Search Results (123)

Perioperative pain remains a major clinical challenge, with many surgical patients experiencing inadequate analgesia and progression to chronic postsurgical pain. Conventional opioid-centered strategies are limited by narrow therapeutic windows, systemic toxicity, tolerance, opioid-induced hyperalgesia, and poor efficacy in neuroimmune-driven pain states. Advances in molecular neuroscience and biomedical engineering have catalyzed the development of nonpharmacologic analgesic technologies that modulate pain pathways through biophysical rather than receptor–ligand mechanisms. This narrative review synthesizes emerging nonpharmacologic analgesic platforms relevant to anesthesiology, integrating molecular, cellular, and systems-level mechanisms with clinical evidence. It examines how peripheral sensitization, spinal dorsal horn plasticity, glial and neuroimmune activation, and supraspinal network dysfunction create ideal targets for device-based interventions. Electrical neuromodulation strategies, including peripheral and central techniques, are discussed alongside temperature-based, photonic, and focused-energy modalities. These include cryoneurolysis, radiofrequency techniques, photobiomodulation, and low-intensity focused ultrasound. Clinical integration within enhanced recovery pathways, patient selection, workflow considerations, and limitations of the current human evidence base are reviewed. While many of these technologies are established in chronic pain management, this review emphasizes available human perioperative data and discusses how chronic pain evidence informs perioperative translation within opioid-sparing multimodal anesthesia care. Collectively, these technologies support a mechanism-based, systems-level approach to pain modulation, with perioperative relevance varying by modality and strength of available human evidence. Full article

Patients with systemic lupus erythematosus (SLE) often suffer from chronic pain due to a lack of effective and safe analgesics. In this study, we investigated the role of spinal TLR7 in the pathogenesis of chronic pain using female MRL lupus prone (MRL/lpr) mice, a SLE mouse model. We found that from 11 weeks of age, MRL/lpr mice exhibited thermal hypersensitivity in the hind paw, which reached plateau between 14 and 16 weeks. MRL/lpr mice with thermal hypersensitivity had increased expression of TLR7 in the spinal dorsal horn. TLR7 was located in microglia in this region. Intrathecal administration of a TLR7 antagonist attenuated the thermal hypersensitivity in MRL/lpr mice, while administration of the TLR7 agonist induced thermal hypersensitivity in control mice. Pharmacological activation of spinal TLR7 in control mice recapitulated molecular, synaptic, and cellular changes in the spinal dorsal horn of MRL/lpr mice with thermal hyperalgesia. These alterations included activation of microglia and astrocytes, increased production of IL-1β and IL-18, upregulated expression of N-type voltage-gated calcium channels (Cav2.2), enhanced glutamatergic synaptic activity, and elevated neuronal activation. Our findings suggest that targeting TLR7 or downstream effectors may represent a promising strategy to alleviate chronic pain induced by SLE. Full article

Myricetin (MYR), a naturally occurring flavonoid widely distributed in fruits and vegetables, was investigated for its potential to reduce inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc), which is associated with hyperalgesia. The study also compared MYR’s impact with that of celecoxib (CEL), a non-steroidal anti-inflammatory drug (NSAID). To induce inflammation, Complete Freund’s adjuvant was injected into the whisker pads of rats. Subsequently, we measured the mechanical escape threshold by applying mechanical stimuli to the orofacial region. We found that inflamed rats exhibited a significantly lower threshold compared to naive rats (each group, n = 4). This reduced threshold returned to the naive level two days after the administration of MYR (16 mg/kg, i.p.), CEL (10 mg/kg, i.p.), and a combination of MYR (8 mg/kg, i.p.) + CEL (5 mg/kg, i.p.). To investigate the nociceptive neural response to orofacial mechanical stimulation, we performed extracellular single-unit recordings to measure the activity of SpVc wide-dynamic range (WDR) neurons in anesthetized subjects. In inflamed rats, administration of MYR, CEL, or 1/2MYR + 1/2CEL (each group, n = 4) significantly reduced both the average spontaneous activity and the evoked firing rate of SpVc neurons in response to non-painful and painful mechanical stimuli. The increased average receptive field size in inflamed rats was normalized to the naive level following treatment with MYR, CEL, or 1/2MYR + 1/2CEL. These findings suggest that MYR administration can mitigate inflammatory hyperalgesia by reducing the heightened excitability of SpVc WDR neurons. This supports the notion that MYR could be a viable therapeutic option in complementary and alternative medicine for preventing trigeminal inflammatory mechanical hyperalgesia, potentially serving as an alternative to selective cyclooxygenase-2 blockers. Full article

