Gary R Strichartz

• BS, AM, PhD
• Managing Director at Brigham and Women's Hospital

Binding of local anesthetics to plasma proteins has been presented as an important determinant of their bioavailability. Local anesthetics with a high potential for systemic toxicity, e.g. bupivacaine (BUP), are bound strongly by alpha1-acid glycoprotein (AAG), more weakly by serum albumin, but drug dissociation may be rapid, thus limiting the impo...

What we already know about this topic: Achieving long-lasting surgical site anesthesia can be problematicCryoneurolysis is effective in providing long-lasting analgesia, but current techniques are nonselective for neural tissue WHAT THIS ARTICLE TELLS US THAT IS NEW: Using a rat sciatic nerve block model, an injectable biocompatible ice slurry pre...

Background Knee osteoarthritis (OA) is among the most common and disabling persistent pain conditions, with increasing prevalence in the developed world, and affects women to a greater degree than men. In the USA, the growth of knee OA has been paralleled by an increase in rates of total knee arthroplasty (TKA), a surgical treatment option for late...

The severity and impact of acute pain after breast surgery varies markedly among individuals, underlining the importance of comprehensively identifying specific risk factors, including psychosocial and psychophysical traits. In this prospective observational study, women (n = 234) undergoing breast-conserving surgery, mastectomy, or mastectomy with...

Endothelin-1 (ET-1) and Nerve Growth Factor (NGF) are proteins, released from cancer-ridden tissues, which cause spontaneous pain and hypersensitivity to noxious stimuli. Here we examined the electrophysiological and behavioral effects of these two agents for evidence of their interactions. Individual small-medium cultured DRG sensory neurons respo...

Oxytocin has known antinociceptive effects and is upregulated perinatally. This pilot study investigated the association of plasma oxytocin and postcesarean incisional pain. Plasma samples from 18 patients undergoing elective cesarean delivery were drawn at 1 hour preoperatively and 1 and 24 hours postoperatively and analyzed by using enzyme-linked...

Background and objectives: Local anesthetics (LAs) are often infiltrated subcutaneously for localized perioperative numbing. In addition to blocking nerve conduction, LAs act on pathways used by a variety of pain-inducing and inflammatory mediators. We describe the effects in isolated model sensory neurons of LAs on responses to the algogenic and...

Nerve growth factor plays a key role in the initiation as well as the prolonged heightened pain sensitivity of the inflammatory response. Previously, we showed that NGF rapidly augmented both the excitability of isolated rat sensory neurons and the mechanical sensitivity of the rat's hind paw. The increase in excitability and sensitivity were block...

Thoracotomy results in chronic post-operative pain (CPTP) in half of the cases. Earlier findings in rat models of persistent post-surgical pain suggest that spinal pathways are critical for pain onset but not its maintenance. Descending systems from the brain stem modulate nociceptive transmission in the spinal cord and contribute to persistent pai...

Thoracotomy results in a high frequency of chronic postoperative pain. Resolvins are endogenous molecules, synthesized and released by activated immune cells, effective against inflammatory and neuropathic pain. Different resolvins have differential actions on selective neuronal and glial receptors and enzymes. This article examines the ability of...

The p75 neurotrophin receptor (p75NTR) and its activation of the sphingomyelin signaling cascade are essential for mechanical hypersensitivity resulting from locally injected nerve growth factor (NGF). Here the role of the same effectors, and of the TrkA receptor, are evaluated for thermal hyperalgesia from NGF. Sensitivity of rat hind paw plantar...

Background: Antidepressant S-duloxetine alleviates intractable pain associated with diabetic peripheral neuropathy and fibromyalgia. It also reduces both acute and persistent pain in various animal models. This study addresses whether the enantiomer, R-duloxetine, and the homolog, N-methyl duloxetine, could act as analgesics and whether they block...

Contralateral hyperalgesia, occurring after unilateral injury, is usually explained by central sensitization in spinal cord and brain. We previously reported that injection of -endothelin-1 (ET-1) into one rat hindpaw induces prolonged mechanical and chemical sensitization of the contralateral hindpaw. Here, we examined the role of contralateral ef...

