Time Course Of Relief Research Articles

When does pleasure start after the end of pain? The time course of relief.

Painful events are suggested to elicit two opponent responses: a negatively valenced and a positively valenced process triggered by their onset and termination, respectively. Consequently, stimuli (conditioned stimulus, CS) associated with pain onset (unconditioned stimulus, US) provoke defensive responses like startle potentiation, while stimuli associated with pain termination elicit appetitive responses like startle attenuation. Here we summarize four studies elucidating the time course of the relief following the termination of a painful US. In these studies, the timing of a relief-associated stimulus (reliefCS) presented after a painful US was varied from immediately (Study1), 3 seconds (Study4), or 6 seconds (Study2 and 3) after the US. Responses to these relief CSs were compared also with responses to a stimulus presented before the US (fearCS), and a third stimulus (safetyCS) that was never associated with the US. The synopsis of these studies reveals that the timing of the reliefCS is crucial to turn a defensive response into an appetitive response. Namely, the reliefCS immediately following the US-induced startle potentiation and negative valence (Study1); 3 seconds later, the startle response was slightly less potentiated and the ratings a little less negative (Study4); finally, the reliefCS presented 6 seconds after the US caused startle attenuation (Study2 and 3) and positively valenced ratings (Study3). In sum, the observed time course of relief closely follows the predictions of opponent process theory. This means that relief may be a reinforcer that elicits conditioned appetitive behavior, but its reinforcing properties strongly depend on its temporal relation to the aversive event.

The evaluation of ICHD-3 beta diagnostic criteria for Tolosa-Hunt syndrome: a study of 22 cases of Tolosa-Hunt syndrome.

The objective of the study was to evaluate the amended International Classification of Headache Disorders (third edition, beta version, ICHD-3 beta) with a retrospective analysis. A total of 22 patients diagnosed with painful ophthalmoplegia and Tolosa-Hunt syndrome (THS) in our hospital were retrospectively studied. The following clinical data were collected: symptoms, signs, location of inflammatory tissue, time interval of paresis following the onset of pain, pain and signs of resolution, follow-up and relapse. Pain and diplopia were found in 22 (100 %) and 20 cases (91 %). The sympathetic nerve was involved in 6 cases (27 %). Paresis followed the pain for an average of 8 ± 5.87 days. Serial magnetic resonance imaging (MRI) revealed granulomatous lesion that was visible in 20 patients (91 %). 19 patients (86 %) demonstrated the lesions located in the cavernous sinus, orbital apex or superior orbital fissure. One lesion extended to the intracranial structure. Pain was relieved in 20 cases (91 %) within 72 h and no patient had complete relief from paresis. According to our study, we think the time course of relief should be undefined. Headache location is hard to describe accurately. Normal MRI should be involved in THS diagnoses. The lesion of THS can extend beyond the cavernous sinus and the orbit. The time interval between headache and paresis can exceed 2 weeks.

Comparison of N- and P/Q-Type Voltage-Gated Calcium Channel Current Inhibition

Activation of N- and P/Q-type voltage-gated calcium channels triggers neurotransmitter release at central and peripheral synapses. These channels are targets for regulatory mechanisms, including inhibition by G-protein-linked receptors. Inhibition of P/Q-type channels has been less well studied than the extensively characterized inhibition of N-type channels, but it is thought that they are inhibited by similar mechanisms although possibly to a lesser extent than N-type channels. The aim of this study was to compare the inhibition of the two channel types. Calcium currents were recorded from adrenal chromaffin cells and isolated by the selective blockers omega-conotoxin GVIA (1 microM) and omega-agatoxin IVA (400 nM). The inhibition was elicited by ATP (100 microM) or intracellular application of GTP-gamma-S. It was classified as voltage-sensitive (relieved by a conditioning prepulse) or voltage-insensitive (present after a conditioning prepulse). The voltage-insensitive inhibition accounted for a 20% reduction of both currents, whereas the voltage-sensitive inhibition reduced the N-type current by 45% but the P/Q-type current by 18%. However, the voltage dependence of the inhibition, the time course of relief from inhibition during a conditioning prepulse, and the time course of reinhibition after such a prepulse showed few differences between the N- and P/Q-type channels. Assuming a simple bimolecular reaction, our data suggest that changes in the kinetics of the G-protein/channel interaction alone cannot explain the differences in the inhibition of the N- and P/Q-type calcium channels. The subtle differences in inhibition may facilitate the selective regulation of neurotransmitter release.

