The journal of pain : official journal of the American Pain Society
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Conditioned pain modulation (CPM) refers to the diminution of perceived pain intensity for a test stimulus following application of a conditioning stimulus to a remote area of the body, and is thought to reflect the descending inhibition of nociceptive signals. Studying CPM in children may inform interventions to enhance central pain inhibition within a developmental framework. We assessed CPM in 133 healthy children (mean age = 13 years; 52.6% girls) and tested the effects of sex and age. Participants were exposed to 4 trials of a pressure test stimulus before, during, and after the application of a cold water conditioning stimulus. CPM was documented by a reduction in pressure pain ratings during cold water administration. Older children (12-17 years) exhibited greater CPM than younger children (8-11 years). No sex differences in CPM were found. Lower heart rate variability at baseline and after pain induction was associated with less CPM, controlling for child age. The findings of greater CPM in the older age cohort suggest a developmental improvement in central pain inhibitory mechanisms. The results highlight the need to examine developmental and contributory factors in central pain inhibitory mechanisms in children to guide effective, age appropriate pain interventions. ⋯ In this healthy sample, younger children exhibited less CPM than did older adolescents, suggesting a developmental improvement in CPM. Cardiac vagal tone was associated with CPM across age. The current findings may inform the development of targeted, developmentally appropriate pain interventions for children.
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Voltage-gated sodium channels (Nav) are essential for the generation and conduction of action potentials. Peripheral inflammation increases the expression of Nav1.7 and Nav1.8 in dorsal root ganglion (DRG) neurons, suggesting that they participate in the induction and maintenance of chronic inflammatory pain. However, how Nav1.7 and Nav1.8 are regulated in the DRG under inflammatory pain conditions remains unclear. Using a complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model and Western blot analysis, we found that phosphorylated Akt (p-Akt) was significantly increased in the ipsilateral L4/5 DRGs of rats on days 3 and 7 after intraplantar CFA injection. Immunohistochemistry showed that the percentage of p-Akt-positive neurons in the DRG was also significantly increased in the ipsilateral L4/5 DRGs at these time points. Moreover, CFA injection increased the colocalization of p-Akt with Nav1.7 and Nav1.8 in L4/5 DRG neurons. Pretreatment of rats with an intrathecal injection of Akt inhibitor IV blocked CFA-induced thermal hyperalgesia and CFA-induced increases in Nav1.7 and Nav1.8 in the L4/5 DRGs on day 7 after CFA injection. Our findings suggest that the Akt pathway participates in inflammation-induced upregulation of Nav1.7 and Nav1.8 expression in DRG neurons. This participation might contribute to the maintenance of chronic inflammatory pain. ⋯ This article presents that inhibition of Akt blocks CFA-induced thermal hyperalgesia and CFA-induced increases in dorsal root ganglion Nav1.7 and Nav1.8. These findings have potential implications for use of Akt inhibitors to prevent and/or treat persistent inflammatory pain.
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Neurofibromatosis type 1 (NF1) is characterized primarily by tumor formation in the nervous system, but patients report other neurological complications including pain and itch. Individuals with NF1 harbor 1 mutated NF1 allele causing heterozygous expression in all of their cells. In mice, Nf1 heterozygosity leads to hyperexcitability of sensory neurons and hyperproliferation of mast cells, both of which could lead to increased hypersensitivity and scratching in response to noxious and pruritic stimuli. To determine whether Nf1 heterozygosity may increase pain and itch behaviors independent of secondary effects of tumor formation, we used mice with a targeted, heterozygous Nf1 gene deletion (Nf1±) that lack tumors. Nf1± mice exhibited normal baseline responses to thermal and mechanical stimuli. Moreover, similar to wild-type littermates, Nf1± mice developed inflammation-induced heat and mechanical hypersensitivity, capsaicin-induced nocifensive behavior, histamine-dependent or -independent scratching, and chronic constriction injury-induced cold allodynia. However, Nf1± mice exhibited an attenuated first phase of formalin-induced spontaneous behavior and expedited resolution of formalin-induced heat hypersensitivity. These results are not consistent with the hypothesis that Nf1 heterozygosity alone is sufficient to increase pain and itch sensation in mice, and they suggest that additional mechanisms may underlie reports of increased pain and itch in NF1 patients. ⋯ This study assessed whether Nf1 heterozygosity in mice increased hypersensitivity and scratching following noxious and pruritic stimuli. Using Nf1± mice lacking tumors, this study finds no increases in pain or itch behavior, suggesting that there is no predisposition for either clinical symptom solely due to Nf1 heterozygosity.
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Repeated injections of the antibiotic ceftriaxone cause analgesia in rodents by upregulating the glutamate transporter, GLT-1. No evidence is available in humans. We studied the effect of a single intravenous administration of ceftriaxone in patients undergoing decompressive surgery of the median or ulnar nerves. Forty-five patients were randomized to receive saline, ceftriaxone (2 g), or cefazolin (2 g), 1 hour before surgery. Cefazolin, which is structurally related to ceftriaxone, was used as a negative control. Pain thresholds were measured 10 minutes before drug injections and then 4 to 6 hours after surgery. Ceftriaxone caused analgesia in all patients, whereas cefazolin was inactive. We also performed animal studies to examine whether a single dose of ceftriaxone was sufficient to induce analgesia. A single intraperitoneal injection of ceftriaxone (200 mg/kg), but not cefazoline (200 mg/kg), caused analgesia in mouse models of inflammatory or postsurgical pain, and upregulated GLT-1 in the spinal cord. Ceftriaxone-induced analgesia was additive to that produced by blockade of mGlu5 receptors, which are activated by extrasynaptic glutamate. These data indicate that a single dose of ceftriaxone causes analgesia in humans and mice and suggest that ceftriaxone should be used for preoperative antimicrobial prophylaxis when a fast relief of pain is desired. ⋯ The study reports for the first time that a single preoperative dose of ceftriaxone causes analgesia in humans. A single dose of ceftriaxone could also relieve inflammatory and postsurgical pain and upregulate GLT-1 expression in mice. Ceftriaxone should be preferred to other antibiotics for antimicrobial prophylaxis to reduce postoperative pain.
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CXBH mice, known as an "opioid receptor-rich" strain, are a recombinant inbred mouse strain established by crossing the C57BL/6By and BALB/cBy strains. In the present study, we investigated nociceptive and antinociceptive sensitivity in CXBH mice and elucidated the underlying molecular mechanisms. CXBH mice exhibited slightly higher morphine-induced antinociception compared with C57BL/6J and BALB/cBy mice in the hot-plate test but not tail-flick test. CXBH mice exhibited a marked reduction of nociceptive sensitivity, regardless of the type of nociceptive stimulus, with the exception of tail stimulation. Changes in gene expression that corresponded to reduced nociceptive sensitivity in the brains of CXBH mice were observed in 62 transcripts, including pain- and analgesia-related transcripts, in a whole-genome expression assay. The total mRNA expression of opioid receptors was higher in CXBH mice than in C57BL/6J and BALB/cBy mice. However, the expression levels of MOR-1 mRNA, a major transcript of the μ opioid receptor gene, were not different among the C57BL/6J, BALB/cBy, and CXBH strains. In conclusion, supraspinal nociceptive responses were reduced in the CXBH mouse strain, and the expression levels of transcripts were altered in the brain of this strain. ⋯ This article presents the nociceptive and antinociceptive properties of CXBH recombinant inbred mice and gene expression differences that may underlie nociceptive tolerance in the strain. The CXBH mouse strain may be a useful animal model to investigate the molecular basis of individual differences in supraspinal pain sensitivity.