The innate immune system is increasingly appreciated to play an important role in the mediation of chronic pain, and one molecule implicated in this process is the Toll-like receptor 4 (TLR4). Here using pharmacological and genetic manipulations we found that activating TLR4 in the spinal cord, with the agonist lipopolysaccharide (LPS), causes robust mechanical allodynia but only in male mice. Spinal LPS had no pain-producing effect in female mice. TLR4 also has a sex-specific role in inflammatory (complete Freund’s adjuvant) and neuropathic (spared nerve injury) pain: pain behaviors were TLR4-dependent in males but TLR4-independent in females. The sex differences appear to be specific to the spinal cord, as LPS administered to the brain or the hindpaw produces equivalent allodynia in both sexes, and specific to pain, as intrathecal LPS produces equivalent hypothermia in both sexes. The involvement of TLR4 in pain behaviors in male mice is dependent on testosterone, as shown by gonadectomy and hormone replacement. We found no sex differences in spinal Tlr4 expression at baseline or after LPS, suggesting the existence of parallel spinal pain processing circuitry in female mice not involving TLR4s.

Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary1. Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da2,3. Using genome-wide linkage analyses, we discovered an association between nerve-injury–induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7. Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain.

Children hospitalized in pediatric intensive care units (PICUs) are subjected to highly invasive interventions necessary in overcoming the critical period of their illness, yet little is known about their subsequent psychological adjustment. The purposes of this study were to compare the psychological responses of children hospitalized in a PICU with those of children hospitalized on a general ward and to identify clinically relevant factors that might be associated with psychological outcome. A prospective cohort design was used to follow 120 children for 6 months after PICU and ward discharge. Groups were compared on the children's sense of control over their health, their medical fears, posttraumatic stress, and changes in behavior. Relationships between children's responses and their age, the invasive procedures to which they were exposed, severity of illness, and length of hospital stay were also examined. No significant group differences were found. However, children who were younger, more severely ill, and who endured more invasive procedures had significantly more medical fears, a lower sense of control over their health, and ongoing posttraumatic stress responses for 6 months postdischarge. Findings indicate that regardless of the hospital setting, invasiveness coupled with length of stay and severity of illness in young children may have adverse long-term effects.

Our knowledge of the prevalence and sources of pain within hospital is limited. The present study is an epidemiological investigation of pain in a pediatric hospital. All children who were inpatients in a tertiary care hospital (excluding Neonatal ICU and psychiatry patients) and one parent per child were potential subjects. Interviews were conducted on three weekdays. Parent interviews were used for children less than 5 years of age (n = 102); child interviews were used for children age 5 years and older (n = 98). Subjects reported the intensity and source of the worst, usual and current pain during the past 24 h, and help received for pain. Medical and demographic variables and analgesics prescribed and administered were obtained from the medical record. Forty-nine percent of subjects reported clinically significant levels of worst pain. Twenty-one percent of subjects had clinically significant levels of usual pain. Causes of pain were variable and included disease, surgery, and intravenous lines (I.V.). Pain intensity was not significantly related to age, gender, patient type (medical, surgical), or diagnostic category. Children were given significantly less medication than was prescribed, regardless of their reported pain level. Nurses, mothers, and 'no-one' were frequently reported as helping with pain. Medications and nonpharmacological methods were reported as helpful in managing pain. Many children endure unacceptable levels of pain during hospitalization. Pain prevention and management must be more aggressive. Pain assessment should be approached with the same attention as vital signs. Improvements in analgesic prescription and administration practices and non-pharmacological pain control methods are needed.

Further conceptual development is essential to continue advancing our understanding of the sustainability of healthcare innovations, especially in nursing where this topic remains largely unexplored.

No abstract

The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) contribute to the regulation of diverse cognitive and physiological functions including nociception. Indeed, OXT has been reported to be analgesic when administered directly into the brain, the spinal cord, or systemically. Here, we characterized the phenotype of oxytocin receptor (OTR) and vasopressin-1A receptor (V1AR) null mutant mice in a battery of pain assays. Surprisingly, OTR knock-out mice displayed a pain phenotype identical to their wild-type littermates. Moreover, systemic administration of OXT dose-dependently produced analgesia in both wild-type and OTR knock-out mice in three different assays, the radiant-heat paw withdrawal test, the von Frey test of mechanical sensitivity, and the formalin test of inflammatory nociception. In contrast, OXT-induced analgesia was completely absent in V1AR knock-out mice.

No abstract