Protein kinase G signaling pathway is involved in sympathetically maintained pain by modulating ATP-sensitive potassium channels

BackgroundSympathetically maintained pain (SMP) involves an increased excitability of dorsal root ganglion (DRG) neurons to sympathetic nerve stimulation and circulating norepinephrine. The current treatment of SMP has limited efficacy, and hence more mechanistic insights into this intractable pain condition are urgently needed.MethodsA caudal trunk transection (CTT) model of neuropathic pain was established in mice.Immunofluorescence staining, small interfering RNA, pharmacological and electrophysiological studies were conducted to test the hypothesis that norepinephrine increases the excitability of small-diameter DRG neurons from CTT mice through the activation of cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway.ResultsBehavior study showed that CTT mice developed mechanical and heat hypersensitivities, which were attenuated by intraperitoneal injection of guanethidine. CTT mice also showed an abnormal sprouting of tyrosine hydroxylase-positive nerve fibers in DRG, and an increased excitability of small-diameter DRG neurons to norepinephrine, suggesting that CTT is a useful model to study SMP. Importantly, inhibiting cGMP-PKG pathway with small interfering RNA and KT5823 attenuated the increased sympathetic sensitivity in CTT mice. In contrast, cGMP activators (Sp-cGMP, 8-Br-cGMP) further increased sympathetic sensitivity. Furthermore, phosphorylation of ATP-sensitive potassium channel, which is a downstream target of PKG, may contribute to the adrenergic modulation of DRG neuron excitability.ConclusionsOur findings suggest an important role of cGMP-PKG signaling pathway in the increased excitability of small-diameter DRG neurons to norepinephrine after CTT, which involves an inhibition of the ATP-sensitive potassium currents through PKG-induced phosphorylation. Accordingly, drugs targeting this pathway may help to treat SMP.

Incidence of inadvertent intercostal or epidural spread during thoracic sympathetic ganglion block

Background: Sympathetic blocks (SBs) have been used widely to relieve the symptoms of sympathetically maintained pain (SMP). The thoracic sympathetic ganglion is not separated from somatic nerves by muscles and connective tissue. The upper thoracic ganglion runs along the posterior surface of the vertebral column in close proximity to the adjacent epidural region. This anatomical difference leads to frequent epidural and intercostal spread in cases of thoracic SBs. The purpose of this study was to investigate the incidence of inadvertent intercostal and epidural injections during thoracic SBs.Methods: Twenty-two patients who were suffering from complex regional pain syndrome or lymphedema after breast cancer surgery were managed with two or three times of thoracic SBs. Therefore, injections of 63 thoracic SBs from 22 patients were enrolled in this study. An investigator who did not attend the procedure evaluated the occurrence of intercostal or epidural spread using anteroposterior fluoroscopic images.Results: The overall incidence of inadvertent intercostal or epidural spread of contrast was 47.5%. Among the inadvertent injections, intercostal spread (34.9%) was more frequent than epidural spread (12.6%). Only 52.5% of the thoracic SBs demonstrated successful contrast spread without any inadvertent spread. The mean difference in skin temperature between the blocked and unblocked sides was 2.5 ± 1.8ºC. Fifty-nine (93.6%) injections demonstrated more than 1.5ºC difference.Conclusions: Thoracic SBs showed a high incidence (47.5%) of inadvertent epidural or intercostal injection. Thus, special attention is required for the diagnosis of SMP or the injection of any neurolytic agent around sympathetic ganglion.