Electroacupuncture (EA) has shown analgesic potential for neuropathic pain, yet its underlying molecular mechanisms remain incompletely understood. This study aimed to investigate whether EA relieves neuropathic pain by modulating CCL2/CCR2 signaling and microglial activation in the spinal cord. Neuropathic pain was induced in rats by L5 spinal nerve ligation. EA was administered at acupoints ST36 and GB34 (1 mA, 2 Hz, 30 min) daily from postoperative days 3 to 7. Rats were assigned to anesthetized control (ANE), non-acupoint stimulation (NAP), and acupoint stimulation (ACU) groups. Pain behavior was evaluated using paw withdrawal threshold and latency. Western blot and immunofluorescence were used to assess CCL2, CCR2, Iba1, IL-1β, and TNF-α expression in the L4–L6 spinal cord. EA significantly attenuated mechanical allodynia and thermal hyperalgesia in the ACU group, accompanied by reductions in CCL2, CCR2, microglial marker Iba1, and pro-inflammatory cytokines. Most importantly, intrathecal administration of recombinant CCL2 completely abolished EA’s analgesic effects, establishing the causal necessity of CCL2/CCR2 signaling in EA-mediated analgesia. These findings suggest that EA exerts its analgesic effects through downregulation of the CCL2/CCR2 pathway and inhibition of microglial activation. The reversal of EA’s effects by exogenous CCL2 supports the critical role of spinal chemokine signaling in EA-mediated analgesia. Full article

Background/Objectives: This study investigates whether systemic ovalbumin–aluminum sensitization followed by cutaneous challenge induces thermal hyperalgesia and spinal cord gliosis in mice. Methods: Adult female ICR-CD1 mice received ovalbumin–aluminum salt solution intraperitoneally on days 0, 7 and 14, and subcutaneously with daily skin application via brush during days 15–21, 28–35 and 42–49. Control animals received saline. Plantar thermal hyperalgesia was assessed on days 21, 35 and 49. On day 49, tissues (dorsal skin, spinal cord, footpads) were harvested after perfusion and processed histologically to detect mast cells, astrocytes, microglia, afferent fibers and intraepidermal nerve profiles. Results: Ovalbumin-treated mice displayed thermal hyperalgesia, increased astrogliosis, and reactive microglia in the spinal cord, and expanded CGRP- and IB4-immunoreactive fiber areas. In footpads, CGRP-positive intraepidermal nerve profile density was elevated, and dorsal skin showed increased mast cell density compared to controls. Conclusions: Combined systemic and cutaneous ovalbumin–aluminum sensitization induces skin inflammation, spinal gliosis, and nociceptive fiber sprouting in both central and peripheral sites, which likely contribute to the observed thermal hyperalgesia. Full article

Background/Objectives: Fibromyalgia causes chronic long-term pain, with symptoms lasting for months to years. Given the lack of evidence-based methods for diagnosing and assessing fibromyalgia, it ranks among the most difficult chronic pain conditions to treat. Programmed cell death ligand 1 (PD-L1) can inhibit acute and chronic pain transmission by inhibiting neuronal ion channels. Methods: Here, we aimed to explore the analgesic efficacy and mechanism of PD-L1/PD1 in an intermittent cold stress-induced fibromyalgia pain mouse model. Results: Von Frey and Hargreaves tests were performed, showing that the mouse model exhibited mechanical (day 4: 2.08 ± 0.13 g, n = 9) and thermal hyperalgesia (day 4: 3.93 ± 0.45 s, n = 9). Electroacupuncture (EA) or intraventricular PD-L1 injection effectively alleviated the nociceptive response and led to low PD-1 levels in the mouse dorsal root ganglia, spinal cord, thalamus, somatosensory cortex, and cerebellum, as measured through Western blots. In contrast, the pain-related kinase levels increased after fibromyalgia induction; these effects were reversed by EA and PD-L1 via the inhibition of microglia/astrocytes and Toll-like receptor 4. Conclusions: Our results show that EA can treat fibromyalgia pain in mice through effects on the PD-L1/PD1 pathway, indicating its potential as a therapeutic target in fibromyalgia. Full article

