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Approximately 50% of patients with chronic neuropathic pain experience cognitive impairment, which negatively impacts their quality of life. The cannabinoid type 2 receptor (CB2R) may be involved in hippocampal cognitive processes. However, its role in chronic neuropathic pain‐induced cognitive impairment remains elusive. Spared nerve injury (SNI) was used to induce chronic neuropathic pain in rats, while the novel‐object recognition test and the Y‐maze test were employed to assess cognitive function. Immunofluorescence, western blotting, and stereotaxic hippocampal microinjection were utilized to elucidate the potential mechanisms. We observed a reduction in mechanical pain threshold and cognitive impairment in SNI rats. This was accompanied by a tendency for hippocampal microglia to adopt pro‐inflammatory functions. Notably, no changes were detected in CB2R expression. However, downregulation of the endogenous ligands AEA and 2‐AG was evident. Hippocampal microinjection of a CB2R agonist mitigated cognitive impairment in SNI rats, which correlated with a tendency for microglia to adopt anti‐inflammatory functions. Additionally, SNI‐induced activation of the p‐ERK/NFκB pathway in the hippocampus. Activation of CB2R reversed this process by upregulating DUSP6 expression in microglia. The effects elicited by CB2R activation could be inhibited through the downregulation of microglial DUSP6 via hippocampal adeno‐associated virus (AAV) microinjection. Conversely, overexpression of hippocampal DUSP6 using AAV ameliorated the cognitive deficits observed in SNI rats, which remained unaffected by the administration of a CB2R antagonist. Our findings demonstrate that activation of hippocampal CB2R can mitigate chronic neuropathic pain‐induced cognitive impairment through the modulation of the DUSP6/ERK/NFκB pathway. [ABSTRACT FROM AUTHOR]

Peripheral neuropathic pain is common in patients with peripheral nerve injury and can significantly impact both their function and quality of life. There is a wide variety of non‐interventional treatment approaches, including pharmacologic therapy, physical/occupational therapy, modalities (therapeutic, mechanical, thermal, etc.), psychology, and lifestyle modification. First line pharmacologic therapy for peripheral neuropathic pain includes gabapentinoids, tricyclic antidepressants, and serotonin‐norepinephrine reuptake inhibitors. Other classes of medications, such as topical treatments, opioids, and cannabinoids, have more limited usefulness in treatment but remain part of a treatment regimen. Physical and occupational therapy, psychological interventions, and lifestyle medicine are important adjuncts in the treatment and prevention of future peripheral neuropathic pain. The strength of the evidence supporting each intervention varies, with that for pharmacologic intervention being the strongest. A combination of these options tailored to the individual needs of the patient likely will result in the best treatment outcome for peripheral neuropathic pain. [ABSTRACT FROM AUTHOR]

Aims: Epidemiological studies in patients with neuropathic pain have demonstrated a strong association between neuropathic pain and psychiatric conditions such as anxiety. Preclinical and clinical work has demonstrated that electroacupuncture (EA) effectively alleviates anxiety‐like behaviors induced by chronic neuropathic pain. In this study, a potential neural circuitry underlying the therapeutic action of EA was investigated. Methods: The effects of EA stimulation on mechanical allodynia and anxiety‐like behaviors in animal models of spared nerve injury (SNI) were examined. EA plus chemogenetic manipulation of glutamatergic (Glu) neurons projecting from the rostral anterior cingulate cortex (rACCGlu) to the dorsal raphe nucleus (DRN) was used to explore the changes of mechanical allodynia and anxiety‐like behaviors in SNI mice. Results: Electroacupuncture significantly alleviated both mechanical allodynia and anxiety‐like behaviors with increased activities of glutamatergic neurons in the rACC and serotoninergic neurons in the DRN. Chemogenetic activation of the rACCGlu‐DRN projections attenuated both mechanical allodynia and anxiety‐like behaviors in mice at day 14 after SNI. Chemogenetic inhibition of the rACCGlu‐DRN pathway did not induce mechanical allodynia and anxiety‐like behaviors under physiological conditions, but inhibiting this pathway produced anxiety‐like behaviors in mice at day 7 after SNI; this effect was reversed by EA. EA plus activation of the rACCGlu‐DRN circuit did not produce a synergistic effect on mechanical allodynia and anxiety‐like behaviors. The analgesic and anxiolytic effects of EA could be blocked by inhibiting the rACCGlu‐DRN pathway. Conclusions: The role of rACCGlu‐DRN circuit may be different during the progression of chronic neuropathic pain and these changes may be related to the serotoninergic neurons in the DRN. These findings describe a novel rACCGlu‐DRN pathway through which EA exerts analgesic and anxiolytic effects in SNI mice exhibiting anxiety‐like behaviors. [ABSTRACT FROM AUTHOR]

