scholarly journals Trigeminal Nerve Injury ErbB3/ErbB2 Promotes Mechanical Hypersensitivity

2012 ◽  
Vol 117 (2) ◽  
pp. 381-388 ◽  
Author(s):  
Fei Ma ◽  
Liping Zhang ◽  
Karin N. Westlund
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Mechanical Allodynia ◽  
Infraorbital Nerve ◽  
Wild Type ◽  
Transgenic Rats ◽  
Neuregulin 1 ◽  
Mechanical Hypersensitivity ◽  
Trigeminal Neuropathic Pain ◽  
Whisker Pad

Background Chronic constriction injury of the trigeminal infraorbital nerve results in transient analgesia followed by whisker pad mechanical allodynia in rats. Neuregulin 1 expressed on axonal membranes binds receptor tyrosine kinase ErbB, promoting Schwann cell development and remyelination. This study investigated whether orofacial mechanical allodynia is signaled by ErbB3-ErbB2 heterodimers in injured nerves. Methods Whisker pad mechanical allodynia (von Frey stimuli) was quantified in wild type rats and in transgenic rats with Sleeping Beauty transposon mutation for neuregulin 1 transgene. Pain-related behavior was retested after intraperitoneal injection of the ErbB2 inhibitor Lapatinib, an agent shown by others to reduce breast cancer pain. Infraorbital nerve injury was evaluated histologically with myelin and neuronal biomarkers. ErbB3 changes over time were measured with western blots. Results Whisker pad mechanical hypersensitivity began in week 2 in wild type rats (3.11 ± 5.93 g vs. 18.72 ± 0.00 g after sham surgery, n = 9, P < 0.001), indicating trigeminal neuropathic pain, but was not evident in transgenic rats (odds ratio: 1.12, 95% confidence interval: 0.38-3.35). Initiation of statistically significant mechanohypersensitivity was delayed until week 6 after surgery in transgenic rats (3.44 ± 4.60 g vs. 18.72 ± 0.00 g, n = 4, P < 0.001). Mechanical allodynia, which persisted 8 weeks in wild type rats was alleviated by Lapatinib (15 ± 3.89 g vs. 2.45 ± 1.13 g, n = 6, P < 0.001). Infraorbital nerve damage was verified histologically. Statistically significant ErbB3 increases (weeks 5 and 10) in wild type and transgenic rats (week 10) coincided with time points when mechanical hypersensitivity was present. Conclusion The Neuregulin 1-ErbB3-ErbB2 complex is a causal mechanism in nerve injury-induced trigeminal neuropathic pain. Understanding peripheral glial mechanisms after nerve injury will improve neuropathic pain treatment.

scholarly journals Increase in IGF-1 Expression in the Injured Infraorbital Nerve and Possible Implications for Orofacial Neuropathic Pain

2019 ◽  
Vol 20 (24) ◽  
pp. 6360 ◽  
Author(s):  
Shiori Sugawara ◽  
Masamichi Shinoda ◽  
Yoshinori Hayashi ◽  
Hiroto Saito ◽  
Sayaka Asano ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Mechanical Allodynia ◽  
Transient Receptor Potential ◽  
Cervical Spinal Cord ◽  
Receptor Potential ◽  
Infraorbital Nerve ◽  
Transient Receptor Potential Vanilloid ◽  
Whisker Pad

Insulin-like growth factor-1 (IGF-1) is upregulated in the injured peripheral nerve bundle and controls nociceptive neuronal excitability associated with peripheral nerve injury. Here, we examined the involvement of IGF-1 signaling in orofacial neuropathic pain following infraorbital nerve injury (IONI) in rats. IONI promoted macrophage accumulation in the injured ION, as well as in the ipsilateral trigeminal ganglion (TG), and induced mechanical allodynia of the whisker pad skin together with the enhancement of neuronal activities in the subnucleus caudalis of the spinal trigeminal nucleus and in the upper cervical spinal cord. The levels of IGF-1 released by infiltrating macrophages into the injured ION and the TG were significantly increased. The IONI-induced the number of transient receptor potential vanilloid (TRPV) subfamily type 4 (TRPV4) upregulation in TRPV subfamily type 2 (TRPV2)-positive small-sized, and medium-sized TG neurons were inhibited by peripheral TRPV2 antagonism. Furthermore, the IONI-induced mechanical allodynia was suppressed by TRPV4 antagonism in the whisker pad skin. These results suggest that IGF-1 released by macrophages accumulating in the injured ION binds to TRPV2, which increases TRPV4 expression in TG neurons innervating the whisker pad skin, ultimately resulting in mechanical allodynia of the whisker pad skin.

