Chronic Constriction Injury-induced Pain Research Articles

Huntington-associated protein 1 inhibition contributes to neuropathic pain by suppressing Cav1.2 activity and attenuating inflammation.

Although pain dysfunction is increasingly observed in Huntington disease, the underlying mechanisms still unknown. As a crucial Huntington-associated protein, Huntington-associated protein 1 (HAP1) is enriched in normal spinal dorsal horn and dorsal root ganglia (DRG) which are regarded as "primary sensory center," indicating its potential functions in pain process. Here, we discovered that HAP1 level was greatly increased in the dorsal horn and DRG under acute and chronic pain conditions. Lack of HAP1 obviously suppressed mechanical allodynia and hyperalgesia in spared nerve injury (SNI)-induced and chronic constriction injury-induced pain. Its deficiency also greatly inhibited the excitability of nociceptive neurons. Interestingly, we found that suppressing HAP1 level diminished the membrane expression of the L-type calcium channel (Cav1.2), which can regulate Ca 2+ influx and then influence brain-derived neurotrophic factor (BDNF) synthesis and release. Furthermore, SNI-induced activation of astrocytes and microglia notably decreased in HAP1-deficient mice. These results indicate that HAP1 deficiency might attenuate pain responses. Collectively, our results suggest that HAP1 in dorsal horn and DRG neurons regulates Cav1.2 surface expression, which in turn reduces neuronal excitability, BDNF secretion, and inflammatory responses and ultimately influences neuropathic pain progression.

Transcribed ultraconserved noncoding RNA uc.153 is a new player in neuropathic pain.

Transcribed ultraconserved regions are a novel class of long noncoding RNAs and are completely conserved in humans, rats, and mice. Transcribed ultraconserved regions have been implicated in diverse biological processes; however, very little is currently known about their role in pain modulation. Here, we found that the level of the spinal transcribed ultraconserved region uc.153 was significantly increased in a mouse model of sciatic nerve chronic constriction injury (CCI)-induced chronic neuropathic pain. The knockdown of spinal uc.153 prevented and reversed chronic constriction injury-induced pain behaviours and spinal neuronal sensitization. By contrast, the overexpression of spinal uc.153 produced pain behaviours and neuronal sensitization in naive mice. Moreover, we found that uc.153 participates in the regulation of neuropathic pain by negatively modulating the processing of pre-miR-182-5p. Collectively, our findings reveal an important role for uc.153 in pain modulation and provide a novel drug target for neuropathic pain therapy.

Neuroprotective and Anti-inflammatory Role of Atorvastatin and Its Interaction with Nitric Oxide (NO) in Chronic Constriction Injury-induced Neuropathic Pain.

Prevention and treatment of neuropathic pain (NP) is one of the most difficult problems in clinical practice since the underlying mechanism of NP is unclear. In previous studies, the increased production of nitric oxide (NO) has been closely linked to the induced NP. In this study, we assessed the effect of atorvastatin through NO mechanism, on inflammation, thermal hyperalgesia, thermal allodynia, and mechanical allodynia as well as sciatic nerve histological score in rat with chronic constriction injury (CCI) model. Finally, we specified the role of cytokines such as TNF-α and IL-6 in the spinal cord. Treatment with atorvastatin and L-NAME (NO inhibitor) attenuated the thermal hyperalgesia, thermal allodynia and mechanical allodynia induced by CCI. The antinociceptive consequence was better elevated with a combination of atorvastatin and L-NAME in comparison with the other groups. In addition, the treatment with these drugs also attenuated the CCI-induced TNF-α and IL-6 level in the spinal cord. Furthermore, the histological analysis showed a low level of inflammation in the sciatic nerve in the CCI rats co-treated with atorvastatin and L-NAME. Findings of our study in NP-induced CCI in the rat model demonstrate that inhibition of NO displays antinociceptive and anti-neuroinflammatory effects of atorvastatin in peripheral and central nervous system. In addition, we found that inhibition of the NO by atorvastatin could be one of the most important anti-inflammatory pathways of atorvastatin effect.

