Nuclear Factor κB-COX2 Pathway Activation in Non-myelinating Schwann Cells Is Necessary for the Maintenance of Neuropathic Pain in vivo

Chronic neuropathic pain leads to long-term changes in the sensitivity of both peripheral and central nociceptive neurons. Glial fibrillary acidic protein (GFAP)-positive glial cells are closely associated with the nociceptive neurons including astrocytes in the central nervous system (CNS), satellite glial cells (SGCs) in the sensory ganglia, and non-myelinating Schwann cells (NMSCs) in the peripheral nerves. Central and peripheral GFAP-positive cells are involved in the maintenance of chronic pain through a host of inflammatory cytokines, many of which are under control of the transcription factor nuclear factor κB (NFκB) and the enzyme cyclooxygenase 2 (COX2). To test the hypothesis that inhibiting GFAP-positive glial signaling alleviates chronic pain, we used (1) a conditional knockout (cKO) mouse expressing Cre recombinase under the hGFAP promoter and a floxed COX2 gene to inactivate the COX2 gene specifically in GFAP-positive cells; and (2) a tet-Off tetracycline transactivator system to suppress NFκB activation in GFAP-positive cells. We found that neuropathic pain behavior following spared nerve injury (SNI) significantly decreased in COX2 cKO mice as well as in mice with decreased glial NFκB signaling. Additionally, experiments were performed to determine whether central or peripheral glial NFκB signaling contributes to the maintenance of chronic pain behavior following nerve injury. Oxytetracycline (Oxy), a blood-brain barrier impermeable analog of doxycycline was employed to restrict transgene expression to CNS glia only, leaving peripheral glial signaling intact. Signaling inactivation in central GFAP-positive glia alone failed to exhibit the same analgesic effects as previously observed in animals with both central and peripheral glial signaling inhibition. These data suggest that the NFκB-COX2 signaling pathway in NMSCs is necessary for the maintenance of neuropathic pain in vivo.

Three Studies Evaluating the Potential for Lidocaine, Bupivacaine or Procaine to Reduce Pain-Related Behaviors following Ring Castration and/or Tail Docking in Lambs

The use of local anesthesia at the time of ring castration and tail docking can improve lamb welfare. However, few local anesthetics are registered for sheep, and data on their duration of effect is limited. Three studies were conducted to evaluate the efficacy of procaine (P), lidocaine (L), and bupivacaine (B) in terms of observed alleviation of behavioral responses to castration and/or tail docking in 10-min blocks in the first 60 min post-treatment. In each study, comparisons were made between two groups of lambs castrated and/or tail docked with rubber rings and either receiving the agent using the NUMNUTS® instrument (N) or receiving no anesthetic agent (RR). Acute pain behavior was lower in NL (n = 28) than RRL (n = 15) males in the first 10 min post-procedure (p < 0.05); lower in NB (n = 16) than RRB (n = 16) males in periods 10–20 min (0.05 < p < 0.01), 20–30 min (p < 0.05) and 40–50 min (0.05 < p < 0.01); lower in NB (n = 16) than RRB (n = 16) females between 20 and 40 min post-procedure (0.05 < p < 0.01); lower in NP (n = 8) than RRP (n = 7) males in period 10–20 min (0.05 < p < 0.01), and lower in NP (n = 9) than RRP (n = 9) females in periods 0–10 min (0.05 < p < 0.01), and 10–40 min (p < 0.05). Benefits were modest, and the effects of procaine appear to last longer than lidocaine, while bupivacaine is slower to take effect than either procaine or lidocaine but may provide longer-lasting pain relief. The duration of action of local anesthetics is short in sheep, and detailed behavioral evaluations are required in the first hour post-procedure to establish efficacy.

A Dyadic Investigation of Depressed Affect and Interspousal Behavior in Couples With Chronic Back Pain

