We aimed to examine the efficacy of combination therapies of Neurotropin® with tramadol and Neurotropin with mirogabalin for neuropathic pain management. A neuropathic pain model (L5 spinal nerve ligation model: L5-SNL) using male Wistar rats was generated through tight ligation of the left fifth lumbar nerve using silk sutures. Mechanical allodynia was assessed using the 50% paw withdrawal threshold. The combined antiallodynic effects were evaluated using isobolographic analyses. Small intestinal transit was evaluated using the charcoal meal test, and motor coordination using the rota-rod test. Neurotropin (50-200 NU/kg, p.o.), tramadol (7.5-60 mg/kg, p.o.), and mirogabalin (3-30 mg/kg, p.o.) showed a dose-dependent antiallodynic effect in L5-SNL rats. The combined antiallodynic effects of Neurotropin and tramadol were additive or synergistic, whereas those of Neurotropin and mirogabalin were additive. Neurotropin (100-400 NU/kg, p.o.) did not affect the small intestinal transit, whereas tramadol (30-100 mg/kg, p.o.) significantly inhibited it. Neurotropin (100-400 NU/kg, p.o.) did not affect the walking time, whereas mirogabalin (10-100 mg/kg, p.o.) significantly decreased it. Neurotropin dose-dependently ameliorated mechanical allodynia in rats, and combination therapy with Neurotropin-tramadol or Neurotropin-mirogabalin may alleviate neuropathic pain without aggravating the adverse effects of tramadol and mirogabalin.

BACKGROUND: This study analyzed the etiologies and treatment of iatrogenic occipital nerve injuries.
METHODS: Patients with occipital neuralgia (ON) who were screened for occipital nerve decompression surgery were prospectively enrolled. Patients with iatrogenic occipital nerve injuries who underwent nerve decompression surgery were identified. Data included surgical history, pain characteristics, and surgical technique. Outcomes included pain frequency (days/month), duration (h/day), intensity (0-10), migraine headache index (MHI), and patient-reported percent-resolution of pain.
RESULTS: Among the 416 patients with ON, who were screened for occipital nerve decompression surgery, 12 (2.9%) cases of iatrogenic occipital nerve injury were identified and underwent surgical treatment. Preoperative headache frequency was 30 (±0.0) days/month, duration was 19.4 (±6.9) h, and intensity was 9.2 (±0.9). Neuroma excision was performed in 5 cases followed by targeted muscle reinnervation in 3, nerve cap in 1, and muscle burial in 1. In patients without neuromas, greater occipital nerve decompression and/or lesser occipital nerve neurectomy were performed. At the median follow-up of 12 months (IQR 12-12 months), mean pain frequency was 4.0 (±6.6) pain days/month (p < 0.0001), duration was 6.3 (±8.9) h (p < 0.01), and intensity was 4.4 (±2.8) (p < 0.001). Median patient-reported resolution of pain was 85% (56.3%-97.5%) and success rate was (≥50% MHI improvement) 91.7%.
CONCLUSIONS: Iatrogenic occipital nerve injuries can be caused by various surgical interventions, including craniotomies, cervical spine interventions, and scalp tumor resections. The associated pain can be severe and chronic. Iatrogenic ON should be considered in the differential diagnosis of post-operative headaches and can be treated with nerve decompression surgery or neuroma excision with reconstruction of the free nerve end.

Occipital nerve decompression is effective in reducing headache symptoms in select patients with migraine and occipital neuralgia. Eligibility for surgery relies on subjective symptoms and responses to nerve blocks and Onabotulinum toxin A (Botox) injections. No validated objective method exists for detecting occipital headache pathologies. The purpose of the study is to explore the potential of high-resolution Magnetic Resolution Imaging (MRI) in identifying greater occipital nerve (GON) pathologies in chronic headache patients. The MRI protocol included three sequences targeting fat-suppressed fluid-sensitive T2-weighted signals. Visualization of the GON involved generating 2-D image slices with sequential rotation to track the nerve course. Twelve patients underwent pre-surgical MRI assessment. MRI identified four main pathologies that were validated against intra-operative examination: GON entanglement by the occipital artery, increased nerve thickness and hyperintensity suggesting inflammation compared to the non-symptomatic contralateral side, early GON branching with rejoining at a distal point, and a connection between the GON and the lesser occipital nerve. MRI possesses the ability to visualize the GON and identify suspected trigger points associated with headache symptoms. This case series highlights MRI\'s potential to provide objective evidence of nerve pathology. Further research is warranted to establish MRI as a gold standard for diagnosing extracranial contributors in headaches.

