Spinal upregulation of glutamate transporter GLT-1 by ceftriaxone: therapeutic efficacy in a range of experimental nervous system disorders.

Glutamate neurotransmission is highly regulated, largely by glutamate transporters. In the spinal cord, the glutamate transporter GLT-1 is primarily responsible for glutamate clearance. Downregulation of GLT-1 can occur in activated astrocytes, and is associated with increased extracellular glutamate and neuroexcitation. Among other conditions, astrocyte activation occurs following repeated opioids and in models of chronic pain. If GLT-1 downregulation occurs in these states, GLT-1 could be a pharmacological target for improving opioid efficacy and controlling chronic pain. The present studies explored whether daily intrathecal treatment of rats with ceftriaxone, a beta-lactam antibiotic that upregulates GLT-1 expression, could prevent development of hyperalgesia and allodynia following repeated morphine, reverse pain arising from central or peripheral neuropathy, and reduce glial activation in these models. Ceftriaxone pre-treatment attenuated the development of hyperalgesia and allodynia in response to repeated morphine, and prevented associated astrocyte activation. In a model of multiple sclerosis (experimental autoimmune encephalomyelitis; EAE), ceftriaxone reversed tactile allodynia and halted the progression of motor weakness and paralysis. Similarly, ceftriaxone reversed tactile allodynia induced by chronic constriction nerve injury (CCI). EAE and CCI each significantly reduced the expression of membrane-bound, dimerized GLT-1 protein in lumbar spinal cord, an effect normalized by ceftriaxone. Lastly, ceftriaxone normalized CCI- and EAE-induced astrocyte activation in lumbar spinal cord. Together, these data indicate that increasing spinal GLT-1 expression attenuates opioid-induced paradoxical pain, alleviates neuropathic pain, and suppresses associated glial activation. GLT-1 therefore may be a therapeutic target that could improve available treatment options for patients with chronic pain.

Long-term control of neuropathic pain in a non-viral gene therapy paradigm.

Traditional approaches to treating chronic neuropathic pain largely focus on manipulations directly altering neuronal activity or neuron-to-neuron communication. Recently, however, it has become clear that glial cells (including microglia and astroglia) play a significant role in pain expression in a variety of neuropathic pain models. Multiple aspects of the inflammatory response of glial cells, commonly observed in neuropathic pain conditions, have been implicated in pain expression. Thus, glial cell inflammation has emerged as a potential therapeutic target in neuropathic pain. Our laboratory has been exploring the use of an anti-inflammatory cytokine, interleukin-10 (IL-10), to control glial inflammatory activation thereby controlling neuropathic pain. IL-10 protein delivery is limited by a short half-life and an inability to cross into the central nervous system from the periphery, making a centrally delivered gene therapy approach attractive. We have recently characterized a non-viral gene therapy approach using two injections of naked DNA to achieve long-term (>3 months) control of neuropathic pain in a peripheral nerve injury model. Timing and dose requirements leading to long-term pain control are discussed in this review, as is recent work using microparticle-encapsulated DNA to achieve long-term therapeutic efficacy with a single injection.

Glia in pathological pain: a role for fractalkine.

Microglia and/or astrocytes play a significant role in the creation and maintenance of exaggerated pain states with inflammatory and/or neuropathic etiologies. The chemokine, fractalkine, has several functions, including the newly recognized role of mediating neuropathic pain conditions. Although constitutively expressed and released during inflammation, increased release of fractalkine binds to and activates microglia leading to pathological pain. We review the critical role of fractalkine in neuron-to-glial communication after peripheral nerve injury and inflammation and explore anti-inflammatory cytokines like interleukin-10 as a novel and effective approach for clinical pain control.

Keeping up with the cancer literature--PDQ ACCESS.

Physician Data Query (PDQ) (National Cancer Institute [NCI], Bethesda, MD) and CANCERLIT (NCI, Bethesda, MD) are two online cancer information databases. PDQ summarizes current cancer therapy literature into specific treatment recommendations. CANCERLIT is a bibliographic system similar to MEDLINE (National Library of Medicine [NLM], Bethesda, MD) that provides a comprehensive source of literature citations for the field of cancer. In this report, we discuss linking PDQ and CANCERLIT with PDQ ACCESS (NCI, Bethesda, MD)--a custom software package that makes searching the cancer literature easy for the practicing physician unfamiliar with database searching.