Spontaneous Impulse Generation Research Articles

Neuropathic pain in diabetes—evidence for a central mechanism

Hyperexcitability of and aberrant spontaneous impulse generation by damaged first-order sensory neurons and their peripheral axons are well-established processes that strongly contribute to pain associated with diabetic neuropathy. Studies in the past 5 years, however, suggest that, as in many neuropathic pain disorders, central neuropathic mechanisms can also contribute to pain experienced with diabetes. These studies have demonstrated that thalamic dysfunction occurs in patients with diabetes mellitus, and that in experimental models of this disease neurons in the ventral posterolateral thalamus can become hyperexcitable, firing at abnormally high frequencies and generating aberrant spontaneous activity. In this article, we discuss these findings, which suggest that thalamic neurons can act as central generators or amplifiers of pain in diabetes.

Re‐emerging microneurography

Re‐emerging microneurography

Regulation of Cardiac L-Type Calcium Current by Phosphorylation and G Proteins

Voltage-dependent Ca2+ channels play a major role in the electromechanical coupling of cardiac cells. During the plateau phase Ca2+ entry induces a Ca2+ -dependent Ca2+ release from the sarcoplasmic reticulum and con­ sequently the initiation of contraction (for review see 41). Voltage-dependent Ca2+ channels are also involved in the spontaneous impulse generation as well as in the duration of the action potentials and hence in refractoriness. Ca2+ channels are also the target of various hormones and neurotransmitters. In an Annual Review of Physiology that appeared ten years ago, Reuter (112) suggested a hypothetical scheme for the �-adrenergic control of Ca2+ chan­ nels by cAMP-dependent phosphorylation, but direct experimental evidence for this was still missing (further reviews see 90, 125, 133, 134). In the subsequent decade the concept of regulation via the signal transduction process and phosphorylation became more elaborate by analysis of the

Carbamazepine inhibits spontaneous activity in experimental neuromas

In eight adult Sprague-Dawley rats the effect of parenteral carbamazepine on spontaneous discharges from saphenous neuromas (7–42 days following nerve section) was tested. Intravenous carbamazepine produced immediate inhibition of spontaneous activity originating in both A- α β and A-δ fibers at doses of 2.51–11.2 (7.9 ± 3.3) mg/kg. In four additional animals, serum levels of carbamazepine were determined following iv administration of the drug. These results indicated that ectopic spontaneous impulse generation from experimental neuromas was inhibited by carbamazepine in the range of serum concentration in which the agent is used to treat trigeminal neuralgia and other painful neuropathies in humans. This implies that the effectiveness of this agent in the treatment of these disorders may result from suppression of peripherally originating ectopic spontaneous activity.

Peripheral nerve Spontaneous impulse generation in normal and denervated dorsal root ganglia:Sensitivity to alpha-adrenergic stimulation and hypoxia: Exp. Neurol., 85 (1984) 257–272

Pain: November 1985 - Volume 23 - Issue 3 - p 308-309 doi: 10.1016/0304-3959(85)90122-8

Spontaneous impulse generation in normal and denervated dorsal root ganglia: Sensitivity to alpha-adrenergic stimulation and hypoxia

Previous experiments indicate that after peripheral nerve lesion, two sites of spontaneous ectopic impulse generation rapidly develop: the peripheral neuroma and the region of the dorsal root ganglion (DRG). In 30 adult Sprague-Dawley rats, micro-filament recordings were made from either the dorsal root of L5 or the proximal sciatic nerve. The locus of the ectopic impulse generator, spontaneous firing patterns, and response to both adrenergic and hypoxic stimulation were observed in 200 spontaneously active isolated fibers. Results indicated that after sciatic transection the neuroma and the DRG behaved as independent sources of ectopic impulse generation. Spontaneous activity originating in the neuroma was responsive to adrenergic and hypoxic stimulation in 57% and 86% of fibers tested, respectively. Spontaneous activity originating in the DRG after chronic sciatic nerve transection demonstrated a response to adrenergic stimulation in 61% of fibers tested, and all fibers showed an increase in activity during hypoxic periods. Furthermore, after acute sciatic neurotomy in otherwise normal animals, spontaneous activity originating in the DRG could be recorded in a few fibers. Likewise, 48% of those fibers showed some response to topical or systemic epinephrine administration, and hypoxia produced some degree of excitation of firing in all fibers tested. Neither epinephrine administration nor hypoxic challenge produced excitation of firing in DRG neurons with intact receptive fields in normal animals. The pharmacology of adrenergic sensitivity of spontaneously active fibers from both the neuroma and the region of the DRG indicated alpha-adrenergic specificity. Furthermore, a number of fibers exhibiting spontaneous activity from both the region of the neuroma and the DRG showed either adrenergic or hypoxic sensitivity, but not both. Thus, the mechanisms of the largely excitatory actions of alpha-agonists and hypoxia on spontaneous discharges from these sites were lelt to be different. These data indicate that adrenergic and/or hypoxic responsiveness is a property of (i) otherwise normal DRG neurons which demonstrate intrinsic spontaneous firing properties, (ii) neurons in chronically denervated ganglia which exhibit spontaneous activity, and (iii) some fibers within neuromas. Normal DRG neurons with intact receptive fields do not appear to increase their firing rate in response to either hypoxia or adrenergic stimulation. These findings may be relevant to the development of chronic pain in man following peripheral nerve injury.

Spontaneous impulse generation in normal and denervated dorsal root ganglia: Sensitivity to alpha-adrenergic stimulation and anoxia

Spontaneous impulse generation in normal and denervated dorsal root ganglia: Sensitivity to alpha-adrenergic stimulation and anoxia

On the mechanism of spontaneous impulse generation in the pacemaker of the heart.

Rhythmic activity in Purkinje fibers of sheep and in fibers of the rabbit sinus can be produced or enhanced when a constant depolarizing current is applied. When extracellular calcium is reduced successively, the required current strength is less, and eventually spontaneous beating occurs. These effects are believed due to an increase in steady-state sodium conductance. A significant hyperpolarization occurs in fibers of the rabbit sinus bathed in a sodium-free medium, suggesting an appreciable sodium conductance of the "resting" membrane. During diastole, there occurs a voltage-dependent and, to a smaller extent, time-dependent reduction in potassium conductance, and a pacemaker potential occurs as a result of a large resting sodium conductance. It is postulated that the mechanism underlying the spontaneous heart beat is a high resting sodium current in pacemaker tissue which acts as the generator of the heart beat when, after a regenerative repolarization, the decrease in potassium conductance during diastole reestablishes the condition of threshold.