This study investigated the potential of astaxanthin (AST), a natural carotenoid, to mitigate inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc) and the associated hyperalgesia. The efficacy of systemic AST application was compared to that of celecoxib (CEL). Inflammation was induced by injecting Complete Freund’s adjuvant into the whisker pads of rats. The mechanical escape threshold was then assessed by delivering mechanical stimuli to the orofacial region. Although inflamed rats exhibited a significantly lower mechanical threshold compared to naïve rats, this threshold was restored to normal levels two days after treatment with AST, CEL, and the 1/2 CEL + 1/2 AST combination. The activity of SpVc wide-dynamic range (WDR) neurons was measured using extracellular single-unit recordings in response to mechanical stimulation of the orofacial area under anesthesia. In inflamed rats, AST, CEL, and 1/2 CEL + 1/2 AST administration significantly reduced the average firing rate of these neurons elicited by both non-noxious and noxious mechanical stimuli. In addition, all three treatments significantly decreased the heightened average spontaneous activity of SpVc neurons and normalized the increased average receptive field size in inflamed rats. This study provides evidence that systemic AST administration attenuates inflammatory mechanical hyperalgesia. This action is associated with the suppression of hyperexcitability in nociceptive SpVc WDR neurons, likely through the inhibition of the cyclooxygenase-2 signaling pathway. These findings support the potential of AST as a therapeutic agent for complementary and alternative medicine. It may provide a valuable alternative to non-steroidal anti-inflammatory drugs for the prevention of trigeminal inflammatory mechanical hyperalgesia. Full article

We recently developed a mechanical acupuncture instrument (MAI) that applies mechanical stimulation to acupuncture points in effectively treating hypertension and addiction in animal models. However, its analgesic effect on inflammatory pain remains unclear. Here, we aimed to determine the optimal duration of MAI treatment at any given acupuncture point to improve analgesic effects. Adult male ICR mice (20–25 g, 6 weeks old, n = 6 per group) were used to evaluate whether MAI administration or TRPV1 (transient receptor potential vanilloid 1) inhibition had analgesic effects. Then, we investigated whether it affected TRPV1 expression and glial cells in the spinal cord of mice. The capsaicin test was used to identify the most effective acupoints and optimal treatment times for MAI. Additionally, we induced inflammatory pain in mice by administering a 2% carrageenan via intraplantar injection. To assess the analgesic effects of MAI treatment and TRPV1 inhibition, we evaluated pain-related behavior using von Frey filaments and a thermal stimulator applied to the hind paw. MAI treatment significantly suppressed pain-related behaviors. In particular, paw-licking duration was markedly reduced in the group treated with MAI for 60 s at ST36 compared to the capsaicin-treated group (p < 0.05), suggesting a robust analgesic effect. Additionally, MAI and capsazepine administration significantly attenuated carrageenan-induced mechanical allodynia and thermal hyperalgesia compared to the carrageenan-only group (p < 0.05 to p < 0.001). Additionally, MAI treatment and capsazepine administration effectively suppressed the carrageenan-induced upregulation of TRPV1 and glial cells in the spinal cord. In conclusion, our findings show that MAI administration at ST36 significantly alleviated inflammatory pain and was associated with downregulation of TRPV1 expression and microglial activation in the spinal cord. The present findings suggest that TRPV1 signaling is involved in the analgesic effects of mechanical acupuncture; however, a direct causal relationship has yet to be established. Full article

Background/Objectives: Fibromyalgia is a chronic pain syndrome with unclear etiology, meaning that it is difficult to treat effectively. The stimulation of cannabinoid receptor 1 (CB1) suppresses neuronal excitability and synaptic transmission in nociceptive pathways via reducing activity in the calcium channel and promoting the opening of the potassium channel. Methods: In this study, we examined whether CB1 activity contributes to the antinociceptive efficacy of electroacupuncture (EA) in a mouse fibromyalgia (FM) pain model established using intermittent cold stress (ICS). The model mice demonstrated both mechanical and thermal hyperalgesia measured using the von Frey and Hargreaves tests, respectively. Results: Electroacupuncture effectively reduced both forms of hyperalgesia and enhanced CB1 expression in the dorsal root ganglia, spinal cord, hypothalamus, and periaqueductal gray. In addition, EA attenuated the fibromyalgia-associated reactive transformation of microglia and astrocytes and the activation of the pain-related TLR4–MyD88–TRAF6 signaling pathway. The effects of ICS were also mitigated by the deletion of Trpv1, the gene encoding the transient receptor potential cation channel TRPV1 (capsaicin channel) implicated in nociceptive and inflammatory signaling. Further, the antinociceptive efficacy of EA was partially recapitulated by the acupoint injection of a CB1 agonist and abolished by the injection of a CB1 antagonist, suggesting that activating CB1 is essential for this therapeutic effect. Conclusions: Electroacupuncture can effectively alleviate mechanical and thermal hyperalgesia in a mouse model affected by fibromyalgia pain by activating the CB1 pathway, highlighting the therapeutic potential of CB1 agonism as a therapeutic strategy. Full article

