Hot off the presses! May 01 Pain

The May 01 issue of the Pain is now up on Pubget (About Pain): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Editorial list
  - Pain 143():iii-iv (2009)
  
• Instructions to authors
  - Pain 143():vi-viii (2009)
  
• Activity and low back pain: A dubious correlation
  - Pain 143():1-2 (2009)
  
• Motor dysfunction in CRPS and its treatment
  - Pain 143():3-4 (2009)
  
• Pain demands attention from others: The approach/avoidance paradox
  - Pain 143():5-6 (2009)
  
• Relief of postoperative pain by local anaesthetic infiltration: Efficacy for major abdominal and orthopedic surgery
  - Pain 143():7-11 (2009)
  
• Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABAA receptor subtypes
  - Pain 143():12-20 (2009)
  Recently, we demonstrated a spinal GABAA receptor (GABAAR)-dependent inhibition on the induction of repetitive stimulation-induced spinal reflex potentiation. However, it remains unclear whether steroid hormones modulate such an inhibition. Here, we show that progesterone is capable of producing GABAARs-dependent inhibition of the induction of spinal reflex potentiation by actions through neurosteroid metabolites. Progesterone (5 mg/kg, twice daily for 4 days) up-regulates the expression of GABAAR α2, α3, α4 and δ subunits, and is associated with attenuated repetitive stimulation-induced spinal reflex activity in ovariectomized rats. These changes were blocked by finasteride (50 mg/kg, twice daily), an antagonist of neurosteroid synthesis from progesterone, but not by the progesterone receptor antagonist, RU486 (100 mg/kg, twice daily). The induction of spinal reflex potentiation was attenuated after a short (30 min) intrathecal treatment with the neurosteroids, al! lopregnanolone (ALLOP, 10 μM, 10 μL) and 3α,5α-tetrahydrodeoxycorticosterone (THDOC, 10 μM, 10 μL). Acute intrathecal administration of the GABAAR antagonist, bicuculline (10 μM, 10 μL) reversed the inhibition produced by progesterone, THDOC and allopregnanolone. These results imply that progesterone-mediated effects on GABAAR expression and neural inhibition are regulated by neurosteroids synthesis rather than progesterone receptor activation.
• Physical activity and low back pain: A U-shaped relation?
  - Pain 143():21-25 (2009)
  Being physically active is often suggested to be important in the prevention and management of low back pain. This simple view does not take into account that the relation between the level of activity and back pain may be a U-shaped curve – i.e. both inactivity and excessive activities (back-unhealthy activity) present an increased risk for back pain. We explored the U-shaped association between physical activity and chronic low back pain (greater-or-equal, slanted3 months duration) by analyzing cross-sectional data from the Dutch population-based Musculoskeletal Complaints and Consequences Cohort study (DMC3, 1998) of a sex–age stratified sample of 25 years and older (n = 3364). Type of activity (daily routine, leisure time and sport activity), intensity of and time spent on these activities, and back exertion of sport activities were taken into account. Physical activity was not associated with chronic low back pain (CLBP) when studied by the dimension of activi! ty, by the intensity or by the duration of physical activity. Only engaging in sport activity was associated with less CLBP (OR 0.78: 95% CI 0.66–0.93). The extremes of the total physical activity pattern were associated with CLBP. A moderate increased risk for CLBP was found for both participants with a sedentary lifestyle (OR 1.31: 95% CI 1.08–1.58) and for those being involved in physical strenuous activities (OR 1.22: 95% CI 1.00–1.49). This was especially true for women (sedentary: OR 1.44: 95% CI 1.10–1.83; physically active: OR 1.36: 95% CI 1.04–1.78). This study provides some evidence that the relation between physical activity and CLBP is U-shaped.
