Jun-Bin Yin

Local Infiltration Analgesia for Postoperative Pain After Hip Arthroplasty: A Systematic Review and Meta-Analysis

UNLABELLED Postoperative pain after hip arthroplasty (HA) is very common and severe. Currently, use of routine analgesic methods is often accompanied by adverse events (AEs). Local infiltration analgesia (LIA) for controlling pain has been a therapeutic option in many surgical procedures. However, its analgesic efficacy in HA and its safety remain unclear. Data from 9 randomized controlled trials, involving 760 participants, comparing the effect of LIA with that of placebo infiltration or no infiltration on patients undergoing HA were retrieved from an electronic database, and the pain scores, analgesic consumption, and AEs were analyzed. Effects were summarized using weighted mean differences, standardized mean differences, or odds ratio with fixed or random effect models. There was strong evidence of an association between LIA and reduced pain scores at 4 hours at rest (P < .00001) and with motion (P < .00001), 6 hours with motion (P = .02), and 24 hours at rest (P = .01), and decreased analgesic consumption during 0 to 24 hours (P = .001) after HA. These analgesic efficacies for LIA were not accompanied by any increased risk for AEs. However, the current meta-analysis did not reveal any associations between LIA and the reduced pain scores or analgesic consumption at other time points. The results suggest that LIA can be used for controlling pain after HA because of its efficacy in reducing pain scores and thus can reduce analgesic consumption on the first day without increased risk of AEs. PERSPECTIVE This is the first pooled database meta-analysis to assess the analgesic effects and safety of LIA in controlling pain after HA. The derived information offers direct evidence that LIA can be used for patients undergoing HA because of its ability to reduce pain scores and analgesic consumption without any additional AEs.

Alterations in the neural circuits from peripheral afferents to the spinal cord: possible implications for diabetic polyneuropathy in streptozotocin-induced type 1 diabetic rats.

Diabetic polyneuropathy (DPN) presents as a wide variety of sensorimotor symptoms and affects approximately 50% of diabetic patients. Changes in the neural circuits may occur in the early stages in diabetes and are implicated in the development of DPN. Therefore, we aimed to detect changes in the expression of isolectin B4 (IB4, the marker for nonpeptidergic unmyelinated fibers and their cell bodies) and calcitonin gene-related peptide (CGRP, the marker for peptidergic fibers and their cell bodies) in the dorsal root ganglion (DRG) and spinal cord of streptozotocin (STZ)-induced type 1 diabetic rats showing alterations in sensory and motor function. We also used cholera toxin B subunit (CTB) to show the morphological changes of the myelinated fibers and motor neurons. STZ-induced diabetic rats exhibited hyperglycemia, decreased body weight gain, mechanical allodynia and impaired locomotor activity. In the DRG and spinal dorsal horn, IB4-labeled structures decreased, but both CGRP immunostaining and CTB labeling increased from day 14 to day 28 in diabetic rats. In spinal ventral horn, CTB labeling decreased in motor neurons in diabetic rats. Treatment with intrathecal injection of insulin at the early stages of DPN could alleviate mechanical allodynia and impaired locomotor activity in diabetic rats. The results suggest that the alterations of the neural circuits between spinal nerve and spinal cord via the DRG and ventral root might be involved in DPN.

Mechanism Underlying the Analgesic Effect Exerted by Endomorphin-1 in the rat Ventrolateral Periaqueductal Gray

