This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.

/pdf/physiology-and-pathophysiology-of-purinergic-1z94g2hz0f.pdf

Physiology and Pathophysiology of Purinergic Neurotransmission

Human malignant hyperthermia is a life-threatening genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking drugs occurring during or after anaesthesia. The skeletal muscle relaxant dantrolene is the only currently available drug for specific and effective therapy of this syndrome in man. After its introduction, the mortality of malignant hyperthermia decreased from 80% in the 1960s to < 10% today. It was soon discovered that dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. However, its precise mechanism of action and its molecular targets are still incompletely known. Recent studies have identified the ryanodine receptor as a dantrolene-binding site. A direct or indirect inhibition of the ryanodine receptor, the major calcium release channel of the skeletal muscle sarcoplasmic reticulum, is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration. Dantrolene is not only used for the treatment of malignant hyperthermia, but also in the management of neuroleptic malignant syndrome, spasticity and Ecstasy intoxication. The main disadvantage of dantrolene is its poor water solubility, and hence difficulties are experienced in rapidly preparing intravenous solutions in emergency situations. Due to economic considerations, no other similar drugs have been introduced into routine clinical practice.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2044.2004.03658.x

Dantrolene – A review of its pharmacology, therapeutic use and new developments

Context. Intense acute pain afflicts millions of patients each year. Despite the recently increased focus on the importance of pain control, management of acute pain has remained suboptimal.

Objective.  The objective of this study was to identify through a review of recent literature the barriers to effective treatment of acute pain and the potential consequences of inadequate pain management.

Design.  A comprehensive literature review was conducted to identify articles relevant to the management of acute pain. Information regarding the underlying causes of inadequate pain management, as well as the sequelae associated with undermanaged pain was extracted and summarized.

Results.  Studies indicate that treatment of acute pain remains suboptimal due to attitudes and educational barriers on the part of both physicians and patients, as well as the intrinsic limitations of available therapies. Inadequate management of acute pain negatively impacts numerous aspects of patient health, and may increase the risk of developing chronic pain. Although opioids are the preferred treatment for most moderate to severe acute pain, their side effects can impede their use, and thus, their clinical effectiveness. Analgesic regimens with an improved efficacy/tolerability balance have the potential to improve acute pain management, and thus reduce the incidence of chronic pain. Studies examining the use of multiple analgesics with different mechanisms of action suggest that multimodal therapies may offer an improved efficacy/tolerability balance over single agent regimens.

Conclusions.  There exists a significant need for effective, well-tolerated analgesic therapies to limit the negative consequences of undermanaged acute pain. The use of multimodal therapy has demonstrated increasing promise and is supported by current practice guidelines.

/pdf/causes-and-consequences-of-inadequate-management-of-acute-18366s8pqj.pdf

Causes and consequences of inadequate management of acute pain.

Damage to the nervous system can cause neuropathic pain, which is in general poorly treated and involves mechanisms that are incompletely known. Currently available animal models for neuropathic pain mainly involve partial injury of peripheral nerves. Multiple inflammatory mediators released from damaged tissue not only acutely excite primary sensory neurons in the peripheral nervous system, producing ectopic discharge, but also lead to a sustained increase in their excitability. Hyperexcitability also develops in the central nervous system (for instance, in dorsal horn neurons), and both peripheral and spinal elements contribute to neuropathic pain, so that spontaneous pain may occur or normally innocuous stimuli may produce pain. Inflammatory mediators and aberrant neuronal activity activate several signaling pathways [including protein kinases A and C, calcium/calmodulin-dependent protein kinase, and mitogen-activated protein kinases (MAPKs)] in primary sensory and dorsal horn neurons that mediate the induction and maintenance of neuropathic pain through both posttranslational and transcriptional mechanisms. In particular, peripheral nerve lesions result in activation of MAPKs (p38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase) in microglia or astrocytes in the spinal cord, or both, leading to the production of inflammatory mediators that sensitize dorsal horn neurons. Activity of dorsal horn neurons, in turn, enhances activation of spinal glia. This neuron-glia interaction involves positive feedback mechanisms and is likely to enhance and prolong neuropathic pain even in the absence of ongoing peripheral external stimulation or injury. The goal of this review is to present evidence for signaling cascades in these cell types that not only will deepen our understanding of the genesis of neuropathic pain but also may help to identify new targets for pharmacological intervention.

Cell Signaling and the Genesis of Neuropathic Pain

Context. Intense acute pain afflicts millions of patients each year. Despite the recently increased focus on the importance of pain control, management of acute pain has remained suboptimal. Objective. The objective of this study was to identify through a review of recent literature the barriers to effective treatment of acute pain and the potential consequences of inadequate pain management. Design. A comprehensive literature review was conducted to identify articles relevant to the management of acute pain. Information regarding the underlying causes of inadequate pain management, as well as the sequelae associated with undermanaged pain was extracted and summarized. Results. Studies indicate that treatment of acute pain remains suboptimal due to attitudes and educational barriers on the part of both physicians and patients, as well as the intrinsic limitations of available therapies. Inadequate management of acute pain negatively impacts numerous aspects of patient health, and may increase the risk of developing chronic pain. Although opioids are the preferred treatment for most moderate to severe acute pain, theirsideeffectscanimpedetheiruse,andthus,their clinical effectiveness. Analgesic regimens with an improved efficacy/tolerability balance have the potential to improve acute pain management, and thus reduce the incidence of chronic pain. Studies examining the use of multiple analgesics with different mechanisms of action suggest that multimodal therapies may offer an improved efficacy/tolerability balance over single agent regimens. Conclusions. There exists a significant need for effective, well-tolerated analgesic therapies to limit the negative consequences of undermanaged acute pain. The use of multimodal therapy has demonstrated increasing promise and is supported by current practice guidelines.