• Cross-inhibition between native and recombinant TRPV1 and P2X3 receptors
  - Pain 143():26-36 (2009)
  Small- to medium-sized neurons in the dorsal root ganglion (DRG) convey nociceptive information to the spinal cord. The co-expression of TRPV1 receptors (sensitive to vanilloids, heat and acidic pH) with P2X3 receptors (sensitive to extracellular ATP) has been found in many DRG neurons. We investigated whether the co-activation of these two receptor classes in small-diameter cells leads to a modulation of the resulting current responses shaping the intensity of pain sensation. The whole-cell patch clamp method was used to record agonist-induced currents in cultured rat DRG neurons and in HEK293 cells transfected with the respective wild-type recombinant receptors or their mutants. Co-immunoprecipitation studies were used to demonstrate the physical association of TRPV1 and P2X3 receptors. At a negative holding potential, the P2X3 receptor agonist α,β-meATP induced less current in the presence of the TRPV1 agonist capsaicin than that in its absence. This inhibitory in! teraction was not changed at a positive holding potential, in a Ba2+-containing superfusion medium, or when the buffering of intrapipette Ca2+ was altered. The C-terminal truncation at Glu362 of P2X3 receptors abolished the TRPV1/P2X3 cross-talk in the HEK293 expression system. Co-immunoprecipitation studies with polyclonal antibodies generated against TRPV1 and P2X3 showed a visible signal in HEK293 cells transfected with both receptors. It is concluded that the two pain-relevant receptors TRPV1 and P2X3 interact with each other in an inhibitory manner probably by a physical association established by a motif located at the C-terminal end of the P2X3 receptor distal to Glu362.
• Ablation of estrogen receptor α or β eliminates sex differences in mechanical pain threshold in normal and inflamed mice
  - Pain 143():37-40 (2009)
  We examined nociceptive responses to mechanical stimulation in mice of both sexes lacking the estrogen receptor α or β and in respective wild types under normal conditions, after inflammation of a hindpaw or peripheral nerve injury. In normal wild-type mice, females had significantly lower paw withdrawal threshold than males. There was no significant difference between wild-type mice and knock-outs of either estrogen receptor α or β in mechanical response threshold in male mice. However, significantly elevated response threshold was observed in both knock-out female mice, which eliminated sex differences in nociception. After carrageenan-induced inflammation of a hindpaw, all wild-type and knock-out mice exhibited similar local edema with no difference between the sexes. Wild-type mice developed hypersensitivity (allodynia) to mechanical stimulation, which was more profound in the females than in males. Again, such sex difference was not observed in the knock-outs ! of either estrogen receptor. Photochemically induced partial sciatic nerve injury caused similar persistent mechanical hypersensitivity in the wild types and both estrogen receptor knock-outs with no difference between the sexes. These results suggest that the sex difference in basal mechanical pain threshold and inflammatory hypersensitivity is eliminated in mice lacking either the estrogen α receptors or β receptors. However, these receptors do not seem to be directly involved in mediating pain sensitivity in general or in the development of neuropathic pain. It is unclear whether the elimination of sex differences observed in the knock-outs reflects an ongoing effect of estrogen acting through its receptors in females or the developmental changes that predominantly affect females.
• Intrathecal baclofen for dystonia of complex regional pain syndrome
  - Pain 143():41-47 (2009)
  Dystonia in complex regional pain syndrome (CRPS) responds poorly to treatment. Intrathecal baclofen (ITB) may improve this type of dystonia, but information on its efficacy and safety is limited. A single-blind, placebo-run-in, dose-escalation study was carried out in 42 CRPS patients to evaluate whether dystonia responds to ITB. Thirty-six of the 38 patients, who met the responder criteria received a pump for continuous ITB administration, and were followed up for 12 months to assess long-term efficacy and safety (open-label study). Primary outcome measures were global dystonia severity (both studies) and dystonia-related functional limitations (open-label study). The dose-escalation study showed a dose-effect of baclofen on dystonia severity in 31 patients in doses up to 450 μg/day. One patient did not respond to treatment in the dose-escalation study and three patients dropped out. Thirty-six patients entered the open-label study. Intention-to-treat analysis revea! led a substantial improvement in patient and assessor-rated dystonia scores, pain, disability and quality-of-life (Qol) at 12 months. The response in the dose-escalation study did not predict the response to ITB in the open-label study. Eighty-nine adverse events occurred in 26 patients and were related to baclofen (n = 19), pump/catheter system defects (n = 52), or could not be specified (n = 18). The pump was explanted in six patients during the follow-up phase. Dystonia, pain, disability and Qol all improved on ITB and remained efficacious over a period of one year. However, ITB is associated with a high complication rate in this patient group, and methods to improve patient selection and catheter-pump integrity are warranted.