Background Depression and marital discord are characteristic not only of individuals with chronic low back pain (ICPs) but also of their spouses. Purpose We examined actor–partner interdependence models to evaluate associations among depressed affect and criticism and support of partners at the same time point (concurrent effects) and 3 hr later (lagged effects). Fully dyadic models were used to account for both within-person and cross-spouse associations among depressed affect, criticism, and support for ICPs and spouses. We also examined the direction of the relationships (depressed affect predicting behavior and behavior predicting depressed affect) all while controlling for pain intensity, pain behavior, and the prior dependent variable. Methods ICPs (n = 105) and their spouses completed electronic diary measures of depressed affect and behavior (criticism and support) five times a day for 2 weeks. Hierarchical linear modeling with person-mean centering was used for data analysis. Results Within the same 3 hr epoch, more depressed affect was related to higher criticism and generally less support. Lagged analyses suggested bidirectional relationships between spouse’s own depressed affect and spouse’s own criticism of ICPs. Spouse depressed affect was also associated with decreased support received from ICPs. Pain behavior and pain intensity were also related to depressed affect, criticism, and support especially concurrently. Conclusions Theories and interventions need to address not only ICP depressed affect but also spouse depressed affect, as spouse depressed affect may be a stress generating precursor to criticism and support.

Anterior Insular-Nucleus Accumbens Pathway Controls Refeeding-Induced Analgesia Under Chronic Inflammatory Pain Condition

Feeding behaviors are closely associated with chronic pain in adult rodents. Our recent study revealed that 2 hr refeeding after 24hr fasting (i.e. refeeding) attenuates pain behavior under chronic inflammatory pain conditions. However, while brain circuits mediating fasting-induced analgesia have been identified, the underlying mechanism of refeeding-induced analgesia is still elusive. Herein, we demonstrate that the neural activities in the nucleus accumbens shell (NAcS) and anterior insular cortex (aIC) were increased in a modified Complete Freund’s Adjuvant (CFA)-induced chronic inflammatory pain condition, which was reversed by refeeding. We also found that refeeding reduced the enhanced excitability of aICCamKII–NAcSD2R projecting neurons in this CFA model. Besides, chemogenetic inhibition of aICCamKII–NAcSD2R neural circuit suppressed chronic pain behavior while activation of this circuit reversed refeeding-induced analgesia. Thus, the present study suggests that aICCamKII – NacSD2R neural circuit mediates refeeding-induced analgesia, thereby serving as a potential therapeutic target to manage chronic pain.

Pain Behavior of People with Intellectual and Developmental Disabilities Coded with the New PAIC-15 and Validation of Its Arabic Translation

Pain management necessitates assessment of pain; the gold standard being self-report. Among individuals with intellectual and developmental disabilities (IDD), self-report may be limited and therefore indirect methods for pain assessment are required. A new, internationally agreed upon and user-friendly observational tool was recently published—the Pain Assessment in Impaired Cognition (PAIC-15). The current study’s aims were: to test the use of the PAIC-15 in assessing pain among people with IDD and to translate the PAIC-15 into Arabic for dissemination among Arabic-speaking professionals. Pain behavior following experimental pressure stimuli was analyzed among 30 individuals with IDD and 15 typically developing controls (TDCs). Translation of the PAIC followed the forward–backward approach; and reliability between the two versions and between raters was calculated. Observational scores with the PAIC-15 exhibited a stimulus–response relationship with pressure stimulation. Those of the IDD group were greater than those of the TDC group. The overall agreement between the English and Arabic versions was high (ICC = 0.89); single items exhibited moderate to high agreement levels. Inter-rater reliability was high (ICC = 0.92). Both versions of the PAIC-15 are feasible and reliable tools to record pain behavior in individuals with IDD. Future studies using these tools in clinical settings are warranted.

Dermal macrophages set pain sensitivity by modulating tissue NGF levels through SNX25–Nrf2 signaling

Crosstalk between peripheral neurons and immune cells plays important roles in pain sensation. We identified sorting nexin 25 (Snx25) as a pain-modulating gene in a transgenic mouse line with reduced pain behavior. Snx25 conditional-KO (cKO) in monocyte/macrophage-lineage cells but not in the peripheral sensory neurons reduced pain responses in both normal and neuropathic conditions. Cross transplantation experiments of bone marrows between cKO and wild type (WT) mice revealed that cKO macrophages caused dull phenotype in WT mice and WT macrophages in turn increased pain behavior in cKO mice. SNX25 in dermal macrophages enhances NGF (one of the key factors in pain sensation) production by inhibiting ubiquitin-mediated degradation of Nrf2, a transcription factor that activates Ngf mRNA synthesis. We conclude that dermal macrophages set pain sensitivity by producing and secreting NGF into the dermis in addition to their host defense functions.

