1.68%, and 14.3%, respectively, in placebo treatment group (p<0.001, p<0.001, and p<0.001, respectively). No adverse effects or complications were found in the group of patients treated with intradiscal MB injection. The current clinical trial indicates that the injection of methylene blue into the painful disc is a safe, effective and minimally invasive method for the treatment of intractable and incapacitating discogenic low back pain.

Sympathetic skin response following painful electrical stimulation is increased in major depression

2010-02-15

Abstract: Patients with major depressive disorder have repeatedly been described to exhibit increased thresholds upon experimentally applied pain stimuli to the skin as compared to respective controls. Since the sensory-discriminative component of stimulus perception, e.g. for warmth, cold and vibration, appears to be unaltered in depression, higher central nervous centres have been assumed to cause this phenomenon. To date, hardly any attention has been paid to the efferent components of the noxious reflex loop. Here, we aimed to assess the autonomic reaction upon a painful stimulus and to examine whether this is likewise reduced in major depression. For this purpose, sympathetic skin response was obtained from 22 patients with major depression and 20 matched controls. To induce sympathetic skin responses, we applied either noxious electrical stimuli (12 and 18mA) or innocuous acoustic stimuli (85dB SPL). Pain intensity was rated using a numeric analogue scale. In contrast to our a priori hypothesis patients showed shorter latencies and higher amplitudes of skin potentials upon noxious stimulation, i.e. a stronger sympathetic response. Intriguingly, the noxious stimuli were still perceived less painful in the patient group. Pain perception weakly correlated with disease severity. From these data, we conclude that despite the diminished pain perception, the autonomic reflex loop following noxious stimulation is not affected in patients with major depressive disorder, and that the increase in sympathetic outflow is not directly related to the perceived pain as in controls, but might rather be attributed to the autonomic dysfunction known for the disease.

Anti-GD2 with an FC point mutation reduces complement fixation and decreases antibody-induced allodynia

2010-02-22

Abstract: Monoclonal antibodies against GD2 ganglioside, such as ch14.18, the human–mouse chimeric antibody, have been shown to be effective for the treatment of neuroblastoma. However, treatment is associated with generalized, relatively opiate-resistant pain. We investigated if a point mutation in ch14.18 antibody (hu14.18K332A) to limit complement-dependent cytotoxicity (CDC) would ameliorate the pain behavior, while preserving antibody-dependent cellular cytotoxicity (ADCC). In vitro, CDC and ADCC were measured using europium-TDA assay. In vivo, allodynia was evaluated by measuring thresholds to von Frey filaments applied to the hindpaws after injection of either ch14.18 or hu14.18K332 into wild type rats or rats with deficient complement factor 6. Other rats were pretreated with complement factor C5a receptor antagonist and tested following ch14.18 injection. The mutation reduces the antibody’s ability to activate complement, while maintaining its ADCC capabilities. Injection of hu14.18K322 (1 or 3mg/kg) produced faster resolving allodynia than that engendered by ch14.18 (1mg/kg). Injection of ch14.18 (1mg/kg) into rats with C6 complement deficiency further reduced antibody-induced allodynia, while pre-treatment with complement factor C5a receptor antagonist completely abolished ch14.18-induced allodynia. These findings showed that mutant hu14.18 K322 elicited less allodynia than ch14.18 and that ch14.18-elicited allodynia is due to activation of the complement cascade: in part, to formation of membrane attack complex, but more importantly to release of complement factor C5a. Development of immunotherapeutic agents with decreased complement-dependent lysis while maintaining cellular cytotoxicity may offer treatment options with reduced adverse side effects, thereby allowing dose escalation of therapeutic antibodies.

Genetic variation in the beta2-adrenergic receptor but not catecholamine-O-methyltransferase predisposes to chronic pain: Results from the 1958 British Birth Cohort Study

2010-02-19

Abstract: More than 1 in 10 adults in the general population experience chronic widespread body pain (CWP), which lies at one end of a continuous spectrum of pain ranging in both severity and duration. Neuroendocrine factors can modify the effect of known psychological and psychosocial risk factors for progression along the spectrum of pain and development of CWP, and genetic variants that affect neuroendocrine and neural processing potentially affect susceptibility to chronic pain development. We have examined variants across genes encoding the beta2-adrenergic receptor (ADRB2) and catecholamine-O-methyltransferase (COMT) – key neuroendocrine signalling factors – in a large population-based sample to determine whether these may be involved in pain progression and CWP development. A nested association study was conducted using individuals from the 1958 British Birth Cohort Study who had been assessed for pain status. Genotypes were available for nine single nucleotide polymorphisms (SNPs) across ADRB2 and 11 SNPs across COMT. ADRB2 SNPs rs12654778 and rs1042713 were associated either with CWP alone (p=0.02 for both) or with position along pain spectrum (pain status; p=0.04). Common functional ADRB2 haplotype combinations were also associated with pain status (pmodel=0.002) and, further, with both extent and duration of pain (pmodel=0.003 and pmodel=0.002, respectively). There were no associations of either CWP or pain status with COMT genotypes or haplotypes. These results are the first to suggest that functional ADRB2 variants are involved in regulating pain status at a population level. A role for COMT in chronic pain development was not identified, though could not be excluded.