• Gabapentin selectively reduces persistent sodium current in injured type-A dorsal root ganglion neurons
  - Pain 143():48-55 (2009)
  It has been confirmed that the voltage-gated persistent sodium currents mediate the generation of subthreshold membrane potential oscillations (SMPOs) and contribute to shaping repetitive firing. Our previous study indicated that gabapentin (GBP) administration induced a dose-dependent inhibition of SMPO in chronically compressed dorsal root ganglion (CCD) neurons. To investigate the mechanisms and possible site(s) of action of GBP, the persistent sodium currents (INaP) were measured and the effects of GBP on INaP were examined in CCD neurons electrophysiologically in vitro. DRG neurons possess slow TTX-sensitive inactivating sodium currents that significantly contribute to the generation of membrane oscillations by amplifying the resonance behavior. GBP reduced the resonant amplitude of DRG neurons as well as inhibiting the firing and SMPO induced by injection current, which was strongly due to the inhibitory effect on persistent sodium currents. Furthermore, we found! that GBP (1–20 μM) administration inhibited the persistent sodium currents in dose-dependent manner, while the changes of K+ and Ca2+ current minimally contributed to the effect of GBP on oscillation and resonant behavior of DRG neurons. In contrast, the amplitude and voltage-dependence of transient sodium current were unchanged by GBP. The results suggest that GBP decreased the amplitude of resonance and abolished the SMPO of A-type DRG neurons through the inhibition of INaP, and thus inhibited the SMPO dependent repetitive and bursting firings.
• Excitatory synapses in the rat superficial dorsal horn are strengthened following peripheral inflammation during early postnatal development
  - Pain 143():56-64 (2009)
  Peripheral inflammation can cause prolonged changes in pain sensitivity if it occurs during a critical period of early postnatal development, suggesting that neonatal pain circuits respond to tissue damage in a fundamentally different manner. However, the effects of early tissue injury on the function of emergent central pain networks have yet to be characterized at the synaptic level. Here, we investigated whether inflammation at different postnatal ages has distinct consequences for synaptic function in the superficial dorsal horn (SDH) of the rat spinal cord using in vitro patch-clamp techniques. Subcutaneous injections of carrageenan (CARR) into the hindpaw at postnatal day (P) 2 significantly increased the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs) in P3–4 SDH neurons compared to naïve controls, while no changes were observed at inhibitory synapses onto the same neurons. The paired-pulse ratio of evoked EPSCs was unalte! red by CARR at P2, suggesting that the elevation in mEPSC frequency following inflammation does not reflect an enhanced probability of glutamate release within the SDH. The potentiation of glutamatergic synapses did not persist beyond the duration of the injury, as the observed difference in mEPSC frequency had resolved by P10–11. In contrast, peripheral inflammation at P9 or P17 failed to significantly alter excitatory or inhibitory synaptic efficacy in the SDH. Meanwhile, carrageenan decreased the inward rectification of AMPAR-mediated currents throughout the first three postnatal weeks. These data suggest that distinct synaptic mechanisms may underlie central sensitization in the immature and mature spinal cords under pathological conditions.
• Altered quantitative sensory testing outcome in subjects with opioid therapy
  - Pain 143():65-70 (2009)
  Preclinical studies have suggested that opioid exposure may induce a paradoxical decrease in the nociceptive threshold, commonly referred as opioid-induced hyperalgesia (OIH). While OIH may have implications in acute and chronic pain management, its clinical features remain unclear. Using an office-based quantitative sensory testing (QST) method, we compared pain threshold, pain tolerance, and the degree of temporal summation of the second pain in response to thermal stimulation among three groups of subjects: those with neither pain nor opioid therapy (group 1), with chronic pain but without opioid therapy (group 2), and with both chronic pain and opioid therapy (group 3). We also examined the possible correlation between QST responses to thermal stimulation and opioid dose, opioid treatment duration, opioid analgesic type, pain duration, or gender in group 3 subjects. As compared with both group 1 (n = 41) and group 2 (n = 41) subjects, group 3 subjects (n = 58) disp! layed a decreased heat pain threshold and exacerbated temporal summation of the second pain to thermal stimulation. In contrast, there were no differences in cold or warm sensation among three groups. Among clinical factors, daily opioid dose consistently correlated with the decreased heat pain threshold and exacerbated temporal summation of the second pain in group 3 subjects. These results indicate that decreased heat pain threshold and exacerbated temporal summation of the second pain may be characteristic QST changes in subjects with opioid therapy. The data suggest that QST may be a useful tool in the clinical assessment of OIH.
