Dana M. Tilley

The Role of Glia and the Immune System in the Development and Maintenance of Neuropathic Pain

Neuropathic pain refers to a variety of chronic pain conditions with differing underlying pathophysiologic mechanisms and origins. Recent studies indicate a communication between the immune system and the nervous system. A common underlying mechanism of neuropathic pain is the presence of inflammation at the site of the damaged or affected nerve(s). This inflammatory response initiates a cascade of events resulting in the concentration and activation of innate immune cells at the site of tissue injury. The release of immunoactive substances such as cytokines, neurotrophic factors, and chemokines initiate local actions and can result in a more generalized immune response. The resultant neuroinflammatory environment can cause activation of glial cells located in the spinal cord and the brain, which appear to play a prominent role in nociception. Glial cells, also known as neuroglia, are nonconducting cells that modulate neurotransmission at the synaptic level. Glial cells can be subdivided into two primary categories: microglia and macroglia, which include astrocytes and oligodendrocytes. Astrocytes and microglia are known to play a role in the development, spread, and potentiation of neuropathic pain. Following peripheral nociceptive activation via nerve injury, microglia become activated and release pro‐inflammatory cytokines such as tumor necrosis factor‐α, interleukin‐1β, and interleukin‐6, thereby initiating the pain process. Microglia propagate the neuroinflammation by recruiting other microglia and eventually activating nearby astrocytes, which prolongs the inflammatory state and leads to a chronic neuropathic pain condition. Our review focuses on the role of glia and the immune system in the development and maintenance of neuropathic pain.

Genomics of the Effect of Spinal Cord Stimulation on an Animal Model of Neuropathic Pain

Few studies have evaluated single‐gene changes modulated by spinal cord stimulation (SCS), providing a narrow understanding of molecular changes. Genomics allows for a robust analysis of holistic gene changes in response to stimulation.

A Continuous Spinal Cord Stimulation Model Attenuates Pain‐Related Behavior In Vivo Following Induction of a Peripheral Nerve Injury

Models that simulate clinical conditions are needed to gain an understanding of the mechanism involved during spinal cord stimulation (SCS) treatment of chronic neuropathic pain. An animal model has been developed for continuous SCS in which animals that have been injured to develop neuropathic pain behavior were allowed to carry on with regular daily activities while being stimulated for 72 hours.

An Ex Vivo Comparison of Cooled-Radiofrequency and Bipolar-Radiofrequency Lesion Size and the Effect of Injected Fluids

Background and Objectives Radiofrequency (RF) neuroablation is a common therapy for alleviating chronic pain. Larger lesion volumes lead to higher chance of ablating small sensory nerves; therefore, bipolar-RF and cooled-RF are improved alternatives to conventional monopolar-RF. This work provides an ex vivo comparison of bipolar-RF to cooled-RF lesioning in the presence of bone structure using some conventional temperature and time programs and in conjunction with injection of a variety of clinically used substances. Methods Studies were performed using chicken muscle near a bone structure. Cooled-RF was applied using standard parameters at 60°C for 150 seconds and perpendicular to the bone. Bipolar-RF was applied using interelectrode distances (IEDs) of 5, 10, or 15 mm at 80°C for 90 or 150 seconds with the electrodes positioned either paralleled between the bone and muscle or perpendicular to the bone. The effect of injection of various fluids (sterile water, 0.9% saline, 7.3% saline, 2% lidocaine, 0.25% bupivacaine, lidocaine/methylprednisolone (Depo-Medrol), or lidocaine/betamethasone (Celestone) on lesion size was compared with no fluid injected in the muscle. Temperature profiles of lesioning were also obtained using an infrared camera. Results The volume of bipolar-RF lesions is dependent on IED, being more favorable at IED equals 10 mm. The injection of some fluids induces significant (P < 0.05) changes in bipolar-RF lesion volume, although the changes are dependent on IED. Cooled-RF induces larger lesions than bipolar-RF, with no changes in volume induced by injecting fluids. Conclusions Cooled-RF yields larger lesions than bipolar-RF under the conditions used in this study. The spherical shape of cooled-RF lesions provides larger volume coverage than lesions obtained with bipolar-RF at IED equals 5, 10, or 15 mm under similar electrode tip temperature and lesioning time.

Spinal Cord Stimulation Modulates Gene Expression in the Spinal Cord of an Animal Model of Peripheral Nerve Injury.

Background and Objectives Previously, we found that application of pulsed radiofrequency to a peripheral nerve injury induces changes in key genes regulating nociception concurrent with alleviation of paw sensitivity in an animal model. In the current study, we evaluated such genes after applying spinal cord stimulation (SCS) therapy. Methods Male Sprague–Dawley rats (n = 6 per group) were randomized into test and control groups. The spared nerve injury model was used to simulate a neuropathic pain state. A 4-contact microelectrode was implanted at the L1 vertebral level and SCS was applied continuously for 72 hours. Mechanical hyperalgesia was tested. Spinal cord tissues were collected and analyzed using real-time polymerase chain reaction to quantify levels of IL1&bgr;, GABAbr1, subP, Na-K ATPase, cFos, 5HT3ra, TNF&agr;, Gal, VIP, NpY, IL6, GFAP, ITGAM, and BDNF. Results Paw withdrawal thresholds significantly decreased in spared nerve injury animals and stimulation attenuated sensitivity within 24 hours (P = 0.049), remaining significant through 72 hours (P = 0.003). Nerve injury caused up-regulation of TNF&agr;, GFAP, ITGAM, and cFOS as well as down-regulation of Na-K ATPase. Spinal cord stimulation therapy modulated the expression of 5HT3ra, cFOS, and GABAbr1. Strong inverse relationships in gene expression relative to the amount of applied current were observed for GABAbr1 (R = −0.65) and Na-K ATPase (R = −0.58), and a positive linear correlations between 5HT3r (R = 0.80) and VIP (R = 0.50) were observed. Conclusions Continuously applied SCS modulates expression of key genes involved in the regulation of neuronal membrane potential.

Spinal Cord Stimulation: Principles and Applications

The concept of electrical stimulation applied to the treatment of pain was first documented in a book published in 47 AD called the Compositiones by Scribonius Largus. Largus demonstrated that shock incurred by the torpedo ray induced analgesia for both gout and headaches. A substantial amount of progress has occurred since that time, providing treatment for a wide range of clinical symptoms using various electrical stimulation modalities. There are two clinical applications for electrical stimulation to nerves. The first is designed to treat motor disorders such as tremors caused by advanced Parkinson’s Disease. The more common use for electrical stimulation uses focused electrical treatment to neural targets resulting in analgesia. Current targets for stimulation include the spinal cord, dorsal root ganglia, and peripheral nerve tracts.

Opiate-Free Pain Therapy Using Carbamazepine-Loaded Microparticles Provides Up to 2 Weeks of Pain Relief in a Neuropathic Pain Model

Opioids remain a mainstay in the treatment of acute and chronic pain, despite numerous and potentially dangerous side effects. There is a great unmet medical need for alternative treatments for patients suffering from pain that do not result in addiction or adverse side effects. Anticonvulsants have been shown to be effective in managing pain, though high systemic levels and subsequent side effects limit their widespread usage. Our goal was to determine if the incorporation of an anticonvulsant, carbamazepine, into a biodegradable microparticle for local sustained perineural release would be an efficacious analgesic following a peripheral injury.