scholarly journals Microglia–Astrocyte Communication via C1q Contributes to Orofacial Neuropathic Pain Associated with Infraorbital Nerve Injury

2020 ◽  
Vol 21 (18) ◽  
pp. 6834
Author(s):  
Sayaka Asano ◽  
Yoshinori Hayashi ◽  
Koichi Iwata ◽  
Akiko Okada-Ogawa ◽  
Suzuro Hitomi ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Glial Fibrillary Acidic Protein ◽  
Nerve Injury ◽  
Fluorescence Intensity ◽  
Time Window ◽  
Infraorbital Nerve ◽  
Nociceptive Neurons ◽  
Mechanical Hypersensitivity ◽  
Injury Causes ◽  
Immunohistochemical Analyses

Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia–astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain.

Alleviation of trigeminal neuropathic pain by electroacupuncture: the role of hyperpolarization-activated cyclic nucleotide-gated channel protein expression in the Gasserian ganglion

2019 ◽  
Vol 37 (3) ◽  
pp. 192-198
Author(s):  
Liuyue Yang ◽  
Weihua Ding ◽  
Zerong You ◽  
Jinsheng Yang ◽  
Shiqian Shen ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Protein Expression ◽  
Cyclic Nucleotide ◽  
Mechanical Allodynia ◽  
Infraorbital Nerve ◽  
Gasserian Ganglion ◽  
Sprague Dawley ◽  
Trigeminal Neuropathic Pain ◽  
Sprague Dawley Rats ◽  
Gated Channel

Introduction: The aim of this study was to examine the effect of electroacupuncture (EA) on trigeminal neuropathic pain in rats and explore the potential mechanism underlying the putative therapeutic effect of EA. Methods: Trigeminal neuropathic pain behavior was induced in rats by unilateral chronic constriction injury of the distal infraorbital nerve (dIoN-CCI). EA was administered at ST2 ( Sibai) and Jiachengjiang. A total of 60 Sprague Dawley rats were divided into the following four groups ( n = 15 per group) to examine the behavioral outcomes after surgery and/or EA treatment: sham (no ligation); dIoN-CCI (received isoflurane only, without EA treatment); dIoN-CCI+EA-7d (received EA treatment for 7 days); and dIoN-CCI+EA-14d (received EA treatment for 14 days). Both evoked and spontaneous nociceptive behaviors were measured. Of these, 12 rats ( n = 4 from sham, dIoN-CCI, and dIoN-CCI+EA-14d groups, respectively) were used to analyze protein expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel in the Gasserian ganglion (GG) by immunohistochemistry. Results: dIoN-CCI rats exhibited mechanical allodynia and increased face-grooming activity that lasted at least 35 days. EA treatment reduced mechanical allodynia and face-grooming in dIoN-CCI rats. Overall, 14 days of EA treatment produced a prolonged anti-nociceptive effect as compared to 7-day EA treatment. The counts of HCN1 and HCN2 immunopositive puncta were increased in the ipsilateral GG in dIoN-CCI rats and were reduced by 14 days of EA treatment. Discussion: EA treatment relieved trigeminal neuropathic pain in dIoN-CCI rats, and this effect was dependent on the duration of EA treatment. The downregulation of HCN expression may contribute to the anti-nociceptive effect of EA in this rat model of trigeminal neuropathic pain.

scholarly journals TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice

2020 ◽  
Author(s):  
Lin-Xia Zhao ◽  
Ming Jiang ◽  
Xue-Qiang Bai ◽  
De-Li Cao ◽  
Xiao-Bo Wu ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Inflammatory Cytokines ◽  
Trigeminal Ganglion ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Infraorbital Nerve ◽  
Trigeminal Neuropathic Pain ◽  
Intracellular Ca ◽  
Significant Health ◽  
Pro Inflammatory Cytokines