Contralateral monoarthritis exacerbated chronic constriction injury-induced pain hypersensitivity through upregulating inducible nitric oxide synthase

IntroductionHigh comorbidity of osteoarthritis (OA) and neuropathic pain has been reported in aged patients. Evidence shows that central sensitization of pain processing occurs in late-phase OA and may facilitate the development of neuropathic pain. Few studies reveal whether acute monoarthritis (MA) aggravates neuropathic pain on the opposite side of the body from the injury.MethodsTo address whether neuropathic pain is affected by contralateral MA through distinct inflammatory pathway, MA was induced by intra-articular injection of complete Freund’s adjuvant (CFA) into the right tibiotarsal joint, and neuropathic pain was established by chronic constriction injury (CCI) of the left sciatic nerve.ResultsWe observed that MA aggravated mechanical allodynia and thermal hyperalgesia in CCI rats. Furthermore, MA affected the other side of the spinal cord in multiple aspects, including the upregulation of iNOS mRNA and the enhancement of forskolin-induced facilitation of excitatory synaptic transmission in the spinal cord dorsal horn substantia gelatinosa neurons.DiscussionInterestingly, intrathecal injection of 1400W, an antagonist of iNOS, attenuated intensity of pain behaviors in CCI rats with contralateral MA to similar levels in CCI rats without MA, and also normalized the facilitatory effect of forskolin on excitatory synaptic transmission in the spinal cord dorsal horn neurons in contralateral MA rats. Therefore, contralateral MA worsened CCI-induced pain hypersensitivity probably through upregulating iNOS and enhancing the facilitation of synaptic transmission following CCI.ConclusionInhibiting the iNOS might be a potential therapeutic strategy for concurrent OA and neuropathic pain.

Neuroanatomical characterization of imidazoline I2 receptor agonist-induced antinociception.

Chronic pain is a significant public health problem with a lack of safe and effective analgesics. The imidazoline I2 receptor (I2 R) is a promising analgesic target, but the neuroanatomical structures involved in mediating I2 R-associated behaviors are unknown. I2 Rs are enriched in the arcuate nucleus, dorsal raphe (DR), interpeduncular nucleus, lateral mammillary body, medial habenula, nucleus accumbens (NAc) and paraventricular nucleus; thus, this study investigated the antinociceptive and hypothermic effects of microinjections of the I2 R agonist 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI). In rats, intra-DR microinjections produced antinociception in complete Freund's adjuvant- and chronic constriction injury-induced pain models. Intra-NAc microinjections produced antinociception and increased noxious stimulus-associated side time in a place escape/avoidance paradigm. Intra-NAc pretreatment with the I2 R antagonist idazoxan but not the D1 receptor antagonist SCH23390 or the D2 receptor antagonist raclopride attenuated intra-NAc 2-BFI-induced antinociception. Intra-NAc idazoxan did not attenuate systemically administered 2-BFI-induced antinociception. Microinjections into the other regions did not produce antinociception, and in none of the regions produced hypothermia. These data suggest that I2 R activation in some but not all I2 R-enriched brain regions is sufficient to produce antinociception and supports the theory that different I2 R-associated effects are mediated via distinct receptor populations, which may in turn be distributed differentially throughout the CNS.