Review Article Causes and Consequences of Inadequate Management of Acute Pain

Background: Local anesthetic actions on the K + channels of dorsal root ganglion (DRG) and dorsal horn neurons may modulate sensory blockade during neuraxial anesthesia. In dorsal horn neurons, local anesthetics are known to inhibit transient but not sustained K + currents. The authors characterized the effects of local anesthetics on K + currents of isolated DRG neurons. Methods: The effects of lidocaine, bupivacaine, and tetracaine on K + currents in isolated rat DRG neurons were measured with use of a whole cell patch clamp method. The currents measured were fast-inactivating transient current (I Af ), slow-inactivating transient current (I As ), and noninactivating sustained current (I Kn ). Results: One group of cells (type 1) expressed I Af and I Kn . The other group (type 2) expressed I As and I Kn . The diameter of type 2 cells was smaller than that of type 1 cells. Lidocaine and bupivacaine inhibited all three K + currents. Tetracaine inhibited I As and I Kn but not I Af . For bupivacaine, the concentration for half-maximal inhibition (IC 50 ) of I Kn in type 2 cells was lower than that for I Kn in type 1 cells (57 vs. 121 μM). Similar results were obtained for tetracaine (0.6 vs. 1.9 mM) and for lidocaine (2.2 vs. 5.1 mM). Conclusions: Local anesthetics inhibited both transient and sustained K + currents in DRG neurons. Because K + current inhibition is known to potentiate local anesthetic-induced impulse inhibition, the lower IC 50 for I Kn of small type 2 cells may reflect preferential inhibition of impulses in nociceptive neurons. The overall modulatory actions of local anesthetics probably are determined by their differential effects on presynaptic (DRG) and postsynaptic (dorsal horn neurons) K + currents.

Local anesthetic inhibition of voltage-activated potassium currents in rat dorsal root ganglion neurons.

Remimazolam (CNS-7056) is a short-acting GABA(A) receptor agonist, under development by PAION, in collaboration with Japanese licensee Ono Pharmaceutical, as an intravenous sedative agent for potential use in day-case procedures, and the induction and maintenance of anesthesia. A member of the benzodiazapene class of drugs, the structure of remimazolam was modified to produce a drug that displays organ-independent metabolism. The incorporation of a carboxylic ester moiety into the benzodiazapene core of remimazolam renders it susceptible to non-specific tissue esterases and it is rapidly metabolized into its pharmacologically inactive metabolite CNS-7054. Preclinical studies in sheep demonstrated that remimazolam produced a more rapid onset of action, and a shorter duration of action, compared with midazolam. In a phase IIa clinical trial evaluating remimazolam as a procedural sedative for upper gastrointestinal endoscopy in patients, the time to recovery from sedation was shorter and more consistent with remimazolam, relative to midazolam. Because of its organ-independent metabolism and rapid and predictable onset and recovery, remimazolam appears to have potential advantages over other currently available short-acting sedatives.

Remimazolam, a short-acting GABA(A) receptor agonist for intravenous sedation and/or anesthesia in day-case surgical and non-surgical procedures.

We report two cases of difficult intubation where a laryngeal mask airway (LMA) was used and changed to a conventional endotracheal tube using a retrograde intubation set. In two patients, following induction of anaesthesia, the trachea could not be intubated in the conventional fashion with a blade. In both patients an LMA was inserted to achieve an airway. In both patients intubation with a conventional endotracheal tube was required. A Cook Retrograde Intubation Kit and fibreoptic bronchoscope were used to change the LMA to conventional endotracheal tube without problems. The Cook retrograde intubation allows an LMA to be replaced with an endotracheal tube with an ID greater than 6 mm with a #3 or 7 mm with a #5 LMA. This technique places an exchange stylet into the airway which is superior to a conventional guidewire. This method allows the airway to be maintained until the LMA is exchanged with an endotracheal tube. Anaesthesia may be maintained and the airway instrumented without difficulty using this technique.

/pdf/intubation-via-the-lma-using-a-cook-retrograde-intubation-1ysyvmo5di.pdf

Intubation via the LMA using a Cook retrograde intubation kit

Activation of CB1 inhibits NGF-induced sensitization of TRPV1 in adult mouse afferent neurons

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2801%2903312-9

Thomas S. McDowell

Papers

Local anesthetic inhibition of voltage-activated potassium currents in rat dorsal root ganglion neurons.

Remimazolam, a short-acting GABA(A) receptor agonist for intravenous sedation and/or anesthesia in day-case surgical and non-surgical procedures.

Intubation via the LMA using a Cook retrograde intubation kit

Activation of CB1 inhibits NGF-induced sensitization of TRPV1 in adult mouse afferent neurons

Functional properties of ryanodine receptors from rat dorsal root ganglia