Loose ligation of the rat sciatic nerve elicits early accumulation of Shank1 protein in the post-synaptic density of spinal dorsal horn neurons

2010-02-19

Abstract: Plasticity in the spinal dorsal horn may contribute to the development of pain following peripheral nerve injury. Shank proteins are a constituent family of the post-synaptic density (PSD), and they may play a role in synaptic plasticity through activity-dependent synaptic remodeling and growth. In this study we examined the early consequences of the loose ligation of the sciatic nerve on Shank1 protein and message levels in the PSD of spinal dorsal horn neurons. Four hours after sciatic ligation, the protein levels of Shank1 increased in the ipsilateral PSD of ligated animals. In contrast, no changes were detected in the contralateral PSD of these ligated animals, or either the ipsilateral or contralateral PSD of sham-operated animals. Shank1 was linked to the PSD marker protein PSD-95 and the NR2B subunit of NMDA receptors. The ligated animals also exhibited two early signs of pain behavior, a shift in weight distribution and thermal hyperalgesia. There was no overall change in Shank1 message in either ligated or sham-operated animals. The accumulation of Shank1 in the PSD was abolished by intrathecal pre-treatment with anisomycin or Shank1 siRNA, but not with non-target siRNA. The same pre-treatment prevented both the early signs of pain behavior. Intrathecal pre-treatment with either MK-801 or U0126 similarly prevented the Shank1 accumulation and alleviated both the behavioral signs of pain. The early accumulation of Shank1 in the PSD of dorsal horn neurons may be a necessary step in the injury-associated plasticity that in time leads to the development of persistent pain.

A failure of the review process? Comment on Ahsin et al. Clinical and endocrinological changes after electro-acupuncture treatment in patients with osteoarthritis of the knee. Pain 2009;147:60–6

Neil E. O’Connell, Benedict M. Wand, David Colquhoun — 2010-02-19

In the recent study by Ahsin et al. , the authors conclude that electro-acupuncture provides pain relief “clearly beyond that of placebo effects” (page 65). An accompanying editorial suggests that the study represents a “major step forward in understanding the role of the HPA axis and EO systems in the effectiveness of acupuncture in chronic pain” (page 11). At first glance, this is surprising news because the evidence from robust systematic reviews strongly suggests that acupuncture in any form offers little or no relevant therapeutic benefit beyond the placebo effect, both in studies of pain generally or specifically for osteoarthritis of the knee . However, closer inspection reveals numerous fundamental threats to the paper’s validity that leave the paper, in our view, uninterpretable.

In defense of science: Investigation and evaluation without bias and prejudice

Sadia Ahsin, Ray Iles — 2010-02-19

We very much welcome scientific critical examination of our work in particular we look forward to the PEDRo Database evaluation of our trial. This is run by the Centre for evidence based Physiotherapy (CEBP) of the George Institute for International Health affiliated with The University of Sydney http://www.pedro.org.au/english/about-us/.

A response to O’Connell et al. letter “A failure of the review process? Comment on Ahsin et al. Clinical and endocrinological changes after electro-acupuncture treatment in patients with osteoarthritis of the knee. Pain 2009;147: 60–6”

Christopher Brown, Anthony Jones — 2010-02-22

We welcome the response of O’Connell et al. and their detailed analysis of the flaws in the paper by Ahsin et al. , on the possible mechanisms of acupuncture in osteoarthritis. It is clear from systematic reviews that the evidence for the efficacy of acupuncture in chronic pain is currently not strong relative to placebo. It is unclear to what extent poorly designed or administered treatments and/or sham treatments are responsible. O’Connell and colleagues are correct to draw attention to weaknesses in the Ahsin et al. paper in the way the efficacy of the acupuncture treatment was assessed. We do not consider the sham acupuncture treatment in the Ahsin et al. paper to be a good placebo control, and in our commentary we called for improvements in the design of such studies to include more convincing sham treatments. We hope this clarifies our view on the study design.