Annexin A10 contributes to chronic constrictive injury-induced pain through activating ERK1/2 signalling in rats

ABSTRACTPurpose: The current study aims at investigating the downstream targets of spinal Annexin A10 in modulating neuropathic pain.Materials and methods: Paw withdrawal latency and paw withdrawal threshold were measured to evaluate the pain-associated behaviour in rats. The expression of spinal Annexin A10, phosphorylated-extracellular regulated kinase 1/2 and extracellular regulated kinase were detected by western blotting. The level of tumour necrosis factor-α and interleukine-1β was tested by enzyme-linked immunosorbent assay (ELISA) kits.Results: Chronic constrictive injury caused pain hypersensitivity in rats, along with increased expression of spinal Annexin A10, phosphorylated-extracellular regulated kinase 1/2, tumour necrosis factor-α and interleukine-1β in rats. Knockdown of spinal Annexin A10 suppressed the chronic constrictive injury-induced hyperalgesia, and inhibited the chronic constrictive injury-induced increased expression of phosphorylated-extracellular regulated kinase 1/2, tumour necrosis factor-α and interleukine-1β in the spinal cord. Inhibition of spinal extracellular regulated kinase activation decreased the release of tumour necrosis factor-α and interleukine-1β, but did not change the increased expression of Annexin A10 caused by chronic constrictive injury.Conclusions: Annexin A10 contributed to the development of neuropathic pain by activating spinal extracellular regulated kinase signalling and the subsequent release of tumour necrosis factor-α and interleukine-1β in the spinal cord.

Mechanism and effects of NMDA receptor NR1 subunit on chronic constriction injury-induced neuropathic pain in a rat model

Objective To investigate the effects of intrathecal injection (IT) of agonist and antagonist of N-methyl-D-aspartate receptor subunit 1 (NMDA NR1) on pain threshold and spinal levels of glutamate and glutamate transporter-1(GLT-1) in rat model of chronic constriction injury (CCI) induced neuropathic pain. Methods Sprague-Dawley (SD) rats were randomly divided into 4 groups (Sham, CCI, NMDA, and Humanin). The CCI model was established by right sciatic nerve constriction. The thermal and mechanical thresholds were assessed by paw withdrawal latency (PWL) to radiant heat and von Frey filaments at 1, 3, 5, 7, 10 and 14 days as well as behavior after CCI. The NMDA and Humanin groups were administered intrathecally for 3 days before surgery. Spinal expression of GLT-1 assessed by Weston blotting and levels of glutamate were measured by enzyme-linked immunosorbent assay (ELISA). Results Compared to Sham group, the rats in CCI group gradually appeared the symptoms of toe close together, foot valgus and repeated licking to the operative side of the hind legs after surgery, and the paw withdrawal thresh-old (PWT), and PWL were greatly decreased, reaching the lowest level on the 7th day. Meanwhile, the glutamate content was increased, and the GLT-1 expression was decreased in spinal cord (P<0.05). Compared to CCI group, the rats in NMDA group were observed with further decrease in PWT, PWL and GLT-1 expressions at all observed timepoints (P<0.05), but increase in glutamate content in spine cord (P<0.05). Compared to CCI group, the rats in Humanin group were observed with increase in PWT, PWL and GLT-1 expressions at all observed timepoint (P<0.05), but decrease in glutamate content in spine cord (P<0.05). Conclusions NMDA receptor NR1 subunit participated in regulating neuropathic pain, inhibiting NMDA receptor NR1 subunit can alleviate neuropathic pain by down-regulating of glutamate and GLT-1. Key words: Receptors, N-methyl-D-aspartate/AG/AI/ME; Neuralgia/ME/DT; Glutamic acid/ME/DE; Spinal cord/ME

Exploring the potential of telmisartan in chronic constriction injury-induced neuropathic pain in rats