There has recently been a substantial increase in the survival of prematurely born neonates and an increase of in utero surgeries. Noxious stimulation in the newborn alters the pain response to injury in adult life. Progesterone, an effective antihyperalgesic agent in the adult, is at high concentration in the pregnant mother. Therefore, we investi...

Duloxetine is an antidepressant effective for major depressive disorder and also the alleviation of pain for patients with diabetic peripheral neuropathy, chronic musculoskeletal pain, and fibromyalgia. How duloxetine works in pain relief remains unknown. In this study, we address whether duloxetine could act as an analgesic via systemic and local...

Postoperative pain is treated incompletely and ineffectively in many circumstances, and chronic postoperative pain causes suffering and diminishes productivity. The objective of this project is to determine whether a recently developed slow-release formulation of bupivacaine was effective in reducing the experimental chronic postoperative pain. In...

Endothelin (ET-1), an endogenous peptide with a prominent role in cutaneous pain, causes mechanical hypersensitivity in the rat hind paw, partly through mechanisms involving local release of algogenic molecules in the skin. The present study investigated involvement of cutaneous ATP, which contributes to pain in numerous animal models. Pre-exposure...

Postoperative pain alters physiological functions and delays discharge. Perioperative local anesthetics are effective analgesics in the immediate 1- to 2-day postoperative period, but acute pain often lasts longer. The goal of this work was to develop a local anesthetic formulation adhering to an intraoperative implanted device that reduces pain fo...

Nerve Growth Factor (NGF) augments excitability of isolated rat sensory neurons through activation of the p75 neurotrophin receptor (p75(NTR)) and its downstream sphingomyelin signaling cascade, wherein neutral sphingomyelinase(s) (nSMase), ceramide, and the atypical PKC (aPKC), PKMζ, are key mediators. Here we examined these same receptor-pathways...

Thoracotomy often results in chronic pain, characterized by resting pain and elevated mechano-sensitivity. This paper defines complex behavioral responses to tactile stimulation in rats after thoracotomy, shown to be reversibly relieved by systemic morphine, in order to develop a novel qualitative "pain" score. A deep incision and 1 hour of rib ret...

In recent years our understanding of molecular mechanisms of drug action and interindividual variability in drug response has grown enormously. Meanwhile, the practice of anesthesiology has expanded to the preoperative environment and numerous locations outside the OR. Anesthetic Pharmacology: Basic Principles and Clinical Practice, 2nd edition, is...

Background: Acute postoperative pain causes physiological deficits and slows recovery. Reduction of such pain by local anesthetics that are delivered for several days postoperatively is a desirable clinical objective, which is approached by a new formulation and applied in animal studies reported here. Methods: We subcutaneously injected a new f...

The potency and efficacy of local anesthetics injected clinically for peripheral nerve block depends strongly on the rate of neural drug uptake. However, because diffusion into surrounding tissues and removal by the vascular system are major factors in the overall distribution of lidocaine in vivo, true kinetics of drug/neural tissue interactions m...

Cutaneous ATP release plays an important role in both epidermal stratification and chronic pain, but little is known about ATP release mechanisms in keratinocytes that comprise the epidermis. In this study, we analyzed ATP release from cultured human neonatal keratinocytes briefly exposed to air, a process previously demonstrated to trigger ATP rel...

Knowledge about the mechanism of impulse blockade by local anesthetics has evolved over the past four decades, from the realization that Na(+) channels were inhibited to affect the impulse blockade to an identification of the amino acid residues within the Na(+) channel that bind the local anesthetic molecule. Within this period appreciation has gr...

Surgery often causes prolonged postoperative pain, the mechanisms of which are unknown. The authors investigated the role of p38, a pain-associated mitogen-activated protein kinase, in induction and maintenance of such pain. Male rats were subjected to the skin-muscle incision retraction procedure at the saphenous region; the procedure causes ~4 we...

Resolvins, including D and E series resolvins, are endogenous lipid mediators generated during the resolution phase of acute inflammation from the omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Resolvins have potent anti-inflammatory and pro-resolution actions in several animal models of inflammation...