Depression has a high rate of comorbidity with neuropathic pain. This study aims to investigate the effect of Mygalin, an acylpolyamine synthesized from a natural molecule in the hemolymph of the Acanthoscurria gomesiana spider, injected into the prelimbic (PrL) region of the medial prefrontal cortex on chronic neuropathic pain and depression comorbidity in rats. To investigate that comorbidity, neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in male Wistar rats. The biotinylated biodextran amine (BDA) bidirectional neural tract tracer was microinjected into the PrL cortex to study brain connections. Rodents were further subjected to von Frey (mechanical allodynia), acetone (cold allodynia), and forced swim (depressive‐like behavior) tests. BDA neural tract tracer‐labeled perikarya were found in the dorsal columns of the periaqueductal gray matter (dPAG) and the dorsal raphe nucleus (DRN). Neuronal activity of DRN neurons decreased in CCI rats. However, PrL cortex treatment with Mygalin increased the number of spikes on DRN neurons. Mygalin treatment in the PrL cortex decreased both mechanical and cold allodynia and immobility behavior in CCI rats. PrL cortex treatment with N‐methyl‐D‐aspartate (NMDA) receptor receptors attenuated the analgesic and antidepressive effects caused by Mygalin. The PrL cortex is connected with the dPAG and DRN, and Mygalin administration into the PrL increased the activity of DRN neurons. Mygalin in the PrL cortex produced antinociceptive and antidepressive‐like effects, and the NMDA agonist reversed these effects. Highlights: Intra‐PrL cortex Mygalin (MY) decreases the mechanical and cold allodynia related to neuropathic pain (NP);MY in the prelimbic (PrL) cortex decreases NP‐related depressivon‐like behavior;PrL cortex NMDA attenuates MY‐induced analgesiaThe PrL cortex sends neural connections to the dPAG and dorsal raphe nucleus (DRN);MY in the PrL cortex increased neuronal activity in the DRN of chronic constriction injury rats. [ABSTRACT FROM AUTHOR]

Objective: Dorsal root ganglion stimulation (DRGS) is able to relieve chronic neuropathic pain. There seems evidence that DRGS might achieve this by gradually influencing pain pathways. We used laser‐evoked potentials (LEP) to verify our hypothesis that the recovery of the LEP may reflect DRGS‐induced changes within the nociceptive system. Methods: Nine patients (mean age 56.8 years, range 36–77 years, two females) diagnosed with chronic neuropathic pain in the knee or groin were enrolled in the study. We measured each patient's LEP at the painful limb and contralateral control limb on the first, fourth, and seventh day after implantation of the DRGS system. We used the numeric rating scale (NRS) for the simultaneous pain assessment. Results: The LEP amplitude of the N2–P2 complex showed a significant increase on day 7 when compared to day 1 (Z = −2.666, p = 0.008) and to day 4 (Z = −2.547, p = 0.011), respectively. There was no significant difference in the N2–P2 complex amplitude between ON and OFF states during DRGS. The patients' NRS significantly decreased after 1 day (p = 0.007), 4 days (p = 0.007), and 7 days (p = 0.007) when compared to the baseline. Conclusions: The results show that with DRGS, the LEP recovered gradually within 7 days in neuropathic pain patients. Therefore, reduction of the NRS in patients with chronic neuropathic pain might be due to DRGS‐induced processes within the nociceptive system. These processes might indicate neuroplasticity mediated recovery of the LEP. [ABSTRACT FROM AUTHOR]

Background and Purpose: The cytokine activin C is mainly expressed in small‐diameter dorsal root ganglion (DRG) neurons and suppresses inflammatory pain. However, the effects of activin C in neuropathic pain remain elusive. Experimental Approach Male rats and wild‐type and TRPV1 knockout mice with peripheral nerve injury ‐ sciatic nerve axotomy and spinal nerve ligation in rats; chronic constriction injury (CCI) in mice – provided models of chronic neuropathic pain. Ipsilateral lumbar (L)4–5 DRGs were assayed for activin C expression. Chronic neuropathic pain animals were treated with intrathecal or locally pre‐administered activin C or the vehicle. Nociceptive behaviours and pain‐related markers in L4–5 DRGs and spinal cord were evaluated. TRPV1 channel modulation by activin C was measured. Key Results: Following peripheral nerve injury, expression of activin βC subunit mRNA and activin C protein was markedly up‐regulated in L4–5 DRGs of animals with axotomy, SNL or CCI. [Correction added on 26 November 2020, after first online publication: The preceding sentence has been corrected in this current version.] Intrathecal activin C dose‐dependently inhibited neuropathic pain in spinal nerve ligated rats. Local pre‐administration of activin C decreased neuropathic pain, macrophage infiltration into ipsilateral L4–5 DRGs and microglial reaction in L4–5 spinal cords of mice with CCI. In rat DRG neurons, activin C enhanced capsaicin‐induced TRPV1 currents. Pre‐treatment with activin C reduced capsaicin‐evoked acute hyperalgesia and normalized capsaicin‐evoked persistent hypothermia in mice. Finally, the analgesic effect of activin C was abolished in TRPV1 knockout mice with CCI. Conclusion and Implications: Activin C inhibits neuropathic pain by modulating TRPV1 channels, revealing potential analgesic applications in chronic neuropathic pain therapy. [ABSTRACT FROM AUTHOR]