The present study was designed to investigate the potential of telmisartan, an angiotensin AT 1 receptor, in chronic constriction injury-induced neuropathic pain in rats. Four loose ligatures were placed around the sciatic nerve to induce chronic constriction injury and neuropathic pain. Acetone drop, pin-prick, hot plate and paint brush tests were performed to assess cold allodynia; mechanical and heat hyperalgesia; and dynamic mechanical allodynia, respectively along with assessment of spontaneous pain and postural index in terms of foot deformity. The levels of TNF-α were measured in the sciatic nerve as an index of inflammation. Chronic constriction injury was associated with development of cold allodynia; mechanical and heat hyperalgesia; dynamic mechanical allodynia; and spontaneous pain and foot deformity along with rise in the levels of TNF-α. Telmisartan (1, 2, 5 mg/kg, p.o.) was administered for 14 days in chronic constriction injury subjected rats. Administration of telmisartan (2, 5 mg/kg) significantly attenuated chronic constriction injury-induced pain related behavior, foot deformity and rise in TNF-α level. It may be concluded that telmisartan has a potential in attenuating neuropathic pain behavior in chronic constriction injury model which may possibly be attributed to its anti-inflammatory properties.

Differential effect of spironolactone in chronic constriction injury and vincristine-induced neuropathic pain in rats

The present study was designed to investigate the ameliorative potential of spironolactone in chronic constriction injury and vincristine-induced neuropathic pain in rats. The chronic constriction injury was induced by placing four loose ligatures around the sciatic nerve, while vincristine (50 μg/kg) was administered for 10 days to induce chemotherapy-induced neuropathic pain. Acetone drop, pin-prick, hot plate and paint brush tests were performed to assess cold allodynia; mechanical and heat hyperalgesia; dynamic mechanical allodynia, respectively. The spontaneous pain and postural index in terms of foot deformity was also assessed. The levels of TNF-α were measured in the sciatic nerve as an index of inflammation. Chronic constriction injury led to significant development of cold allodynia; mechanical and heat hyperalgesia; dynamic mechanical allodynia; spontaneous pain and foot deformity along with rise in the levels of TNF-α. Administration of vincristine was associated with the development of allodynia and hyperalgesia without spontaneous pain, foot deformity and elevation in the levels of TNF-α. Administration of spironolactone (10 and 20 mg/kg) significantly attenuated chronic constriction injury-induced pain related behaviour and foot deformity along with attenuation of TNF-α levels, without modulating vincristine-induced neuropathic pain. The attenuating effect of spironolactone in chronic constriction injury may be due to its anti-inflammatory properties and ability to decrease pro-inflammatory cytokines, while involvement of non-inflammatory mechanisms in the pathogenesis of vincristine-induced pain may probably explain its lack of beneficial effect in chemotherapy associated pain.

530. Spinal Interleukin-10 (IL-10) Gene Therapy Using Viral and Non-Viral Vectors Controls Inflammatory- and Chronic Constriction Injury-Induced Pain States in Rats

Spinal cord glia, via proinflammatory cytokines (interleukin-1, tumor necrosis factor, & interleukin-6), critically mediate the creation/maintenance of pathological pain such as sciatic inflammatory neuropathy (SIN) & chronic constriction injury (CCI). The anti-inflammatory cytokine, IL-10, suppresses proinflammatory cytokine production & function. We have used a variety of gene therapy approaches to examine the efficacy of IL-10 in rat models of neuropathic pain. Behavior was assessed before & after induction of various pain models. Adenoviral vectors expressing the IL-10 gene block &/or reverse exaggerated pain (mechanical allodynia [von Frey test] & thermal hyperalgesia [Hargreaves test]) produced by intrathecal (IT) lumbosacral spinal (LS) delivery of gp120, SIN, & CCI. IT LS delivery of AAV2 encoding IL-10 (AAV2-IL-10) was able to block SIN allodynia [amp] reverse CCI allodynia [amp] thermal hyperalgesia. However, the effects of viral IL-10 delivery systems resulted in reversals in the pain state of short duration. An IL-10-encoding non-viral plasmid vector (NVV) was also introduced IT in the CCI model. In contrast to the viral vectors, this approach resulted in long-lasting reversals of the pain state. Ongoing experiments will assess additional effects of NVV-driven IL-10 protein expression, including the identification of transfected tissue(s). These results suggest that NVV-based IL-10 gene therapy may be a potent addition to the treatments available to neuropathic pain patients.