Michael S. Gold

Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8.

&NA; Neuropathic pain is a debilitating chronic syndrome that often arises from injuries to peripheral nerves. Such pain has been hypothesized to be the result of an aberrant expression and function of sodium channels at the site of injury. Here, we show that intrathecal administration of specific antisense oligodeoxynucleotides (ODN) to the peripheral tetrodotoxin (TTX)‐resistant sodium channel, NaV1.8, resulted in a time‐dependent uptake of the ODN by dorsal root ganglion (DRG) neurons, a selective ‘knock‐down’ of the expression of NaV1.8, and a reduction in the slow‐inactivating, TTX‐resistant sodium current in the DRG cells. The ODN treatment also reversed neuropathic pain induced by spinal nerve injury, without affecting non‐noxious sensation or response to acute pain. These data provide direct evidence linking NaV1.8 to neuropathic pain. As NaV1.8 expression is restricted to sensory neurons, this channel offers a highly specific and effective molecular target for the treatment of neuropathic pain.

Nociceptor sensitization in pain pathogenesis.

The incidence of chronic pain is estimated to be 20–25% worldwide. Few patients with chronic pain obtain complete relief from the drugs that are currently available, and more than half report inadequate relief. Underlying the challenge of developing better drugs to manage chronic pain is incomplete understanding of the heterogeneity of mechanisms that contribute to the transition from acute tissue insult to chronic pain and to pain conditions for which the underlying pathology is not apparent. An intact central nervous system (CNS) is required for the conscious perception of pain, and changes in the CNS are clearly evident in chronic pain states. However, the blockage of nociceptive input into the CNS can effectively relieve or markedly attenuate discomfort and pain, revealing the importance of ongoing peripheral input to the maintenance of chronic pain. Accordingly, we focus here on nociceptors: their excitability, their heterogeneity and their role in initiating and maintaining pain.

Excitatory amino acid antagonists (kynurenic acid and MK-801) attenuate the development of morphine tolerance in the rat

To investigate the possible role of excitatory amino acids (EAAs) in the mechanisms of morphine tolerance, rats were treated either with the wide-spectrum EAA antagonist, kynurenic acid (150 mg/kg), or the specific N-methyl-D-aspartic acid (NMDA) receptor antagonist. MK-801 (0.05 mg/kg), during a four-day induction period of morphine tolerance. Morphine was given once daily at a dose of 15 mg kg. On the fifth day rats were injected only with morphine (15 mg/kg), and analgesia was assessed using the hot-plate test. Morphine tolerance was significantly reduced by both EAA antagonists. Control experiments showed that at the same doses neither acute nor chronic administration of these antagonists affected morphine analgesia itself in a manner that can explain these findings. The possible involvement of EAAs in the mechanisms of morphine tolerance is discussed.

2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management

2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure : implant and follow-up recommendations and management

A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat

We report evidence for a contribution of tetrodotoxin-resistant sodium current (TTX-R INa) to prostaglandin E2 (PGE2)-induced hyperalgesia. Behavioral experiments were performed in rats chronically implanted with spinal cannulae. The study employed intrathecal administration of oligodeoxynucleotide (ODN) antisense to the recently cloned channel underlying TTX-R INa (PN3/SNS). The nociceptive flexion reflex was employed to determine changes in mechanical stimulus-induced paw-withdrawal threshold. Administration of antisense but not of sense or mismatch ODN, led to a decrease in PGE2-induced hyperalgesia. PGE2-induced hyperalgesia returned to normal 7 days after the last injection of antisense ODN. Antisense ODN selectively and significantly reduced TTX-R INa current density in cultured sensory neurons. Our observations support the hypothesis that modulation of TTX-R INa, present in peripheral terminals of primary afferent nociceptors, contributes, at least in part, to inflammatory hyperalgesia. Since TTX-R INa is found only in primary afferent nociceptors, our findings suggest TTX-R INa as a promising target for novel therapeutic interventions for the treatment of inflammatory pain.

Electrical Storm Presages Nonsudden Death

Background—Electrical storm, multiple temporally related episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF), is a frequent problem among recipients of implantable cardioverter defibrillators (ICDs). However, insufficient data exist regarding its prognostic significance. Methods and Results—This analysis includes 457 patients who received an ICD in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial and who were followed for 31±13 months. Electrical storm was defined as ≥3 separate episodes of VT/VF within 24 hours. Characteristics and survival of patients surviving electrical storm (n=90), those with VT/VF unrelated to electrical storm (n=184), and the remaining patients (n=183) were compared. The 3 groups differed in terms of ejection fraction, index arrhythmia, revascularization status, and baseline medication use. Survival was evaluated using time-dependent Cox modeling. Electrical storm occurred 9.2±11.5 months after ICD implantation, and most episodes (86%) were ...