AbstractTrigeminal neuropathic pain (TNP) is a significant health problem but the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) have recently been demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. Here, we show that TLR8 was persistently increased in the trigeminal ganglion (TG) neurons in model of TNP induced by partial infraorbital nerve ligation (pIONL). In addition, deletion or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38-MAPK, and decreased the expression of pro-inflammatory cytokines in the TG. Furthermore, intra-TG injection of the TLR8 agonist VTX-2337 induced pain hypersensitivity. VTX-2337 also increased the intracellular Ca2+ concentration, induced the activation of ERK and p38, and increased the expression of pro-inflammatory cytokines in the TG. These data indicate that TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP.

scholarly journals Pathophysiological implication of CaV3.1 T-type Ca2+ channels in trigeminal neuropathic pain

2016 ◽  
Vol 113 (8) ◽  
pp. 2270-2275 ◽  
Author(s):  
Soonwook Choi ◽  
Eunah Yu ◽  
Eunjin Hwang ◽  
Rodolfo R. Llinás
Keyword(s):  
Neuropathic Pain ◽  
Somatosensory Cortex ◽  
Sensory Processing ◽  
Knockout Mice ◽  
Low Frequency ◽  
Infraorbital Nerve ◽  
Primary Somatosensory Cortex ◽  
Wild Type ◽  
Neuropathic Pain Syndrome ◽  
Trigeminal Neuropathic Pain

A crucial pathophysiological issue concerning central neuropathic pain is the modification of sensory processing by abnormally increased low-frequency brain rhythms. Here we explore the molecular mechanisms responsible for such abnormal rhythmicity and its relation to neuropathic pain syndrome. Toward this aim, we investigated the behavioral and electrophysiological consequences of trigeminal neuropathic pain following infraorbital nerve ligations in CaV3.1 T-type Ca2+ channel knockout and wild-type mice. CaV3.1 knockout mice had decreased mechanical hypersensitivity and reduced low-frequency rhythms in the primary somatosensory cortex and related thalamic nuclei than wild-type mice. Lateral inhibition of gamma rhythm in primary somatosensory cortex layer 4, reflecting intact sensory contrast, was present in knockout mice but severely impaired in wild-type mice. Moreover, cross-frequency coupling between low-frequency and gamma rhythms, which may serve in sensory processing, was pronounced in wild-type mice but not in CaV3.1 knockout mice. Our results suggest that the presence of CaV3.1 channels is a key element in the pathophysiology of trigeminal neuropathic pain.

scholarly journals Antagonism of Transient Receptor Potential Ankyrin Type-1 Channels as a Potential Target for the Treatment of Trigeminal Neuropathic Pain: Study in an Animal Model

2018 ◽  
Vol 19 (11) ◽  
pp. 3320 ◽  
Author(s):  
Chiara Demartini ◽  
Rosaria Greco ◽  
Anna Zanaboni ◽  
Oscar Francesconi ◽  
Cristina Nativi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Infraorbital Nerve ◽  
Trigeminal Neuropathic Pain ◽  
Trpv1 Channels ◽  
Transient Receptor

Transient receptor potential ankyrin type-1 (TRPA1) channels are known to actively participate in different pain conditions, including trigeminal neuropathic pain, whose clinical treatment is still unsatisfactory. The aim of this study was to evaluate the involvement of TRPA1 channels by means of the antagonist ADM_12 in trigeminal neuropathic pain, in order to identify possible therapeutic targets. A single treatment of ADM_12 in rats 4 weeks after the chronic constriction injury of the infraorbital nerve (IoN-CCI) significantly reduced the mechanical allodynia induced in the IoN-CCI rats. Additionally, ADM_12 was able to abolish the increased levels of TRPA1, calcitonin gene-related peptide (CGRP), substance P (SP), and cytokines gene expression in trigeminal ganglia, cervical spinal cord, and medulla induced in the IoN-CCI rats. By contrast, no significant differences between groups were seen as regards CGRP and SP protein expression in the pars caudalis of the spinal nucleus of the trigeminal nerve. ADM_12 also reduced TRP vanilloid type-1 (TRPV1) gene expression in the same areas after IoN-CCI. Our findings show the involvement of both TRPA1 and TRPV1 channels in trigeminal neuropathic pain, and in particular, in trigeminal mechanical allodynia. Furthermore, they provide grounds for the use of ADM_12 in the treatment of trigeminal neuropathic pain.