The ventrolateral periaqueductal gray (vlPAG) is an important brain area, in which 5-HTergic neurons play key roles in descending pain modulation. It has been proposed that opioid peptides within the vlPAG can excite the 5-HTergic neurons by alleviating tonic inhibition from GABAergic neurons, the so-called disinhibitory effect. However, no direct morphological evidence has been observed for the micro-circuitry among the opioid peptide-, GABA-, and 5-HT-immunoreactive (ir) profiles nor for the functional involvement of the opioid peptides in the intrinsic properties of GABAergic and 5-HTergic neurons. In the present study, through microscopic observation of triple-immunofluorescence, we firstly identified the circuitry among the endomorphin-1 (EM1, an endogenous ligand for the μ-opioid receptor)-ir terminals and GABA-ir and 5-HT-ir neurons within the rat vlPAG. The synaptic connections of these neurons were further confirmed by electron microscopy. Through the in vitro whole-cell patch-clamp method, we showed that EM1 has strong inhibitory effects on the spiking of GABAergic neurons. However, although the resting membrane potential was hyperpolarized, EM1 actually increased the firing of 5-HTergic neurons. More interestingly, EM1 strongly inhibited the excitatory input to GABAergic neurons, as well as the inhibitory input to 5-HTergic neurons. Finally, behavioral results showed that pretreatment with a GABAA receptor antagonist potentiated the analgesic effect of EM1, while treatment with a GABAA receptor agonist blocked its analgesic effect. In summary, by utilizing morphological and functional methods, we found that the analgesic effect of EM1 is largely dependent on its potent inhibition on the inhibitory inputs to 5-HTergic neurons, which overwhelms EM1’s direct inhibitory effect on 5-HTergic neurons.

Inhibiting Spinal Neuron-Astrocytic Activation Correlates with Synergistic Analgesia of Dexmedetomidine and Ropivacaine

Background This study aims to identify that intrathecal (i.t.) injection of dexmedetomidine (Dex) and ropivacaine (Ropi) induces synergistic analgesia on chronic inflammatory pain and is accompanied with corresponding “neuron-astrocytic” alterations. Methods Male, adult Sprague-Dawley rats were randomly divided into sham, control and i.t. medication groups. The analgesia profiles of i.t. Dex, Ropi, and their combination detected by Hargreaves heat test were investigated on the subcutaneous (s.c.) injection of complete Freund adjuvant (CFA) induced chronic pain in rat and their synergistic analgesia was confirmed by using isobolographic analysis. During consecutive daily administration, pain behavior was daily recorded, and immunohistochemical staining was applied to investigate the number of Fos-immunoreactive (Fos-ir) neurons on hour 2 and day 1, 3 and 7, and the expression of glial fibrillary acidic protein (GFAP) within the spinal dorsal horn (SDH) on day 1, 3, 5 and 7 after s.c. injection of CFA, respectively, and then Western blot to examine spinal GFAP and β-actin levels on day 3 and 7. Results i.t. Dex or Ropi displayed a short-term analgesia in a dose-dependent manner, and consecutive daily administrations of their combination showed synergistic analgesia and remarkably down-regulated neuronal and astrocytic activations indicated by decreases in the number of Fos-ir neurons and the GFAP expression within the SDH, respectively. Conclusion i.t. co-delivery of Dex and Ropi shows synergistic analgesia on the chronic inflammatory pain, in which spinal “neuron-astrocytic activation” mechanism may play an important role.

Neurochemical properties of BDNF-containing neurons projecting to rostral ventromedial medulla in the ventrolateral periaqueductal gray.

The periaqueductal gray (PAG) modulates nociception via a descending pathway that relays in the rostral ventromedial medulla (RVM) and terminates in the spinal cord. Previous behavioral pharmacology and electrophysiological evidence suggests that brain-derived neurotrophic factor (BDNF) plays an important role in descending pain modulation, likely through the PAG-RVM pathway. However, detailed information is still lacking on the distribution of BDNF, activation of BDNF-containing neurons projecting to RVM in the condition of pain, and neurochemical properties of these neurons within the PAG. Through fluorescent in situ hybridization (FISH) and immunofluorescent staining, the homogenous distributions of BDNF mRNA and protein were observed in the four subregions of PAG. Both neurons and astrocytes expressed BDNF, but not microglia. By combining retrograde tracing methods and formalin pain model, there were more BDNF-containing neurons projecting to RVM being activated in the ventrolateral subregion of PAG (vlPAG) than other subregions of PAG. The neurochemical properties of BDNF-containing projection neurons in the vlPAG were investigated. BDNF-containing projection neurons expressed the autoreceptor TrkB in addition to serotonin (5-HT), neurotensin (NT), substance P (SP), calcitonin gene related peptide (CGRP), nitric oxide synthase (NOS), and parvalbumin (PV) but not tyrosine decarboxylase (TH). It is speculated that BDNF released from projection neurons in the vlPAG might participate in the descending pain modulation through enhancing the presynaptic release of other neuroactive substances (NSs) in the RVM.