• Unconscious affective processing and empathy: An investigation of subliminal priming on the detection of painful facial expressions
  - Pain 143():71-75 (2009)
  Results from recent functional neuroimaging studies suggest that facial expressions of pain trigger empathic mimicry responses in the observer, in the sense of an activation in the pain matrix. However, pain itself also signals a potential threat in the environment and urges individuals to escape or avoid its source. This evolutionarily primitive aspect of pain processing, i.e., avoidance from the threat value of pain, seems to conflict with the emergence of empathic concern, i.e., a motivation to approach toward the other. The present study explored whether the affective values of targets influence the detection of pain at the unconscious level. We found that the detection of pain was facilitated by unconscious negative affective processing rather than by positive affective processing. This suggests that detection of pain is primarily influenced by its inherent threat value, and that empathy and empathic concern may not rely on a simple reflexive resonance as generall! y thought. The results of this study provide a deeper understanding of how fundamental the unconscious detection of pain is to the processes involved in the experience of empathy and sympathy.
• Childhood psychosocial stressors and adult onset arthritis: Broad spectrum risk factors and allostatic load
  - Pain 143():76-83 (2009)
  Neural, endocrine, and immune stress mediators are hypothesized to increase risks of diverse chronic diseases, including arthritis. Retrospective data from the World Mental Health Surveys (N = 18,309) were employed to assess whether adult onset of arthritis was associated with childhood adversities and early onset psychological disorder. Cox proportional hazard models assessed the association of number of childhood adversities and the presence of early onset psychological disorder with arthritis age of onset. Controlling for age, sex, and early onset mental disorder, relative to persons with no childhood adversities, persons with two adversities had an increased risk of adult onset arthritis (hazard ratio = 1.27, 95% CI = 1.08, 1.50), while persons with three or more adversities had a higher risk (HR = 1.44, CI = 1.24, 1.67). Early onset depressive and/or anxiety disorder was associated with an increased risk of adult onset arthritis after controlling for childhood adv! ersities (HR = 1.43, CI = 1.28, 1.61). Since psychosocial stressors may be broad spectrum risk factors that increase risks of diverse chronic conditions in later life (e.g. arthritis, heart disease, diabetes, asthma, and chronic pain), prospective studies of childhood psychosocial stressors may be most productive if multiple disease outcomes are assessed in the same study. Results from this study provide methodological guidance for future prospective studies of the relationship between childhood psychosocial stressors and subsequent risk of adult onset arthritis.
• Influence of heterotopic noxious conditioning stimulation on spontaneous pain and dynamic mechanical allodynia in central post-stroke pain patients
  - Pain 143():84-91 (2009)
  In 10 patients with central post-stroke pain (CPSP), the influence of ischemia-induced heterotopic noxious conditioning stimulation (HNCS) on the intensity of spontaneous ongoing- and brush-evoked pain was examined. In addition, the modulating effect of ongoing pain and HNCS on pain sensitivity in a remote pain-free area was explored. A semi-quantitative brushing technique was employed in combination with a computerized visual analogue scale (VAS) to monitor the allodynic percept over time, by calculating the area under the VAS curve as the total brush-evoked pain intensity. Heat- and pressure pain thresholds and sensitivity to suprathreshold heat- and pressure pain in the pain-free area were assessed before and during HNCS. No significant alterations of ongoing- or brush-evoked pain were found during HNCS, although 6 of 10 patients rated a reduction of about 50% of the brush-evoked pain. At baseline significantly increased pressure pain sensitivity (threshold P < 0.05! ; suprathreshold P = 0.05) were demonstrated in patients compared to controls. During HNCS, higher pressure pain thresholds were demonstrated in patients and controls alike (P < 0.001), whereas in controls only decreased sensitivity to suprathreshold pressure pain was found (P < 0.05). Lack of influence from HNCS on ongoing- and brush-evoked pain on a group level, indicates inability of modulation from endogenous pain controlling systems on nociceptive activity generated in the brain. Increased pressure pain sensitivity at baseline suggests alteration in corticofugal control of nociceptive sensitivity due to the brain lesion, whereas patients during HNCS seemed to activate modulatory systems interacting with nociceptive input from the spinal level equal to controls.