Neuromodulation is a clinical tool used for treating chronic neuropathic pain by transmitting controlled physical energy to the pre‐identified neural targets in the central nervous system. Its drug‐free, nonaddictive, and improved targeting characteristics have attracted increasing attention among neuroscience research and clinical practices. This article provides a brief overview of the neuropathic pain and pharmacological routines for treatment, summarizes both the invasive and noninvasive neuromodulation modalities for pain management, and highlights an emerging brain stimulation technology, transcranial focused ultrasound (tFUS), with a focus on ultrasound transducer devices and the achieved neuromodulation effects and applications on pain management. Practical considerations of spatial guidance for tFUS are discussed for clinical applications. The safety of transcranial ultrasound neuromodulation and its future prospectives on pain management are also discussed. [ABSTRACT FROM AUTHOR]

Objectives: To assess the supraspinal working mechanisms of the burst spinal cord stimulation (SCS) mode, we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge burst SCS would induce a more profound blood oxygenation level–dependent (BOLD) signal increase in areas associated with cognitive‐emotional aspects of pain, as compared to tonic SCS. Methods: Sprague Dawley rats (n = 17) underwent a unilateral partial sciatic nerve ligation, which resulted in chronic neuropathic pain. Quadripolar SCS electrodes were epidurally positioned on top of the dorsal columns at Th13. Isoflurane‐anesthetized (1.5%) rats received either tonic SCS (n = 8) or burst SCS (n = 9) at 66% of motor threshold. BOLD fMRI was conducted before, during, and after SCS using a 9.4‐T horizontal bore scanner. Results: Overall, both tonic and burst SCS induced a significant increase of BOLD signal levels in areas associated with the location and intensity of pain, and areas associated with cognitive‐emotional aspects of pain. Additionally, burst SCS significantly increased BOLD signal levels in the raphe nuclei, nucleus accumbens, and caudate putamen. Tonic SCS did not induce a significant increase in BOLD signal levels in these areas. Conclusions: In conclusion, active recharge burst and tonic SCS have different effects on the intensity and localization of SCS‐induced activation responses in the brain. This work demonstrates that active recharge burst is another waveform that can engage brain areas associated with cognitive‐emotional aspects of pain as well as areas associated with location and intensity of pain. Previous studies showing similar engagement used only passive recharge burst. [ABSTRACT FROM AUTHOR]

Chronic neuropathic pain is a common consequence of spinal cord injury ( SCI), develops over time and negatively impacts quality of life, often leading to substance abuse and suicide. Recent evidence has demonstrated that reactive oxygen species ( ROS) play a role in contributing to neuropathic pain in SCI animal models. This investigation examines four compounds that reduce ROS and the downstream lipid peroxidation products, apocynin, 4-oxo-tempo, U-83836E, and tirilazad, and tests if these compounds can reduce nocioceptive behaviors in chronic SCI animals. Apocynin and 4-oxo-tempo significantly reduced abnormal mechanical hypersensitivity measured in forelimbs and hindlimbs in a model of chronic SCI-induced neuropathic pain. Thus, compounds that inhibit ROS or lipid peroxidation products can be used to ameliorate chronic neuropathic pain. [ABSTRACT FROM AUTHOR]

Background and purpose: Central neuropathic pain (CNP) is a prevalent and distressing symptom in patients with multiple sclerosis (MS). The anticonvulsant levetiracetam (LEV) has been shown to be efficacious in some types of CNP, but its efficacy in MS-related CNP has not been confirmed. Methods: To investigate the tolerability and potential effects of LEV against CNP in MS subjects, we performed a single-center, prospective, randomized, single-blind, placebo-controlled study in twenty patients with MS and CNP. Outcomes before and during the 3-month study were assessed using validated measures of pain, depression, disability and quality of life. Results: The medication was well tolerated and analysis revealed a significant difference between the LEV and placebo arm in all study outcomes related to pain (mean pain intensity score, mean pain difference, percentage of patients with a clinically significant pain reduction). Furthermore, the individual quality of life rating improved in treated patients, showing a significant correlation with pain reduction. Conclusions: These findings suggest that further studies with larger samples of patients be carried out in order to confirm the efficacy of LEV in MS-related CNP population. [ABSTRACT FROM AUTHOR]