scholarly journals Macrophage angiotensin II type 2 receptor triggers neuropathic pain

2018 ◽  
Vol 115 (34) ◽  
pp. E8057-E8066 ◽  
Author(s):  
Andrew J. Shepherd ◽  
Aaron D. Mickle ◽  
Judith P. Golden ◽  
Madison R. Mack ◽  
Carmen M. Halabi ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Angiotensin Ii ◽  
Nerve Injury ◽  
Hematopoietic Cell Transplantation ◽  
Tissue Cell ◽  
Chronic Neuropathic Pain ◽  
Cold Pain ◽  
Pain Hypersensitivity ◽  
Recent Success

Peripheral nerve damage initiates a complex series of structural and cellular processes that culminate in chronic neuropathic pain. The recent success of a type 2 angiotensin II (Ang II) receptor (AT2R) antagonist in a phase II clinical trial for the treatment of postherpetic neuralgia suggests angiotensin signaling is involved in neuropathic pain. However, transcriptome analysis indicates a lack of AT2R gene (Agtr2) expression in human and rodent sensory ganglia, raising questions regarding the tissue/cell target underlying the analgesic effect of AT2R antagonism. We show that selective antagonism of AT2R attenuates neuropathic but not inflammatory mechanical and cold pain hypersensitivity behaviors in mice. Agtr2-expressing macrophages (MΦs) constitute the predominant immune cells that infiltrate the site of nerve injury. Interestingly, neuropathic mechanical and cold pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MΦs and AT2R-null hematopoietic cell transplantation. Our study identifies AT2R on peripheral MΦs as a critical trigger for pain sensitization at the site of nerve injury, and therefore proposes a translatable peripheral mechanism underlying chronic neuropathic pain.

scholarly journals Macrophage-to-sensory neuron crosstalk mediated by Angiotensin II type-2 receptor elicits neuropathic pain

2017 ◽  
Author(s):  
Andrew J. Shepherd ◽  
Aaron D. Mickle ◽  
Bryan A. Copits ◽  
Páll Karlsson ◽  
Suraj Kadunganattil ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Angiotensin Ii ◽  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Hematopoietic Cell Transplantation ◽  
Cell Damage ◽  
Chronic Neuropathic Pain ◽  
Cold Pain ◽  
Pain Hypersensitivity

ABSTRACTPeripheral nerve damage initiates a complex series of cellular and structural processes that culminate in chronic neuropathic pain. Our study defines local angiotensin signaling via activation of the Angiotensin II (Ang II) type-2 receptor (AT2R) on macrophages as the critical trigger of neuropathic pain. An AT2R-selective antagonist attenuates neuropathic, but not inflammatory pain hypersensitivity in mice, and requires the cell damage-sensing ion channel transient receptor potential family-A member-1 (TRPA1). Mechanical and cold pain hypersensitivity that are characteristic of neuropathic conditions can be attenuated by chemogenetic depletion of peripheral macrophages and AT2R-null hematopoietic cell transplantation. Our findings show no AT2R expression in mouse or human sensory neurons, rather AT2R expression and activation in macrophages triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on sensory neurons. Our study defines the precise neuro-immune crosstalk underlying nociceptor sensitization at the site of nerve injury. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic neuropathic pain, and therefore identifies multiple analgesic targets.

Chronic neuropathic pain after traumatic peripheral nerve injuries in the upper extremity: prevalence, demographic and surgical determinants, impact on health and on pain medication

2019 ◽  
Vol 20 (1) ◽  
pp. 95-108
Author(s):  
Adriana Miclescu ◽  
Antje Straatmann ◽  
Panagiota Gkatziani ◽  
Stephen Butler ◽  
Rolf Karlsten ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Upper Extremity ◽  
Nerve Injury ◽  
Persistent Pain ◽  
Peripheral Nerve Injuries ◽  
Nerve Injuries ◽  
Chronic Neuropathic Pain ◽  
Younger Age

AbstractBackground and aimsAside from the long term side effects of a nerve injury in the upper extremity with devastating consequences there is often the problem of chronic neuropathic pain. The studies concerning the prevalence of persistent pain of neuropathic origin after peripheral nerve injuries are sparse. The prevalence and risk factors associated with chronic neuropathic pain after nerve injuries in the upper extremity were assessed.MethodsA standardized data collection template was employed prospectively and retrospectively for all patients with traumatic nerve injuries accepted at the Hand Surgery Department, Uppsala, Sweden between 2010 and 2018. The template included demographic data, pain diagnosis, type of injured nerve, level of injury, date of the lesion and repair, type of procedure, reoperation, time since the procedure, S-LANSS questionnaire (Self report-Leeds Assessment of Neuropathic Symptoms and Signs), RAND-36 (Item short form health survey), QuickDASH (Disability of Shoulder, Arm and Hand) and additional questionnaires concerned medication, pain intensity were sent to 1,051 patients with nerve injuries. Partial proportional odds models were used to investigate the association between persistent pain and potential predictors.ResultsMore than half of the patients undergoing a surgical procedure developed persistent pain. Prevalence of neuropathic pain was 73% of the patients with pain (S-LANSS ≥ 12 or more). Multivariate analysis indicated that injury of a major nerve OR 1.6 (p = 0.013), years from surgery OR 0.91 (p = 0.01), younger age OR 0.7 (p < 0.001), were the main factors for predicting pain after surgery. The type of the nerve injured was the strongest predictor for chronic pain with major nerves associated with more pain (p = 0.019).ConclusionsA high prevalence of chronic pain and neuropathic pain with a negative impact on quality of life and disability were found in patients after traumatic nerve injury. Major nerve injury, younger age and less time from surgery were predictors for chronic pain.