Slow-releasing rapamycin-coated bionic peripheral nerve scaffold promotes the regeneration of rat sciatic nerve after injury

AIMS To investigate the effect of locally slow-released rapamycin (RAPA) from the bionic peripheral nerve scaffold on rat sciatic nerve regeneration in the early phase of nerve injury. MAIN METHODS Slow-releasing RAPA-polyhydroxy alcohol (PLGA) microspheres were prepared and tested for microsphere diameter and slow-release effect in vitro after loading onto nerve scaffold. A total of 48 male SD rats were randomly divided into control group and 3 experimental groups as follows: group 1: RAPA-PLGA scaffold; group 2: RAPA scaffold; and group 3: scaffold alone. In the control group, a 15mm sciatic nerve was excised and religated reversely. In the experimental groups, the scaffolds were used to bridge a defect of 15mm sciatic nerve. The outcome of nerve regeneration was evaluated using neurophysiological and neuromuscular morphological techniques. KEY FINDINGS The RAPA-PLGA microspheres displayed a smooth exterior. The slow-release of RAPA in group 1 lasted for 14days. The sciatic nerve function index (SFI) and electrophysiological and morphological features were examined 12weeks after the surgery in all groups to reveal various degrees of ipsilateral sciatic nerve regeneration. The SFI values at 12weeks showed no significant difference between the RAPA-PLGA scaffold and control groups; morphological observations revealed that the outcomes of nerve regeneration in the above 2 groups were similar and significantly better than those in the RAPA scaffold and scaffold alone groups. SIGNIFICANCE RAPA-PLGA microsphere-loaded bionic peripheral nerve scaffold gradually released RAPA locally in the early phase of sciatic nerve regeneration, reduced the secondary nerve injury, and evidently promoted the regeneration of peripheral nerve.

Collateral projections from the lateral parabrachial nucleus to the paraventricular thalamic nucleus and the central amygdaloid nucleus in the rat

Combined the retrograde double tracing with immunofluorescence histochemical staining, we examined the neurons in the lateral parabrachial nucleus (LPB) sent collateral projections to the paraventricular thalamic nucleus (PVT) and central amygdaloid nucleus (CeA) and their roles in the nociceptive transmission in the rat. After the injection of Fluoro-gold (FG) into the PVT and tetramethylrhodamine-dextran (TMR) into the CeA, respectively, FG/TMR double-labeled neurons were observed in the LPB. The percentages of FG/TMR double-labeled neurons to the total number of FG- or TMR-labeled neurons were 6.18% and 9.09%, respectively. Almost all of the FG/TMR double-labeled neurons (95%) exhibited calcitonin gene-related peptide (CGRP) immunoreactivity. In the condition of neuropathic pain, 94% of these neurons showed FOS immunoreactivity. The present data indicates that some of CGRP-expressing neurons in the LPB may transmit nociceptive information toward the PVT and CeA by way of axon collaterals.

Neural tissue engineering scaffold with sustained RAPA release relieves neuropathic pain in rats