Lumbar Sympathetic Plexus Radiofrequency Ablation for Chronic Non-Cancer Pain: A Brief Review and Two Case Reports

Background: Lumbar sympathetic plexus (LSP) has been described as a target for managing chronic pain with a sympathetic component in the lower limbs such as complex regional pain syndrome (CRPS) or pain of ischemic origin. LSP neurolysis with phenol or ethanol has been applied; more recently, radiofrequency (RF) lesioning has been proposed as an alternative. RF denervation has the advantage of avoiding the complications associated with ethanol/phenol spread. Case Report: We describe 2 cases in which RF denervation of LSP was performed in patients suffering from chronic pain from CRPS and chronic ischemic disease of the lower limb. Conclusion: RF denervation of LSP could be considered as a treatment for CRPS and chronic ischemic pain when conventional medical therapy fails. Compared to chemical neurolysis, RF denervation carries less risk for postprocedural deafferentation pain. Key words: Complex regional pain syndrome; ischemic pain; lumbar sympathetic plexus; neurolysis; radiofrequency; sympathetically maintained pain

Interventional Treatment of Neuropathic Pain

Neuropathic pain has been reported to be highly prevalent, severely disabling, and often refractory to pharmacological and noninterventional conservative treatment. There is an emerging body of exciting evidence to support interventional therapies in selected refractory neuropathic pain states, although more randomized controlled trials or comparative effective trials are needed. This chapter updates the scientific evidence in support of the efficacy of neural blockade techniques and neural ablative procedures in neuropathic pain states, including peripheral compression or trauma-related neuropathic pain, herpes zoster and postherpetic neuralgia (PHN), lumbosacral and cervical radiculopathy, sympathetically maintained pain, complex regional pain syndrome (CRPS), trigeminal neuralgia and trigeminal neuropathy, and painful diabetic polyneuropathies.

Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) is a neuropathic pain condition classified as type 1 and type 2. The two classifications are distinguished by the presence of documented nerve injury in CRPS type 2. The symptoms of CRPS, including cold, blue, and painful extremities, are believed to occur from vasoconstriction caused by sympathetic dysfunction. Treatment in CRPS focuses on targeting neuropathic and sympathetically maintained pain. Traditional antineuropathic pain medications include membrane stabilizers and serotonin and norepinephrine reuptake inhibitors. Corticosteroids and nonsteroidals target the inflammatory process present in the initial stages of CRPS. Bone resorption has been treated with calcium-modulating drugs. Interventional therapies include sympathetic blockade of the affected extremity, spinal cord stimulation, and intrathecal drug delivery. All these therapies have been implemented in an effort to facilitate functional restoration of the affected limb. Physical and occupational therapies have demonstrated some of the most significant improvements in pain, mobility, and function.

Cervical Sympathetic Block: Fluoroscopy

In those patients with significant sympathetically maintained pain, repeated blocks may provide a therapeutic value and help facilitate physical therapy and rehabilitation. Cervical sympathetic blocks have been traditionally performed by using surface landmarks, however imaging-guided blocks are strongly recommended to avoid potential serious complications. Most preganglionic sympathetic efferents innervating the head, neck, and upper extremity either pass through or synapse at the stellate ganglion. This provides an ideal target for blockade of sympathetic innervation to the head, neck, and upper limbs. The stellate ganglion block can be performed at the C6 and C7 transverse processes. Fluoroscopy is a reliable method for identifying bony surfaces, which facilitates identifying the C6 and C7 transverse processes; however, this is only a surrogate marker, because the location of the cervical sympathetic trunk is defined by the fascial plane of the prevertebral fascia, which cannot be visualized with fluoroscopy.

Lumbar Sympathetic Block: Fluoroscopy

Lumbar sympathetic blocks (LSB) result in the interruption of the sympathetic efferent fibers to the lower extremities with sparing of the somatic nerves, thus providing a diagnostic value as to the relative sympathetic contribution to the patient’s pain syndrome. In those patients with significant sympathetically maintained pain, repeated blocks may provide a therapeutic value and help facilitate physical therapy. The original described technique is the paramedian or “classic” approach described by Mandl in 1926. A more lateral approach was later developed by Reid and colleagues. The incidence of complications related to lumbar sympathetic blockade is minimal. The complications result either from insertion and manipulation of the needle or as a direct result of the injected solution.