Somatic and sympathetic tones fluctuate together seamlessly across daily behaviors. In this issue of Cell, Zhang et al. describe populations of spinal projecting neurons in the rostral ventromedial medulla (rVMM) that harmonize somatic motor function and sympathetic activation. The coordinated regulation plays a vital role in supporting behaviors associated with various arousal states.

Neuropathic pain, defined as the most terrible of all tortures, which a nerve wound may inflict, is a common chronic painful condition caused by gradual damage or dysfunction of the somatosensory nervous system. As with many chronic diseases, neuropathic pain has a profound economic and emotional impact worldwide and represents a major public health issue from a treatment standpoint. This condition involves multiple sensory symptoms including impaired transmission and perception of noxious stimuli, burning, shooting, spontaneous pain, mechanical or thermal allodynia and hyperalgesia. Current pharmacological options for the treatment of neuropathic pain are limited, ineffective and have unacceptable side effects. In this framework, a deeper understanding of the pathophysiology and molecular mechanisms associated with neuropathic pain is key to the development of promising new therapeutical approaches. For this purpose, a plethora of experimental models that mimic common clinical features of human neuropathic pain have been characterized in rodents, with the spinal nerve ligation (SNL) model being one of the most widely used. In this chapter, we provide a detailed surgical procedure of the SNL model used to induce neuropathic pain in rats and mice. We further describe the behavioral approaches used for stimulus-evoked and spontaneous pain assessment in rodents. Finally, we demonstrate that our SNL model induces multiple pain behaviors in rats and mice.

OBJECTIVE: to provide anatomic confirmation that standard methods which practitioners skilled in palpation use, can reliably identify the most likely site of emergence of the greater occipital nerve in most patients. The location and frequency of subcutaneous emergence of the greater occipital nerve and occipital artery with respect to the external occipital protuberance-mastoid line are reported.
METHODS: The external occipital protuberance and the mastoid processes were identified by palpation bilaterally on 57 body donors and the medial trisection point of a line connecting these bony landmarks was identified. A 4 cm circular dissection guide divided into 4 quadrants was centered on the trisection point and used to guide the removal of a circle of skin. The in-situ location of the nerve and artery were exposed by deep dissection within the circle. The frequency of the emergence and occurrence of the nerve and artery by quadrant were analyzed.
RESULTS: In 114 total dissections the greater occipital nerve was found to emerge within the circle 96 times (84%) and the occipital artery 100 times (88%). The nerve (90%) and artery (81%) emerged from the two inferior quadrants most of the time with no difference noted between male and female donors. The greater occipital nerve and occipital artery were found to emerge together most commonly in inferior lateral quadrant. Branches of the nerve and artery traveled together most frequently through the two lateral quadrants.
CONCLUSIONS: This study confirmed that the medial trisection point of the external occipital protuberance-mastoid line can be located via palpation and reliably used to pinpoint the subcutaneous emergence of the greater occipital nerve and occipital artery in most individuals. When relying on palpation alone to identify the trisection point in the clinic, infusion of nerve block inferior and lateral to this point is most likely to bathe the greater occipital nerve in anesthetic.

BACKGROUND: Gastrodin (GAS), a main bioactive component of the herbal plant, Gastrodia elata Blume, has shown to have beneficial effects on neuroinflammatory diseases such as Alzheimer\'s disease in animal studies and migraine in clinical studies. Inflammasome is a multimeric protein complex having a core of pattern recognition receptor and has been implicated in the development of neuroinflammatory diseases. Gastrodin has shown to modulate the activation of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. This study investigated the effects of GAS on the intensity of mechanical allodynia and associated changes in NLRP3 inflammasome expression at the spinal level using L5/6 spinal nerve ligation model (SNL) in rats.
METHODS: Intrathecal (IT) catheter implantation and SNL were used for drug administration and pain model in male Sprague-Dawley rats. The effect of gastrodin or MCC950 (NLRP3 inflammasome inhibitor) on mechanical allodynia was measured by von Frey test. Changes in NLRP3 inflammasome components and interleukin-1β (IL-1β) and cellular expression were examined in the spinal cord and dorsal root ganglion.
RESULTS: The expression of NLRP3 inflammasome components was found mostly in the neurons in the spinal cord and dorsal root ganglion. The protein and mRNA levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and IL-1β were upregulated in SNL animals compared to Sham animals. IT administration of GAS significantly attenuated the expression of NLRP3 inflammasome and the intensity of SNL-induced mechanical allodynia. NLRP3 inflammasome inhibitor, MCC950, also attenuated the intensity of allodynia, but the effect is less strong and shorter than that of GAS.
CONCLUSIONS: Expression of NLRP3 inflammasome and IL-1β is greatly increased and mostly found in the neurons at the spinal level in SNL model, and IT gastrodin exerts a significant anti-allodynic effect in SNL model partly through suppressing the expression of NLRP3 inflammasome.