Depolarization-induced slowing of Ca2+ channel deactivation in squid neurons

Properties of squid giant fiber lobe (GFL) Ca2+ channel deactivation (closing) were studied using whole-cell voltage clamp. Tail currents displayed biexponential decay, and fast and slow components of these tails exhibited similar external Ca(2+)- and voltage-dependence. Both components also shared similar inactivation properties. Increasing duration pulses to strongly depolarizing potentials caused a substantial slowing of the rate of deactivation for the fast component, and also led to an apparent conversion of fast tail currents to slow without an increase in total tail amplitude. A five-state kinetic model that computed the closing of channels differentially populating two open states could simulate the kinetic characteristics of GFL Ca2+ pulse and tail currents over a wide voltage range. The kinetics of the proposed state transition was very similar to the time course of relief of omega-Agatoxin IVA Ca2+ channel block with long pulses. A similar model predicted that the relief of block could occur via faster toxin dissociation from the second open state. Thus, GFL Ca2+ channels possess a unique form of voltage-dependent gating modification, in which maintained prior depolarization leads to a significant delay to channel closure at negative potentials. At the nerve terminal, amplified Ca2+ signals generated by such a mechanism might alter synaptic responses to repetitive stimulation.

Different mechanisms of the inhibition of the transient outward current in rat ventricular myocytes.

The mechanism of drug-induced inhibition of the transient outward current, Ito, has been investigated in rat ventricular myocytes using the whole cell patch clamp technique. Ito was activated by 300 ms depolarizing voltage clamp steps in 10 mV increments from -50 mV up to +40 mV. At +40 mV, Ito peaked after about 3 ms, and the time course of inactivation was appropriately described by two time constants, tau fast = 17 ms and tau slow = 203 ms. Verapamil, quinidine sulfate and nifedipine preferentially depressed Ito at the end of the 300 ms depolarizing voltage clamp step; the inactivation of Ito was accelerated by all drugs, whereas peak Ito was less affected. The time course of drug action at +40 mV was calculated by the fractional changes of Ito. Verapamil, quinidine sulfate and nifedipine exerted a block of Ito increasing during the depolarizing voltage clamp step. The onset of block in response to verapamil, quinidine sulfate and nifedipine (30 mumol/each) was appropriately described by monoexponential functions with time constants tau on = 9.3, 1.7 and 1.1 ms, respectively. Relief from block by verapamil, quinidine sulfate and nifedipine at -50 mV was assessed by comparison of the recovery process of peak Ito from inactivation with or without drugs. tau off amounted to 695 ms in the case of quinidine sulfate; verapamil and nifedipine did not significantly affect the recovery process so that the determination of the time course of relief from block was not possible.(ABSTRACT TRUNCATED AT 250 WORDS)

THE PLASTICITY OF CUTANEOUS HYPERALGESIA DURING SYMPATHETIC GANGLION BLOCKADE IN PATIENTS WITH NEUROPATHIC PAIN

In order to investigate the plasticity of cutaneous sensory abnormalities in neuropathic pain, we monitored sensory and vasomotor effects of diagnostic sympathetic ganglion blocks in 24 patients, who suffered from chronic pain and cutaneous hyperalgesia following peripheral nerve or tissue injury. Ongoing pain was rated on a visual analogue scale, and pain evoked by innocuous tactile and cooling stimuli (hyperalgesia) on a verbal rating scale. Skin temperatures were determined at symmetric sites. In two patients, cutaneous blood flow was measured with a laser Doppler device. The sympathetic blocks led to a significant reduction of the group mean ongoing pain (40%) and cutaneous hyperalgesia (50%). Between patients, however, there was a large variability that could not be related merely to adequacy of sympathetic blockade. Neither the magnitude of change in skin temperature nor the final skin temperature after the block correlated with the amount of pain relief. The relief of hyperalgesia, however, correlated with the relief of ongoing pain. Nine patients experienced pain relief of greater than 50%. In these patients, the time course of hyperalgesia relief was similar to the time course of relief of ongoing pain. Pain relief occurred simultaneously with or a few minutes before cutaneous vasodilatation. During the block, even vigorous mechanical or cold stimuli did not rekindle hyperalgesia. In all patients, pain and hyperalgesia returned within a day after the block. In three patients tested, passive warming of the limb to the temperature achieved by the sympathetic block had negligible effects on pain and hyperalgesia. The hyperalgesia of sympathetically maintained pain is thought to be due to sensitization of central pain-signalling neurons to mechanoreceptor input. The present data indicate that this sensitization is highly plastic even when the disease has persisted for months or years. It could be reversed within minutes by a sympathetic blockade, but returned when sympathetic block subsided. Mechanoreceptor input by itself was not sufficient to maintain or rekindle the central sensitization. This supports the hypothesis that low-grade activity of nociceptors, possibly due to development of alpha-adrenergic sensitivity after injury, is involved in the maintenance of central sensitization.