• Adverse events in childhood and chronic widespread pain in adult life: Results from the 1958 British Birth Cohort Study
  - Pain 143():92-96 (2009)
  Chronic widespread pain (CWP) is a common and frequently disabling condition. Several studies have shown that early life adversity is associated with CWP in later life; however, the majority are retrospective and suffer from potential recall bias. Using data from the 1958 British Birth Cohort Study, the aim of the current study was to examine, prospectively, the relationship between childhood physical and psychological adversity and CWP in adulthood. At 7 yrs data were collected, by parental report, on physically traumatic events (hospitalisation following a road traffic accident, or for surgery); and factors indicating poor social and psychological environment (periods in local authority care, death of a parent; or parental divorce, alcoholism, or financial hardship). CWP was assessed at 45 yrs using self-completion questionnaires. The relationship between childhood events and CWP was examined using Poisson regression. 7571 individuals provided pain data at 45 yrs (71! .5%). There was no association between childhood surgery and CWP in adulthood (relative risk: 1.0; 95%CI: 0.9–1.1). However, children who had been hospitalised following a road traffic accident experienced a significant increase in the risk of future CWP (1.5; 1.05–2.1). Children who had resided in institutional care also experienced an increase in the risk of CWP (1.7; 1.3–2.4) as did those who experienced maternal death (2.0; 1.08–3.7) and familial financial hardship (1.6; 1.3–1.9). Further these associations were not explained by adult psychological distress or social class. To prevent long-term consequences of adverse childhood events, future research should study the mechanisms, in particular the biological mechanisms, underlying these relationships.
• Explicit episodic memory for sensory-discriminative components of capsaicin-induced pain: Immediate and delayed ratings
  - Pain 143():97-105 (2009)
  Pain memory is thought to affect future pain sensitivity and thus contribute to clinical pain conditions. Systematic investigations of the human capacity to remember sensory features of experimental pain are sparse. In order to address long-term pain memory, nine healthy male volunteers received intradermal injections of three doses of capsaicin (0.05, 1 and 20 μg, separated by 15 min breaks), each given three times in a balanced design across three sessions at one week intervals. Pain rating was performed using a computerized visual analogue scale (0–100) digitized at 1/s, either immediately online or one hour or one day after injection. Subjects also recalled their pains one week later. Capsaicin injection reliably induced a dose-dependent flare (p < 0.001) without any difference within or across sessions. The strong burning pain decayed exponentially within a few minutes. Subjects were able to reliably discriminate pain magnitude and duration across capsaicin dos! es (both p < 0.001), regardless of whether first-time ratings were requested immediately, after one hour or after one day. Pain recall after one week was similarly precise (magnitude: p < 0.01, duration: p < 0.05). Correlation with rating recall after one week was best when first-time ratings were requested as late as one day after injection (R2 = 0.79) indicating that both rating retrievals utilized similar memory traces. These results indicate a reliable memory for magnitude and duration of experimentally induced pain. The data further suggest that the consolidation of this memory is an important interim stage, and may take up to one day.
• Pain assessment and treatment disparities: A virtual human technology investigation
  - Pain 143():106-113 (2009)
  Pain assessment and treatment is influenced by patient demographic characteristics and nonverbal expressions. Methodological challenges have limited the empirical investigation of these issues. The current analogue study employed an innovative research design and novel virtual human (VH) technology to investigate disparities in pain-related clinical decision-making. Fifty-four nurses viewed vignettes consisting of a video clip of the VH patient and clinical summary information describing a post-surgical context. Participants made assessment (pain intensity and unpleasantness) and treatment (non-opioid and opioid medications) decisions on computerized visual analogue scales. VH demographic cues of sex, race, and age, as well as facial expression of pain, were systematically manipulated and hypothesized to influence decision ratings. Idiographic and nomothetic statistical analyses were conducted to test these hypotheses. Idiographic results indicated that sex, race, age,! and pain expression cues accounted for significant, unique variance in decision policies among many nurses. Pain expression was the most salient cue in this context. Nomothetic results indicated differences within VH cues of interest; the size and consistency of these differences varied across policy domains. This study demonstrates the application of VH technology and lens model methodology to the study of disparities in pain-related decision-making. Assessment and treatment of acute post-surgical pain often varies based on VH demographic and facial expression cues. These data contribute to the existing literature on disparities in pain practice and highlight the potential of a novel approach that may serve as a model for future investigation of these critical issues.
