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Stress facilitates pain perception and sensitizes pain pathways，but the underlying mechanism is still unclear. The purpose of this study was to investigate whether activation of 5-hydroxytryptamine (5-HT) subtype-3 receptor in the spinal cord contributes to somatic hyperalgesia induced by repeated 3 day forced swim (FS) in the estradiol (E2) replacement rats after ovariectomy (OVx). Somatic sensitivity was assessed by thermal withdrawal latency to radiant heat and mechanical withdrawal threshold to von Frey filaments. The expression of 5-HT3A receptor in the L4-L5 dorsal spinal cord was examined by Western blot. Repeated FS stress reduced the thermal withdrawal latency and mechanical withdrawal threshold, and the presence of E2 exaggerated this hyperalgesia. The expression of 5-HT3A receptor in the L4-L5 dorsal spinal cord increased significantly following repeated FS in E2 replacement rats. Intrathecal injection of 5-HT3 receptor antagonist Y-25130 blocked the somatic hyperalgesia induced by FS stress. These data indicate that 5-HT3 receptor activation through the descending facilitation system contributes to the somatic hyperalgesia evoked by FS stress. The results may provide a new therapeutic avenue for alleviating pain induced by stress.
Learn More >Neuropathic pain results from nerve injuries that cause ectopic firing and increased nociceptive signal transmission due to activation of key membrane receptors and channels. The dysregulation of trafficking of voltage-gated ion channels is an emerging mechanism in the etiology of neuropathic pain. We identify increased phosphorylation of collapsin response mediator protein 2 (CRMP2), a protein reported to regulate presynaptic voltage-gated calcium and sodium channels. A spared nerve injury (SNI) increased expression of a cyclin dependent kinase 5 (Cdk5)-phosphorylated form of CRMP2 in the dorsal horn of the spinal cord and the dorsal root ganglia (DRG) in the ipsilateral (injured) versus the contralateral (non-injured) sites. Biochemical fractionation of spinal cord from SNI rats revealed the increase in Cdk5-mediated CRMP2 phosphorylation to be enriched to pre-synaptic sites. CRMP2 has emerged as a central node in assembling nociceptive signaling complexes. Knockdown of CRMP2 using a small interfering RNA (siRNA) reversed SNI-induced mechanical allodynia implicating CRMP2 expression as necessary for neuropathic pain. Intrathecal expression of a CRMP2 resistant to phosphorylation by Cdk5 normalized SNI-induced mechanical allodynia, whereas mimicking constitutive phosphorylation of CRMP2 resulted in induction of mechanical allodynia in naïve rats. Collectively, these results demonstrate that Cdk5-mediated CRMP2 phosphorylation is both necessary and sufficient for peripheral neuropathic pain.
Learn More >To assess the utility of corneal confocal microscopy in identifying small fiber damage in patients with burning mouth syndrome (BMS).
Learn More >Premature infants in the Neonatal Intensive Care Unit (NICU) may be subjected to numerous painful procedures without analgesics. One necessary, though acutely painful, procedure is the use of heel lances to monitor blood composition. The current study examined the acute effects of neonatal pain on maternal behavior as well as amygdalar and hypothalamic activation, and the long-term effects of neonatal pain on later-life anxiety-like behavior, using a rodent model. Neonatal manipulations consisted of either painful needle pricks or non-painful tactile stimulation in subjects' left plantar paw surface which occurred four times daily during the first week of life (PND 1 – 7). Additionally, maternal behaviors in manipulated litters were compared against undisturbed litters via scoring of videotaped interactions to examine the long-term effects of pain on dam-pup interactions. Select subjects underwent neonatal brain collection (PND 6) and fluorescent hybridization (FISH) for corticotropin releasing hormone (CRH) and the immediate early gene c-fos. Other subjects were raised to juvenile age (PND 24 and PND 25) and underwent innate anxiety testing utilizing an elevated plus maze protocol. FISH indicated that neonatal pain influenced amygdalar CRH and c-fos expression, predominately in males. No significant increase in c-fos or CRH expression was observed in the hypothalamus. Additionally, neonatal pain altered anxiety behaviors independent of sex, with neonatal pain subjects showing the highest frequency of exploratory behavior. Neonatal manipulations did not alter maternal behaviors. Overall, neonatal pain drives CRH expression and produces behavioral changes in anxiety that persist until the juvenile stage. This report expands on current rodent model research performed to assess the long-term effects of highly utilized neonatal intensive care unit (NICU) procedures. The NICU plays an integral role in pediatric medicine by significantly reducing infant mortality and providing necessary procedures to preterm or unwell newborns. However, procedures in the NICU are often stressful and painful. A common procedure performed in the NICU is heel lances to monitor blood composition. This, along with numerous other painful procedures, are often performed on NICU babies without the benefit of analgesics. Our study identifies key neurological indicators which are altered in response to neonatal pain. Additionally, we explore the later anxiety of subjects exposed to neonatal pain.
