Silencing the α2 subunit of γ-aminobutyric acid type A receptors in rat dorsal root ganglia reveals its major role in antinociception posttraumatic nerve injury.

Background: Neuropathic pain (NPP) is likely the result of repetitive high-frequency bursts of peripheral afferent activity leading to long-lasting changes in synaptic plasticity in the spinal dorsal horn. Drugs that promote γ-aminobutyric acid (GABA) activity in the dorsal horn provide partial relief of neuropathic symptoms. The authors examined how in vivo silencing of the GABA receptor type A (GABAA) α2 gene in dorsal root ganglia (DRG) controls NPP.

Selective T-type calcium channel blockade alleviates hyperalgesia in ob/ob mice.

Objective: Morbid obesity may be accompanied by diabetes and painful diabetic neuropathy, a poorly understood condition that is manifested by mechanical or thermal allodynia and hyperalgesia. Recent studies have highlighted the importance of T-type calcium channels (T-channels) in peripheral nociception; therefore, our goal was to examine the function of these channels in the pathophysiology and development of painful diabetic neuropathy.

Research Design And Methods: In vivo testing of mechanical and thermal sensation, morphometric peripheral nerve studies, and electrophysiological and biochemical measurements were used to characterize the role of T-channels and the development of painful diabetic neuropathy in leptin-deficient (ob/ob) mice.

GABAA receptor modulation in dorsal root ganglia in vivo affects chronic pain after nerve injury.

Neuropathic pain (NPP) due to sensory nerve injury is, in part, the result of peripheral sensitization leading to a long-lasting increase in synaptic plasticity in the spinal dorsal horn. Thus, activation of GABA-mediated inhibitory inputs from sensory neurons could be beneficial in the alleviation of NPP symptoms. Dorsal root ganglia (DRG) conduct painful stimulation from the periphery to the spinal cord.

Upregulation of the T-type calcium current in small rat sensory neurons after chronic constrictive injury of the sciatic nerve.

Recent data indicate that peripheral T-type Ca2+ channels are instrumental in supporting acute pain transmission. However, the function of these channels in chronic pain processing is less clear. To address this issue, we studied the expression of T-type Ca2+ currents in small nociceptive dorsal root ganglion (DRG) cells from L4-5 spinal ganglia of adult rats with neuropathic pain due to chronic constrictive injury (CCI) of the sciatic nerve.

Cell-specific alterations of T-type calcium current in painful diabetic neuropathy enhance excitability of sensory neurons.

Recent data indicate that T-type Ca2+ channels are amplifiers of peripheral pain signals, but their involvement in disorders of sensory neurons such as those associated with diabetes is poorly understood. To address this issue, we used a combination of behavioral, immunohistological, molecular, and electrophysiological studies in rats with streptozotocin (N-[methylnitrosocarbamoil]-D-glucosamine)-induced early diabetic neuropathy. We found that, in parallel with the development of diabetes-induced pain, T-type current density increased by twofold in medium-size cells from L4-L5 dorsal root ganglia (DRG) with a depolarizing shift in steady-state inactivation.

Differential effects of endogenous cysteine analogs on peripheral thermal nociception in intact rats.

Previous in vivo studies indicate that locally injected redox-modulating agents can sensitize polymodal peripheral skin nociceptors resulting in acute changes in pain perception. Since endogenous thiol-modifying redox agents are normally present in the interstitial tissue, and could be found in higher concentration in certain conditions (e.g.

5alpha-reduced neuroactive steroids alleviate thermal and mechanical hyperalgesia in rats with neuropathic pain.

5alpha-reduced neuroactive steroids with selective modulatory action in vitro on T or combined modulatory action on T and GABA(A) currents present in peripheral sensory neurons have been shown to induce potent peripheral analgesia in vivo in intact animals. Although the role of T and GABA(A) currents in pathophysiology of neuropathic pain (NPP) is not established, it appears that blockade of T currents and/or potentiation of GABA(A) currents could be beneficial in the management of NPP. To study the potential usefulness of 5alpha-reduced neuroactive steroids in alleviating NPP, we selected two newly synthesized steroids-ECN and CDNC24-with a selective blocking effect on T currents and a selective potentiating effect on GABA(A) currents, respectively, and commercial analogs-alphaxalone and 3alpha5alphaP-with the effects on both ion channels.

New evidence that both T-type calcium channels and GABAA channels are responsible for the potent peripheral analgesic effects of 5alpha-reduced neuroactive steroids.

Neurosteroids are potent blockers of neuronal low-voltage activated (T-type) Ca(2+) channels and potentiators of GABA(A) ligand-gated channels, but their effects in peripheral pain pathways have not been studied previously. To investigate potential analgesic effects and the ion channels involved, we tested the ability of locally injected 5alpha-reduced neurosteroids to modulate peripheral thermal nociception to radiant heat in adult rats in vivo and to modulate GABA(A) and T-type Ca(2+) channels in vitro. The steroid anesthetic alphaxalone (ALPX), the endogenous neurosteroid allopregnanolone (3alpha5alphaP), and a related compound ((3alpha,5alpha,17beta)-3-hydroxyandrostane-17-carbonitrile, (ACN)), induced potent, dose-dependent, enantioselective anti-nociception in vivo and modulation of both T-type Ca(2+) currents and GABA(A)-mediated currents in vitro.

5beta-reduced neuroactive steroids are novel voltage-dependent blockers of T-type Ca2+ channels in rat sensory neurons in vitro and potent peripheral analgesics in vivo.

T-type Ca(2+) channels are believed to play an important role in pain perception, and anesthetic steroids such as alphaxalone and allopregnanolone, which have a 5alpha-configuration at the steroid A, B ring fusion, are known to inhibit T-type Ca(2+) channels and cause analgesia in a thermal nociceptive model (Soc Neurosci Abstr 29:657.9, 2003). To define further the structure-activity relationships for steroid analgesia, we synthesized and examined a series of 5beta-reduced steroids for their ability to induce thermal antinociception in rats when injected locally into the peripheral receptive fields of the nociceptors and studied their effects on T-type Ca(2+) channel function in vitro.

Mechanical and thermal anti-nociception in rats after systemic administration of verapamil.

Voltage-gated Ca(2+) channels expressed in neurons may contribute to nociceptive information processing. However, the role of L-type Ca(2+) channels in pain transmission is not well understood. In this study, we examined the effects of systemically administered verapamil, an antihypertensive agent and L-type Ca(2+) channel blocker, on mechanical and thermal withdrawal thresholds in rats.