scholarly journals A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats

2011 ◽  
Vol 115 (4) ◽  
pp. 812-821 ◽  
Author(s):  
Jing Wang ◽  
Yossef Goffer ◽  
Duo Xu ◽  
David S. Tukey ◽  
D. B. Shamir ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Forced Swim Test ◽  
Preference Test ◽  
Sucrose Preference ◽  
Spared Nerve Injury ◽  
Chronic Neuropathic Pain ◽  
Swim Test ◽  
Forced Swim ◽  
Sucrose Preference Test

Background Chronic pain is associated with depression. In rodents, pain is often assessed by sensory hypersensitivity, which does not sufficiently measure affective responses. Low-dose ketamine has been used to treat both pain and depression, but it is not clear whether ketamine can relieve depression associated with chronic pain and whether this antidepressant effect depends on its antinociceptive properties. Methods The authors examined whether the spared nerve injury model of neuropathic pain induces depressive behavior in rats, using sucrose preference test and forced swim test, and tested whether a subanesthetic dose of ketamine treats spared nerve injury-induced depression. Results Spared nerve injury-treated rats, compared with control rats, showed decreased sucrose preference (0.719 ± 0.068 (mean ± SEM) vs. 0.946 ± 0.010) and enhanced immobility in the forced swim test (107.3 ± 14.6s vs. 56.2 ± 12.5s). Further, sham-operated rats demonstrated depressive behaviors in the acute postoperative period (0.790 ± 0.062 on postoperative day 2). A single subanesthetic dose of ketamine (10 mg/kg) did not alter spared nerve injury-induced hypersensitivity; however, it treated spared nerve injury-associated depression-like behaviors (0.896 ± 0.020 for ketamine vs. 0.663 ± 0.080 for control rats 1 day after administration; 0.858 ± 0.017 for ketamine vs. 0.683 ± 0.077 for control rats 5 days after administration). Conclusions Chronic neuropathic pain leads to depression-like behaviors. The postoperative period also confers vulnerability to depression, possibly due to acute pain. Sucrose preference test and forced swim test may be used to compliment sensory tests for assessment of pain in animal studies. Low-dose ketamine can treat depression-like behaviors induced by chronic neuropathic pain.

scholarly journals Upregulation of fatty acid amide hydrolase in the dorsal periaqueductal gray is associated with neuropathic pain and reduced heart rate in rats

2017 ◽  
Vol 312 (4) ◽  
pp. R585-R596 ◽  
Author(s):  
Caron Dean ◽  
Cecilia J. Hillard ◽  
Jeanne L. Seagard ◽  
Francis A. Hopp ◽  
Quinn H. Hogan
Keyword(s):  
Heart Rate ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Chronic Neuropathic Pain ◽  
Transcript Levels ◽  
Amide Hydrolase ◽  
Catabolic Enzyme ◽  
Fatty Acid Amide

Nerve damage can induce a heightened pain response to noxious stimulation, which is termed hyperalgesia. Pain itself acts as a stressor, initiating autonomic and sensory effects through the dorsal periaqueductal gray (dPAG) to induce both sympathoexcitation and analgesia, which prior studies have shown to be affected by endocannabinoid signaling. The present study addressed the hypothesis that neuropathic pain disrupts autonomic and analgesic regulation by endocannabinoid signaling in the dPAG. Endocannabinoid contents, transcript levels of endocannabinoid signaling components, and catabolic enzyme activity were analyzed in the dPAG of rats at 21 days after painful nerve injury. The responses to two nerve injury models were similar, with two-thirds of animals developing hyperalgesia that was maintained throughout the postinjury period, whereas no sustained change in sensory function was observed in the remaining rats. Anandamide content was lower in the dPAG of rats that developed sustained hyperalgesia, and activity of the catabolic enzyme fatty acid amide hydrolase (FAAH) was higher. Intensity of hyperalgesia was correlated to transcript levels of FAAH and negatively correlated to heart rate and sympathovagal balance. These data suggest that maladaptive endocannabinoid signaling in the dPAG after nerve injury could contribute to chronic neuropathic pain and associated autonomic dysregulation. This study demonstrates that reduced anandamide content and upregulation of FAAH in the dPAG are associated with hyperalgesia and reduced heart rate sustained weeks after nerve injury. These data provide support for the evaluation of FAAH inhibitors for the treatment of chronic neuropathic pain.

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