scholarly journals Oxytocin-Dependent Regulation of TRPs Expression in Trigeminal Ganglion Neurons Attenuates Orofacial Neuropathic Pain following Infraorbital Nerve Injury in Rats

2020 ◽  
Vol 21 (23) ◽  
pp. 9173
Author(s):  
Masatoshi Ando ◽  
Yoshinori Hayashi ◽  
Suzuro Hitomi ◽  
Ikuko Shibuta ◽  
Akihiko Furukawa ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Trigeminal Ganglion ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Infraorbital Nerve ◽  
Transient Receptor Potential Vanilloid ◽  
Withdrawal Threshold ◽  
Whisker Pad ◽  
Ganglion Neurons

We evaluated the mechanisms underlying the oxytocin (OXT)-induced analgesic effect on orofacial neuropathic pain following infraorbital nerve injury (IONI). IONI was established through tight ligation of one-third of the infraorbital nerve thickness. Subsequently, the head withdrawal threshold for mechanical stimulation (MHWT) of the whisker pad skin was measured using a von Frey filament. Trigeminal ganglion (TG) neurons innervating the whisker pad skin were identified using a retrograde labeling technique. OXT receptor-immunoreactive (IR), transient receptor potential vanilloid 1 (TRPV1)-IR, and TRPV4-IR TG neurons innervating the whisker pad skin were examined on post-IONI day 5. The MHWT remarkably decreased from post-IONI day 1 onward. OXT application to the nerve-injured site attenuated the decrease in MHWT from day 5 onward. TRPV1 or TRPV4 antagonism significantly suppressed the decrement of MHWT following IONI. OXT receptors were expressed in the uninjured and Fluoro-Gold (FG)-labeled TG neurons. Furthermore, there was an increase in the number of FG-labeled TRPV1-IR and TRPV4-IR TG neurons, which was inhibited by administering OXT. This inhibition was suppressed by co-administration with an OXT receptor antagonist. These findings suggest that OXT application inhibits the increase in TRPV1-IR and TRPV4-IR TG neurons innervating the whisker pad skin, which attenuates post-IONI orofacial mechanical allodynia.

scholarly journals Plasticity-Related PKMζSignaling in the Insular Cortex Is Involved in the Modulation of Neuropathic Pain after Nerve Injury

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Jeongsoo Han ◽  
Minjee Kwon ◽  
Myeounghoon Cha ◽  
Motomasa Tanioka ◽  
Seong-Karp Hong ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Neural Plasticity ◽  
Mechanical Allodynia ◽  
Insular Cortex ◽  
Long Term Potentiation ◽  
Inhibitory Peptide ◽  
Term Potentiation ◽  
Potential Applications

The insular cortex (IC) is associated with important functions linked with pain and emotions. According to recent reports, neural plasticity in the brain including the IC can be induced by nerve injury and may contribute to chronic pain. Continuous active kinase, protein kinase Mζ(PKMζ), has been known to maintain the long-term potentiation. This study was conducted to determine the role of PKMζin the IC, which may be involved in the modulation of neuropathic pain. Mechanical allodynia test and immunohistochemistry (IHC) of zif268, an activity-dependent transcription factor required for neuronal plasticity, were performed after nerve injury. Afterζ-pseudosubstrate inhibitory peptide (ZIP, a selective inhibitor of PKMζ) injection, mechanical allodynia test and immunoblotting of PKMζ, phospho-PKMζ(p-PKMζ), and GluR1 and GluR2 were observed. IHC demonstrated that zif268 expression significantly increased in the IC after nerve injury. Mechanical allodynia was significantly decreased by ZIP microinjection into the IC. The analgesic effect lasted for 12 hours. Moreover, the levels of GluR1, GluR2, and p-PKMζwere decreased after ZIP microinjection. These results suggest that peripheral nerve injury induces neural plasticity related to PKMζand that ZIP has potential applications for relieving chronic pain.

Sign in / Sign up

Export Citation Format

Share Document