AIMS To investigate the effect of locally slow-released rapamycin (RAPA) from bionic peripheral nerve stent to reduce the incidence of neuropathic pain or mitigate the degree of pain after nerve injury. MAIN METHODS We constructed a neural tissue engineering scaffold with sustained release of RAPA to repair 20mm defects in rat sciatic nerves. Four presurgical and postsurgical time windows were selected to monitor the changes in the expression of pain-related dorsal root ganglion (DRG) voltage-gated sodium channels 1.3 (Nav1.3), 1.7 (Nav1.7), and 1.8 (Nav1.8) through immunohistochemistry (IHC) and Western Blot, along with the observation of postsurgical pathological pain in rats by pain-related behavior approaches. KEY FINDINGS Relatively small upregulation of DRG sodium channels was observed in the experimental group (RAPA+poly(lactic-co-glycolic acid) (PLGA)+stent) after surgery, along with low degrees of neuropathic pain and anxiety, which were similar to those in the Autologous nerve graft group. SIGNIFICANCE Autoimmune inflammatory response plays a leading role in the occurrence of post-traumatic neuropathic pain, and that RAPA significantly inhibits the abnormal upregulation of sodium channels to reduce pain by alleviating inflammatory response.

Connections between EM2-containing terminals and GABA/μ-opioid receptor co-expressing neurons in the rat spinal trigeminal caudal nucleus.

Endomorphin-2 (EM2) demonstrates a potent antinociceptive effect via the μ-opioid receptor (MOR). To provide morphological evidence for the pain control effect of EM2, the synaptic connections between EM2-immunoreactive (IR) axonal terminals and γ-amino butyric acid (GABA)/MOR co-expressing neurons in lamina II of the spinal trigeminal caudal nucleus (Vc) were investigated in the rat. Dense EM2-, MOR- and GABA-IR fibers and terminals were mainly observed in lamina II of the Vc. Within lamina II, GABA- and MOR-neuronal cell bodies were also encountered. The results of immunofluorescent histochemical triple-staining showed that approximately 14.2 or 18.9% of GABA-IR or MOR-IR neurons also showed MOR- or GABA-immunopositive staining in lamina II; approximately 45.2 and 36.1% of the GABA-IR and MOR-IR neurons, respectively, expressed FOS protein in their nuclei induced by injecting formalin into the left lower lip of the mouth. Most of the GABA/MOR, GABA/FOS, and MOR/FOS double-labeled neurons made close contacts with EM2-IR fibers and terminals. Immuno-electron microscopy confirmed that the EM2-IR terminals formed synapses with GABA-IR or MOR-IR dendritic processes and neuronal cell bodies in lamina II of the Vc. These results suggest that EM2 might participate in pain transmission and modulation by binding to MOR-IR and GABAergic inhibitory interneuron in lamina II of the Vc to exert inhibitory effect on the excitatory interneuron in lamina II and projection neurons in laminae I and III.

Analgesic Effects of Duloxetine on Formalin-Induced Hyperalgesia and Its Underlying Mechanisms in the CeA

In rodents, the amygdala has been proposed to serve as a key center for the nociceptive perception. Previous studies have shown that extracellular signal-regulated kinase (ERK) signaling cascade in the central nucleus of amygdala (CeA) played a functional role in inflammation-induced peripheral hypersensitivity. Duloxetine (DUL), a serotonin and noradrenaline reuptake inhibitor, produced analgesia on formalin-induced spontaneous pain behaviors. However, it is still unclear whether single DUL pretreatment influences formalin-induced hypersensitivity and what is the underlying mechanism. In the current study, we revealed that systemic pretreatment with DUL not only dose-dependently suppressed the spontaneous pain behaviors, but also relieved mechanical and thermal hypersensitivity induced by formalin hindpaw injection. Consistent with the analgesic effects of DUL on the pain behaviors, the expressions of Fos and pERK that were used to check the neuronal activities in the spinal cord and CeA were also dose-dependently reduced following DUL pretreatment. Meanwhile, no emotional aversive behaviors were observed at 24 h after formalin injection. The concentration of 5-HT in the CeA was correlated with the dose of DUL in a positive manner at 24 h after formalin injection. Direct injecting 5-HT into the CeA suppressed both the spontaneous pain behaviors and hyperalgesia induced by formalin injection. However, DUL did not have protective effects on the formalin-induced edema of hindpaw. In sum, the activation of CeA neurons may account for the transition from acute pain to long-term hyperalgesia after formalin injection. DUL may produce potent analgesic effects on the hyperalgesia and decrease the expressions of p-ERK through increasing the concentration of serotonin in the CeA.