BACKGROUND: Occipital nerve stimulation (ONS) is a treatment with evidence in refractory chronic cluster headache (CCH). However, the variable response rate and cost make it necessary to investigate predictors of response.
METHODS: This is a cross-sectional study conducted through the review of medical records of CCH patients from six hospitals in Madrid. Epidemiological and clinical variables were compared between patients with ONS failure and the rest. ONS failure was defined as the need for device withdrawal or switch off because of lack of response or adverse events.
RESULTS: From a series of 88 CCH, 26 (29.6%) underwent ONS surgery, of whom 13/26 (50.0%) failed because lack of response. ONS failure group had an earlier headache onset (mean ± SD) of 27.7 ± 6.9 vs. 36.7 ± 11.8 years, p = 0.026) and a higher smoking rate (100% vs. 42.9%, p = 0.006). Stational fluctuations (58.3% vs. 7.7%, p = 0.007) and nocturnal exacerbations (91.7% vs. 53.9%, p = 0.035) were more frequent in the ONS failure group as well. There was no difference between groups in diagnostic delay, years of evolution prior to surgery, mental illness, comorbidity with other headache disorders or chronic pain conditions or prior response to occipital nerves anesthetic blocks.
CONCLUSIONS: Some clinical features such as an early debut, smoking and seasonal or circadian fluctuations could be related to failure of ONS in refractory CCH.

The study aims to retrospectively compare steroid and radiofrequency treatments for the greater occipital nerve(GON) under ultrasound guidance in chronic migraine.
Monthly average headache attack frequency, attack duration, visual analog scale(VAS) and the number of days analgesics were taken were recorded. Under ultrasound guidance, GON block was administered once a week for a total of four sessions. In the final session, 4 mg of dexamethasone was added to the local anesthetic for the steroid group (n:26). Pulsed radiofrequency (RF) treatment was applied to the RF group (n:25) just before the last session of the GON block. The pain course in the week following the procedure monthly average headache attack frequency, attack duration, VAS and the number of days analgesics were taken in a month were compared for both groups at 1-3-6 months.
In the first month, a statistically significant decrease in attack frequency was observed in the RF group. However, no statistically significant differences were found between the groups in other findings at different time intervals. A significant decrease headache attack duration,VAS, and the number of days analgesics were taken in a month was observed in both treatment groups. Both treatments were found to be effective, but the effect size of the treatment was higher in the RF group compared to the steroid group.
Although the results were better in the group receiving pulsed RF treatment, except for the attack frequency in the first month, no statistically significant superiority of one treatment method over the other was determined.

OBJECTIVE: MIXTURE is a simultaneous morphological and quantitative imaging sequence developed by Philips that provides high-resolution T2 maps from the imaged series. We aimed to compare the T2 maps of MIXTURE and SHINKEI-Quant (S-Q) in the cervical spine and to examine their usefulness in the functional diagnosis of cervical radiculopathy.
METHODS: Seven healthy male volunteers (mean age: 31 ± 8.0 years) and one patient with cervical disc herniation (44 years old, male) underwent cervical spine magnetic resonance imaging (MRI), and T2-mapping of each was performed simultaneously using MIXTURE and S-Q in consecutive sequences in one imaging session. The standard deviation (SD) of the T2 relaxation times and T2 relaxation times of the bilateral C6 and C7 dorsal root ganglia (DRG) and C5/6 level cervical cord on the same slice in the 3D T2-map of the cervical spine coronal section were measured and compared between MIXTURE and S-Q.
RESULTS: T2 relaxation times were significantly shorter in MIXTURE than in S-Q for all C6, C7 DRG, and C5/6 spinal cord measurements. The SD values of the T2 relaxation times were significantly lower for MIXTURE in the C5/6 spinal cord and C7 DRG. In cervical disc herniation, MRI showed multiple intervertebral compression lesions with spinal canal stenosis at C5/6 and disc herniation at C6/7.
CONCLUSIONS: MIXTURE is useful for preoperative functional diagnosis. T2-mapping using MIXTURE can quantify cervical nerve roots more accurately than the S-Q method and is expected to be clinically applicable to cervical radiculopathy.