Neuropathic pain, characterized by chronic allodynia, remains difficult to manage with current pharmacotherapies. Microglial activation plays a pivotal role in the development and maintenance of neuropathic pain and represents a promising therapeutic target. We previously demonstrated that Miyako Bidens pilosa extract powder (MBP), derived from Miyako Island, Okinawa, suppresses glial activation in a mouse model of amyotrophic lateral sclerosis. In this study, we investigated the analgesic potential of MBP in a mouse model of neuropathic pain. Neuropathic pain was induced in male ICR mice by partial sciatic nerve ligation (PSNL). Mice were orally administered MBP (2 g/kg) or vehicle daily. Mechanical allodynia was assessed using von Frey filaments. On postoperative day 7, MBP-treated mice exhibited significantly reduced allodynia compared to vehicle-treated mice. MBP also attenuated thermal hyperalgesia on postoperative day 7. Lumbar spinal cords (L5) were subjected to immunohistochemical analysis for ionized calcium-binding adaptor molecule 1 (Iba1), a microglial marker. MBP significantly decreased the number of Iba1-positive microglia in the ipsilateral dorsal horn. These results suggest that MBP alleviates neuropathic pain, at least in part, by suppressing microglial activation in the spinal cord. MBP may represent a novel plant-derived therapeutic candidate for treating neuropathic pain. Full article

Neuropathic pain resulting from injury to the somatosensory nervous system affects approximately 6.9–10% of the general population and significantly impacts quality of life. Common presentations include burning, stabbing, tingling, or electrical sensations, occurring spontaneously or through hyperalgesia or allodynia. Treatment approaches follow a tiered system. First-line therapies include gabapentinoids (e.g., gabapentin, pregabalin), which target voltage-gated calcium channels; tricyclic antidepressants (e.g., amitriptyline, nortriptyline); and serotonin-norepinephrine reuptake inhibitors such as duloxetine. Second-line options encompass topical agents (e.g., 5% lidocaine, 8% capsaicin), opioid-like medications (e.g., tramadol, tapentadol), and adjunctive therapies including psychological therapies and lifestyle interventions. For refractory cases, third-line treatments include NMDA receptor antagonists (e.g., ketamine, dextromethorphan), cannabinoids, and botulinum toxin type A, though these have more limited clinical evidence. Procedural interventions such as spinal cord stimulation and transcutaneous electrical nerve stimulation provide alternatives when pharmacological approaches fail. Despite advances in treatment options, many patients remain undertreated, highlighting the need for individualized, multimodal approaches and continued research into the complex pathophysiology of neuropathic pain conditions. Full article

Neuropathic pain is a chronic disorder that arises from damaged or malfunctioning nerves. Hypersensitivity to stimuli, also known as hyperalgesia, can cause a person to experience pain from non-painful stimuli, termed allodynia. Cannabis-based medicines (CBMs) may provide new treatment options to manage neuropathic pain. A review of the relevant studies was conducted to evaluate the effectiveness of CBMs in treating neuropathic pain. Scientific literature was systematically searched from January 2003 to December 2024 using the Web of Science Core Collection, PubMed, and MEDLINE. A total of 22 randomized controlled trials (RCTs) were identified that considered the use of 1′,1′-dimethylheptyl-Δ⁸-tetrahydrocannabinol-11-oic acid (CT-3), Δ⁹-tetrahydrocannabinol (Δ⁹-THC), cannabidiol (CBD), combinations of Δ⁹-THC with CBD, and cannabidivarin for treatment of neuropathic pain. Significant reductions in pain were reported in 15 studies focused on the treatment of multiple sclerosis, spinal cord injuries, diabetic neuropathy, postherpetic neuralgia, HIV-associated sensory neuropathy, peripheral neuropathic pain, complex regional pain syndrome, chronic radicular neuropathic pain, and peripheral neuropathy of the lower extremities. These positive outcomes often adopted personalized and adjusted dosing strategies. By contrast, seven RCTs observed no significant pain relief compared to placebo, although some had minor improvements in secondary outcomes, such as mood and sleep. Collectively, CBM treatments may improve pain scores, but study limitations such as small sample sizes and study durations, high placebo response rates, and trial unblinding because of the psychoactive effects of cannabinoids all hinder data interpretation and the extrapolation to chronic pain conditions. Hence, future RCTs will need to have larger numbers and be more extended studies that explore optimal dosing and delivery methods and identify patient subgroups that are most likely to benefit. While CBMs show potential, their current use balances modest benefits against possible adverse effects and variable outcomes. Full article