Learn More >Avoidance is considered key in the development of chronic pain. However, little is known about how avoidance behaviour subsequently affects pain-related fear and pain. We investigated this using a robotic arm reaching avoidance task to investigate this. In a between-subjects design both Experimental Group (n=30) and Yoked Control Group (n=30) participants perform either of three movement trajectories (T1-T3) to reach a target location. During acquisition, only participants of the Experimental Group could partially or fully avoid a painful electrocutaneous stimulus by choosing the intermediate trajectory (T2; 50% reinforcement) or the longest trajectory (T3; 0% reinforcement) versus the shortest trajectory (T1: 100% reinforcement). After acquisition, contingencies changed (all trajectories 50% reinforced), and the acquired avoidance behaviour no longer effectively prevented pain from occurring. The Yoked Control Group received the same reinforcement schedule as the Experimental Group irrespective of their behaviour. When avoidance behaviour became ineffective for the Experimental Group, pain-related fear increased for the previously safe(r) trajectories (T2 and T3) and remained the same for T1, whereas pain threshold and tolerance declined. For the Yoked Group, pain-related fear increased for all trajectories. The Experimental Group persisted in emitting avoidance behaviour following the contingency change, albeit at a lower frequency than during acquisition. PERSPECTIVE: Results indicate participants become more afraid of and sensitive to pain, when previously acquired avoidance is no longer effective. Also, participants continue to show avoidance behaviour despite it being not adaptive anymore. These findings suggest that ineffective avoidance may play role in the maintenance and development of chronic pain.
Learn More >Mechanisms of below-level pain are discoverable as rostral neural adaptations to spinal injury. Accordingly, the strategy of investigations summarized here has been to characterize behavioral and neural responses to below-level stimulation over time following selective lesions of spinal gray and/or white matter. Assessments of human pain and the pain sensitivity of humans and laboratory animals following spinal injury have revealed common disruptions of pain processing. Interruption of the spinothalamic pathway partially deafferents nocireceptive cerebral neurons, rendering them spontaneously active and hypersensitive to remaining inputs. The spontaneous activity among these neurons is disorganized and unlikely to generate pain. However, activation of these neurons by their remaining inputs can result in chronic pain. Also, injury to spinal gray matter results in a cascade of secondary events, including excitotoxicity, with rostral propagation of excitatory influences that contribute to activation of deafferented neurons and chronic pain. Establishment and maintenance of below-level pain results from combined influences of injured and spared axons in the spinal white matter and injured neurons in spinal gray matter on processing of nociception by hyperexcitable cerebral neurons that are partially deafferented. A model of spinal stenosis suggests that ischemic injury to the core spinal region can generate below-level pain. Additional questions are raised about demyelination, epileptic discharge, autonomic activation, prolonged activity of C nocireceptive neurons and thalamocortical plasticity in the generation of below-level pain. PERSPECTIVE: An understanding of mechanisms can direct therapeutic approaches to prevent development of below-level pain or arrest it following SCI. Among the possibilities covered here are surgical and other means of attenuating gray matter excitotoxicity and ascending propagation of excitatory influences from spinal lesions to thalamocortical systems involved in pain encoding and arousal.
Learn More >Chronic pain is often linked to comorbidities such as anxiety and cognitive dysfunction, alterations that are reflected in brain plasticity in regions such as the prefrontal cortex and the limbic area. Despite the growing interest in pain-related cognitive deficits, little is known about the relationship between the emotional valence of the stimulus and the salience of its memory following painful injuries. We used the tibia fracture model of chronic pain in mice to determine whether pleasant and unpleasant odor location memories differ in their salience 7 weeks following the onset of the painful injury. Our results indicate that injured mice show a bias towards recalling unpleasant memories, thereby propagating the vicious cycle of chronic pain and negative affect. Next, we linked these behavioral differences to mechanisms of molecular plasticity by measuring the levels of global methylation and hydroxymethylation in the olfactory bulb. Compared to controls, global methylation levels were shown to be increased while hydroxymethylation levels were decreased in the olfactory bulb of injured mice, indicative of overall changes in DNA regulation machinery and the subsequent alterations in sensory systems.
Learn More >Degranulation of meningeal mast cells leading to a sensitization of trigeminal vascular afferent processing is believed to be one of the mechanisms underlying the migraine pain pathway. Recent work suggests that Toll-receptor 4 (TLR4) may be involved in signaling states of central sensitization. Using a murine model of light aversion produced by compound 48/80 (2 mg/kg, i.p.) mast cell degranulation, employed as a surrogate marker for photophobia observed in migraineurs, we examined the role of TLR4 in migraine-like behavior and neuronal activation. Using a two-chambered light/dark box, we found that compound 48/80 administration in male and female C57Bl/6 mice produced light aversion lasting up to 2 hours, and that pre-treatment with sumatriptan (1 mg/kg, i.p.) reliably prevented this effect. Genetic deletion and pharmacological blockade of TLR4 with TAK-242 (3 mg/kg, i.p.) reversed the light aversive effects of compound 48/80 in males, but not in females. Assessing the downstream signaling pathway in mutant mice, we found that the TLR4 mediated, light aversion was dependent upon MyD88, but not TRIF signaling. In separate groups, male mice sacrificed at 10 min following compound 48/80 revealed a significant increase in the incidence of evoked p-ERK (+) neurons in the nucleus caudalis of WT, but not Tlr4-/- mice or in mice pretreated with sumatriptan. The present study thus provides the first evidence for involvement of TLR4 signaling through MyD88 in initiating and maintaining migraine-like behavior and nucleus caudalis neuronal activation in the mouse.
Learn More >Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
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