• Profiling of dynamically changed gene expression in dorsal root ganglia post peripheral nerve injury and a critical role of injury-induced glial fibrillary acetic protein in maintenance of pain behaviors
  - Pain 143():114-122 (2009)
  To explore cellular changes in sensory neurons after nerve injury and to identify potential target genes contributing to different stages of neuropathic pain development, we used Affymetrix oligo arrays to profile gene expression patterns in L5/6 dorsal root ganglia (DRG) from the neuropathic pain model of left L5/6 spinal nerve ligation at different stages of neuropathic pain development. Our data indicated that nerve injury induced changes in expression of genes with similar biological functions in a temporal specific manner that correlates with particular stages of neuropathic pain development, indicating dynamic neuroplasticity in the DRG in response to peripheral nerve injury and during neuropathic pain development. Data from post-array validation indicated that there was a temporal correlation between injury-induced expression of the glial fibrillary acidic protein (GFAP), a marker for activated astrocytes, and neuropathic pain development. Spinal nerve ligation ! injury in GFAP knockout mice resulted in neuropathic pain states with similar onset, but a shortened duration compared with that in age, and gender-matched wild-type littermates. Intrathecal GFAP antisense oligonucleotide treatment in injured rats with neuropathic pain states reversed injury-induced behavioral hypersensitivity and GFAP upregulation in DRG and spinal cord. Together, these findings indicate that injury-induced GFAP upregulation not only serves as a marker for astrocyte activation, but it may also play a critical, but yet identified, role in the maintenance of neuropathic pain states.
• Psychological determinants of problematic outcomes following Total Knee Arthroplasty
  - Pain 143():123-129 (2009)
  The primary objective of the present study was to examine the role of pain-related psychological factors in predicting pain and disability following Total Knee Arthroplasty (TKA). The study sample consisted of 75 (46 women, 29 men) individuals with osteoarthritis of the knee who were scheduled for TKA. Measures of pain severity, pain catastrophizing, depression, and pain-related fears of movement were completed prior to surgery. Participants completed measures of pain severity and self-reported disability 6 weeks following surgery. Consistent with previous research, cross-sectional analyses revealed significant correlations among measures of pre-surgical pain severity, pain catastrophizing, depression and pain-related fears of movement. Prospective analyses revealed that pre-surgical pain severity and pain catastrophizing were unique predictors of post-surgical pain severity (6-week follow-up). Pain-related fears of movement were predictors of post-surgical functional ! difficulties in univariate analyses, but not when controlling for pre-surgical co-morbidities (e.g. back pain). The results of this study add to a growing literature highlighting the prognostic value of psychological variables in the prediction of post-surgical health outcomes. The results support the view that the psychological determinants of post-surgical pain severity differ from the psychological determinants of post-surgical disability. The results suggest that interventions designed to specifically target pain-related psychological risk factors might improve post-surgical outcomes.
• Role of rat sensory neuron-specific receptor (rSNSR1) in inflammatory pain: Contribution of TRPV1 to SNSR signaling in the pain pathway
  - Pain 143():130-137 (2009)
  Sensory neuron-specific receptors (SNSRs) belong to a large family of GPCRs, known as Mrgs (Mas-related genes), many of which are preferentially expressed in primary afferent nociceptors. Selective SNSR agonists produce pain-like behaviors in rats, showing that SNSR activation is sufficient to produce pain. However, it is unknown whether SNSR activation is necessary for pain either in the normal condition or in pathological pain states. Here we used small interfering RNA (siRNA) to acutely knockdown rat SNSR1 and test the hypothesis that this receptor mediates pain responses. Administration of siRNA to the lumbar spinal cord in rats dose-dependently knocked down rSNSR1 mRNA and protein and abolished heat hyperalgesia evoked by intradermal administration of specific rSNSR1 agonists. In rats with levels of rSNSR1 knockdown sufficient to block responses to the SNSR1 agonists, there was no effect on normal pain responses, but there was a significant reduction of heat hyper! algesia in an inflammatory pain model (Complete Freund's Adjuvant), supporting a role for rSNSR1 in inflammatory pain. Further in vivo studies revealed that SNSR1 knockdown had no effect on responses to intradermal capsaicin, a selective TRPV1 agonist. In contrast, a selective TRPV1 antagonist abolished heat hyperalgesia produced by an SNSR agonist, suggesting that TRPV1 receptors mediate rSNSR1-evoked responses. We also found that rSNSR1-like immunoreactivity, like TRPV1, is localized in the superficial dorsal horn of the spinal cord. We propose that rSNSR1 represents a new member of the receptors expressed on chemosensitive nociceptors responsible for detecting the "inflammatory soup" of mediators generated by tissue damage.
• Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants
  - Pain 143():138-146 (2009)
  Procedural pain in the neonatal intensive care unit triggers a cascade of physiological, behavioral and hormonal disruptions which may contribute to altered neurodevelopment in infants born very preterm, who undergo prolonged hospitalization at a time of physiological immaturity and rapid brain development. The aim of this study was to examine relationships between cumulative procedural pain (number of skin-breaking procedures from birth to term, adjusted for early illness severity and overall intravenous morphine exposure), and later cognitive, motor abilities and behavior in very preterm infants at 8 and 18 months corrected chronological age (CCA), and further, to evaluate the extent to which parenting factors modulate these relationships over time. Participants were N = 211 infants (n = 137 born preterm less-than-or-equals, slant32 weeks gestational age [GA] and n = 74 full-term controls) followed prospectively since birth. Infants with significant neonatal brain in! jury (periventricular leucomalacia, grade 3 or 4 intraventricular hemorrhage) and/or major sensori-neural impairments, were excluded. Poorer cognition and motor function were associated with higher number of skin-breaking procedures, independent of early illness severity, overall intravenous morphine, and exposure to postnatal steroids. The number of skin-breaking procedures as a marker of neonatal pain was closely related to days on mechanical ventilation. In general, greater overall exposure to intravenous morphine was associated with poorer motor development at 8 months, but not at 18 months CCA, however, specific protocols for morphine administration were not evaluated. Lower parenting stress modulated effects of neonatal pain, only on cognitive outcome at 18 months.
• Acceptance of pain: A study in patients with advanced cancer
  - Pain 143():147-154 (2009)
  Pain, among the most common symptoms of cancer, impacts on multiple domains of wellbeing. Significant numbers of patients continue to experience pain despite pharmacological interventions. Although there is evidence to suggest that acceptance of pain is related to better wellbeing among patients with chronic nonmalignant pain, little is known about acceptance of cancer pain. The purpose of this cross-sectional study was to determine the correlates of pain acceptance in 81 patients with advanced cancer and pain. Demographic, disease, and treatment-related information was collected, and patients completed measures of pain, physical, psychological, and social/relational wellbeing and pain acceptance. Multivariate regression models, using backward elimination, determined the correlates of each subscale of the Chronic Pain Acceptance Questionnaire separately. Activity Engagement was negatively associated with depressive symptoms. Pain Willingness was negatively associated w! ith pain catastrophizing. Parents living with children had lower Pain Willingness scores than non-parents. These relationships were independent of pain severity and physical functioning. These preliminary results suggest that acceptance of cancer pain is related to better psychological wellbeing and that there may be a relational element, with parents at risk of experiencing difficulty in adapting to ongoing cancer pain. These data lay the groundwork for future research and interventions designed to enhance quality of life for patients with advanced cancer and pain.
• Two novel SCN9A mutations causing insensitivity to pain
  - Pain 143():155-158 (2009)
  The sensation of pain is important and there may be serious consequences if it is missing. Recently, the genetic basis for a channelopathy characterised by a congenital inability to experience pain has been described and channelopathy-associated insensitivity to pain has been proposed as a suitable name for this condition. Different mutations in the SCN9A gene causing loss of function of the voltage-gated sodium channel Nav1.7 have been reported in patients with this rare disease. Here we describe a woman with insensitivity to pain with two novel mutations in the SCN9A gene, coding for the Nav1.7 channel. We also discuss the finding of anosmia which apparently is a common feature in these patients.
• Nociception in Kyoto
  - Pain 143():159 (2009)
  
• Does the central nervous system play a role in vitamin D deficiency-related chronic pain?
  - Pain 143():159-160 (2009)