Niacinamide and undenatured type II collagen modulates the inflammatory response in rats with monoiodoacetate-induced osteoarthritis

The current work aimed to examine the properties of oral supplementation of niacinamide and undenatured type II collagen (UCII) on the inflammation and joint pain behavior of rats with osteoarthritis (OA). Forty-nine Wistar rats were allocated into seven groups; control (no MIA), MIA as a non-supplemental group with monosodium iodoacetate (MIA)-induced knee osteoarthritis, MIA + undenatured type II collagen (UCII) at 4 mg/kg BW, MIA + Niacinamide at 40 mg/kg BW (NA40), MIA + Niacinamide at 200 mg/kg BW (NA200), MIA + UCII + NA40 and MIA + UCII + NA200. Serum IL‐1β, IL‐6, TNF-α, COMP, and CRP increased in rats with OA and decreased in UCII and NA groups (p < 0.05). Rats with osteoarthritis had greater serum MDA and knee joint MMP-3, NF-κB, and TGβ protein levels and decreased in treated groups with UCII and NA (p < 0.05). The rats with OA also bore elevated joint diameters with joint pain behavior measured as decreased the stride lengths, the paw areas, and the paw widths, and increased the Kellgren-Lawrence and the Mankin scores (p < 0.05) and decreased in UCII treated groups. These results suggest the combinations with the UCII + NA supplementation as being most effective and reduce the inflammation responses for most OA symptoms in rats.

Three Studies Evaluating the Potential For Lidocaine, Bupivacaine or Procaine to Reduce Pain-Related Behaviors Following Ring Castration and/or Tail Docking in Lambs

Use of local anesthesia at the time of ring castration and tail docking can improve lamb welfare. However, few local anesthetics are registered for sheep, and data on their duration of effect is limited. Three studies were conducted to evaluate the efficacy of procaine (P), lidocaine (L) and bupivacaine (B) in terms of observed alleviation of behavioral responses to castration and/or tail docking in 10-min blocks in the first 60 min post treatment. In each study, comparisons were made between two groups of lambs castrated and/or tail docked with rubber rings and either receiving the agent using the NUMNUTS&reg; instrument (N) or receiving no anesthetic agent (RR). Acute pain behavior was lower in NL (n = 28) than RRL (n = 15) males in the first 10 min post procedure (P &amp;lt; 0.05); lower in NB (n = 16) than RRB (n = 16) males in periods 10-20 min (0.05 &amp;lt; P &amp;lt; 0.01), 20-30 min (P &amp;lt; 0.05) and 40-50 min (0.05 &amp;lt; P &amp;lt; 0.01); lower in NB (n = 16) than RRB (n = 16) females between 20 and 40 min post-procedure (0.05 &amp;lt; P &amp;lt; 0.01); lower in NP (n = 8) than RRP (n = 7) males in period 10-20 min (0.05 &amp;lt; P &amp;lt; 0.01), and lower in NP (n = 9) than RRP (n = 9) females in periods 0-10 min (0.05 &amp;lt; P &amp;lt; 0.01), and 10-40 min (P &amp;lt; 0.05). Analgesic benefits were modest, and the effects of procaine appear to last longer than lidocaine, while bupivacaine is slower to take effect than either procaine or lidocaine but may provide longer lasting analgesia. The duration of action of local anesthetics is short in sheep, and detailed behavioral evaluations are required in the first hour post procedure to establish efficacy.

Opposing and Operated Side Electroacupuncture Generates Similar Analgesic Effects on Pain after Knee Surgery

The purpose of this study was to investigate whether opposing electroacupuncture (EA) could produce similar analgesic effects as operated side EA after knee surgery in rats. Sprague Dawley rats were randomly divided into the sham surgery group, and three surgery groups: opposing EA, operated side EA, and model. After surgery, compared with the sham surgery group, three kinds of pain behavior test methods (mechanical withdrawal threshold (MWT), cumulative pain score [CPS], and mechanical hypersensitivity of knee) were used to assess the pain behavior of the rats in the surgery groups. After knee surgery, the three surgery groups were intervened for three consecutive days: EA on the nonoperated side in the opposing EA group, EA on the operated side in the operated side EA group, and no intervention in the model group. It was shown that MWT was higher and CPS was lower in the two EA groups than in the model group on the first and second days after surgery. On the third day after surgery, MWT in the two EA groups was the highest among the 3 days, CPS was the lowest among the 3 days, and the number of nonvocalizations in rats also increased compared with the model group. Moreover, the MWT of the nonoperated side increased more in the opposing EA group than in the model and operated side EA groups. This indicated that both opposing EA and operated side EA methods can be used to relieve pain after knee joint surgery.