Fibromyalgia, one of the most challenging pains to treat, lacks impartial considerations for diagnosis and useful assessment. The core symptoms are persistent extensive pain accompanied by fatigue, psychological disorders, sleep disturbance, and obesity. This study aims to explore the role of cannabinoid receptor 1 (CB1) on transient receptor potential V1 (TRPV1) signaling pathways in a mouse model of fibromyalgia. This model was subjected to intermittent cold stress (ICS) to induce fibromyalgia, as measured by the nociceptive behavior determined by von Frey and Hargreaves’ tests. Our results showed a lower mechanical threshold (2.32 ± 0.12 g) and thermal latency (4.14 ± 0.26 s) in ICS-induced fibromyalgia mice. The hyperalgesia could be alleviated by 2 Hz electroacupuncture (EA) or by TRPV1 knockout. We found decreased CB1 receptors, upregulated TRPV1, and related kinases in the dorsal root ganglion, spinal cord, hypothalamus, and periaqueductal gray in fibromyalgia mice. EA reversed these effects associated with fibromyalgia, aligning with observations in Trpv1^−/− mice. Peripheral acupoint or the intracerebral ventricle injection of a CB1 agonist significantly attenuated mechanical and thermal hyperalgesia. The EA analgesic effect was reversed by a CB1 antagonist injection, suggesting the involvement of the CB1 signaling pathway. The accurate chemogenetic activation of paraventricular nucleus (PVN), which is a structure of the hypothalamus, initiated fibromyalgia pain. The chemogenetic inhibition of PVN attenuated fibromyalgia pain via the downregulation of TRPV1 pathway. Our discoveries shed light on the involvement of CB1 in the TRPV1 signaling pathway in the effects of EA in fibromyalgia, suggesting its potential as a treatment target. Full article

Neuropathic pain after spinal cord injury lacks any effective treatments, often leading to chronic pain. This study tested whether the daily administration of fully characterized polyphenolic extracts from grape stalks and coffee could prevent both reflexive and non-reflexive chronic neuropathic pain in spinal cord-injured mice by modulating the neuroimmune axis. Female CD1 mice underwent mild spinal cord contusion and received intraperitoneal extracts in weeks one, three, and six post-surgery. Reflexive pain responses were assessed weekly for up to 10 weeks, and non-reflexive pain was evaluated at the study’s end. Neuroimmune crosstalk was investigated, focusing on glial activation and the expression of CCL2/CCR2 and CX3CL1/CX3CR1 in supraspinal pain-related areas, including the periaqueductal gray, rostral ventromedial medulla, anterior cingulate cortex, and amygdala. Repeated treatments prevented mechanical allodynia and thermal hyperalgesia, and also modulated non-reflexive pain. Moreover, they reduced supraspinal gliosis and regulated CCL2/CCR2 and CX3CL1/CX3CR1 signaling. Overall, the combination of polyphenols in these extracts may offer a promising pharmacological strategy to prevent chronic reflexive and non-reflexive pain responses by modifying central sensitization markers, not only at the contusion site but also in key supraspinal regions implicated in neuropathic pain. Overall, these data highlight the potential of polyphenolic extracts for spinal cord injury-induced chronic neuropathic pain. Full article

Background and Objectives: Docosahexaenoic acid (DHA) has been shown to modulate various voltage-gated ion channels and both excitatory and inhibitory synapses. Nonetheless, its exact effect on nociceptive signaling in the trigeminal system has yet to be elucidated. The purpose of the current investigation was to assess if acute DHA given intravenously to rats diminished the excitability of wide dynamic range spinal trigeminal nucleus caudalis (SpVc) neurons in response to mechanical stimulation in vivo. Methods: Single-unit extracellular activity was recorded from SpVc neurons in response to mechanical stimulation of the whisker pad in anesthetized rats. Responses to both non-noxious and noxious mechanical stimuli were analyzed in the present study. Results: The mean firing frequency of SpVc wide dynamic range neurons in response to both non-noxious and noxious mechanical stimuli was significantly dose-dependently inhibited by DHA, and the effect was seen within 5 min. After approximately 20 min, the inhibiting effects dissipated. Conclusions: These results suggest that, in the absence of inflammatory or neuropathic pain, the acute intravenous administration of DHA reduces the activity of trigeminal sensory neurons, including those responsible for pain, indicating that DHA could be utilized as an adjunct and alternative therapeutic agent for managing trigeminal nociceptive pain, including hyperalgesia. Full article