Right Ventricular Outflow Versus Apical Pacing in Pacemaker Patients with Congestive Heart Failure and Atrial Fibrillation

Introduction: Prior studies suggest that right ventricular apical (RVA) pacing has deleterious effects. Whether the right ventricular outflow tract (RVOT) is a more optimal site for permanent pacing in patients with congestive heart failure (CHF) has not been established.

Calcium Channel α2δ1 Subunit Mediates Spinal Hyperexcitability in Pain Modulation

&NA; Mechanisms of chronic pain, including neuropathic pain, are poorly understood. Upregulation of voltage‐gated calcium channel (VGCC) &agr;2&dgr;1 subunit (Cav&agr;2&dgr;1) in sensory neurons and dorsal spinal cord by peripheral nerve injury has been suggested to contribute to neuropathic pain. To investigate the mechanisms without the influence of other injury factors, we have created transgenic mice that constitutively overexpress Cav&agr;2&dgr;1 in neuronal tissues. Cav&agr;2&dgr;1 overexpression resulted in enhanced currents, altered kinetics and voltage‐dependence of VGCC activation in sensory neurons; exaggerated and prolonged dorsal horn neuronal responses to mechanical and thermal stimulations at the periphery; and pain behaviors. However, the transgenic mice showed normal dorsal horn neuronal responses to windup stimulation, and behavioral responses to tissue‐injury/inflammatory stimuli. The pain behaviors in the transgenic mice had a pharmacological profile suggesting a selective contribution of elevated Cav&agr;2&dgr;1 to the abnormal sensations, at least at the spinal cord level. In addition, gabapentin blocked VGCC currents concentration‐dependently in transgenic, but not wild‐type, sensory neurons. Thus, elevated neuronal Cav&agr;2&dgr;1 contributes to specific pain states through a mechanism mediated at least partially by enhanced VGCC activity in sensory neurons and hyperexcitability in dorsal horn neurons in response to peripheral stimulation. Modulation of enhanced VGCC activity by gabapentin may underlie at least partially its antihyperalgesic actions.

Characterization of basal and re-inflammation-associated long-term alteration in pain responsivity following short-lasting neonatal local inflamatory insult

&NA; Recently, several studies have suggested that neonatal noxious insult could alter future responses to painful stimuli. However, the manifestations, mechanisms, and even developmental nature of these alterations remain a matter of controversy. In part, this is due to the lack of detailed information on the neonatal sensitive period(s) during which noxious stimulation influences future nociception, and the time‐course and distribution of the resultant abnormalities. The present paper describes these parameters in a rat model of short‐lasting (∼24 h) neonatal local inflammation of a hindpaw produced by injection of 0.25% carrageenan (1 &mgr;l/g). Examinations of paw withdrawal responses to thermal and mechanical stimulations in adult animals, which as neonates were subjected to this insult, showed that the previously‐reported long‐term hypoalgesia and hyperalgesia are not mutually exclusive outcomes of early noxious experience. Long‐term hypoalgesia was apparent at the basal conditions and was equally strong in the previously injured and uninjured paws, which suggests a globally‐driven deficit. In contrast, long‐term excessive hyperalgesia had the strongest manifestation in the neonatally‐injured paw after re‐inflammation, indicating significant segmental involvement in its generation. The differences between mechanisms underlying the observed hypoalgesia and hyperalgesia are further underscored by the finding that, while the former is detectable only after animals reach the second month of life, the latter is elicitable immediately upon cessation of the initial neonatal inflammation. Nevertheless, we detected a significant overlap in the neonatal sensitive periods for generation of these effects (both occurring within the first postnatal week). Also, neither the basal hypoalgesia nor excessive re‐inflammation‐associated hyperalgesia subsided with age and were detectable in 120–125‐day‐old rats. These finding provide a framework within which the entire complex of long‐term effects of early noxious experience can be understood and examined.

Review ArticleCardiac sarcoidosis

Cardiac sarcoidosis (CS) is a rare but potentially fatal condition that may present with a wide range of clinical manifestations including congestive heart failure, conduction abnormalities, and most notably, sudden death. Recent advances in imaging technology allow easier detection of CS, but the diagnostic guidelines with inclusion of these techniques have yet to be written. It has become clear that minimally symptomatic or asymptomatic cardiac involvement is far more prevalent than previously thought. Because of the potential life-threatening complications and potential benefit of treatment, all patients diagnosed with sarcoidosis should be screened for cardiac involvement. Patients with CS and symptoms such as syncope need an aggressive workup for a potentially life-threatening etiology, and often require implantable cardioverter-defibrillator therapy. CS patients without arrhythmic symptoms are still at risk for sudden death and may warrant an implantable cardioverter-defibrillator for primary prevention reasons. Although corticosteroids are regarded as the first-line drug of choice, therapy for CS is not yet standardized, and it is unclear at this point whether asymptomatic patients require therapy. Randomized clinical trials are clearly warranted to answer these very important patient care questions, and are endorsed fully by the authors.