Endothelin-1 (ET-1) is a pain mediator, elevated in skin after injury, which potentiates noxious thermal and mechanical stimuli (hyperalgesia) through the activation of ET(A) (and, perhaps, ET(B)) receptors on pain fibers. Part of the mechanism underlying this effect has recently been shown to involve potentiation of neuronal TRPV1 by PKCɛ. However...

Postoperative pain slows surgical recovery, impacting the return of normal function for weeks, months, or longer. Here we report the antihyperalgesic actions of a new compound, resolvin D1 (RvD1), known to reduce inflammation and to suppress pain after peripheral nerve injury, on the acute pain occurring after paw incision and the prolonged pain af...

Capsaicin selectively binds to TRPV1, the vanilloid subtype 1 of the superfamily of transient receptor potential ion channels, which is highly expressed in pain-transmitting C fibers. Recent reports have demonstrated that the coadministration of capsaicin with a local anesthetic (LA) at the rat sciatic nerve elicits a prolonged nociceptive-selectiv...

Postoperative pain can occur despite nerve blocks during the surgical period. Here we tested Xybrex (Orthocon, Inc., Irvington, NY), a slow-release formulation of lidocaine that blocks rat sciatic nerve for 1-2 days, for its ability to suppress postincisional pain. A plantar paw incision was made in rats, either along the midline (Brennan model) or...

Nerve blocks of long duration are often desirable in perioperative and postoperative situations. The relationship between the duration of such blocks and the rate at which a local anesthetic is released is important to know for developing a localized drug delivery system that will optimize block duration. Lidocaine concentration was varied in 1 ser...

A profound tachyphylaxis of the acute nocifensive flinching (pain) response to subcutaneous injection of endothelin-1 (ET-1) into the hind paw footpad is shown by the reduced response to a second injection. Flinching from the second injection was 20% 5%, 57% 18%, 79% 35%, and 100% 17% of that from the first injection (both 200mol/L, 2nmol) at respe...

Subcutaneous injection of the peptide endothelin-1 (ET-1) into the rat's footpad is known to cause rapid, transient ipsilateral mechanical and thermal sensitization and nocifensive hind paw flinching. Here we report that local injection of ET-1 (2 nmoles) into one hind paw slowly sensitizes the contralateral paw to chemical and mechanical stimulati...

Unlabelled: Subcutaneous injection of endothelin-1 (ET-1) into the glabrous skin of the rat's hind paw is known to produce impulses in nociceptors and acute nocifensive behavioral responses, such as hind paw flinching, and to sensitize the skin to mechanical and thermal stimulation. In this report, we show that in contrast to the responses in glab...

Minimally invasive applications of thermal and mechanical energy to selective areas of the human anatomy have led to significant advances in treatment of and recovery from typical surgical interventions. Image-guided focused ultrasound allows energy to be deposited deep into the tissue, completely noninvasively. There has long been interest in usin...

Unlabelled: Intraplantar injection of endothelin-1 (ET-1) (1.5-10 muM) in the rat produces mechanical allodynia. Here we identify the receptor subtypes for ET-1, glutamate and CGRP critical to such allodynia. Antagonism of ET(A) or ET(B) receptors alone, by BQ123 or BQ788, respectively, only partially suppressed allodynia; the combined antagonists...

Exposure to endothelin-1 (ET-1, 50 nM) of sensory neurons, acutely isolated from rat dorsal root ganglia (DRG), results in an increase in the number of action potentials elicited by a linear ramp of stimulating current. The changes are complete in 5 min after ET-1 treatment and do not reverse in 5-10 min after ET-1's removal. Neither the resting po...

Injection of endothelin-1 (ET-1) into the plantar rat hindpaw causes acute pain at high concentrations and tactile sensitization at low concentrations. The pro-nociceptive actions are driven through ET(A) receptors for both levels of [ET-1], but the ET(B) receptors are only pro-nociceptive for allodynia from low [ET-1] and anti-nociceptive for pain...

Mitogen-activated protein kinases (MAPKs) are important for intracellular signal transduction and play critical roles in regulating neural plasticity and inflammatory responses. The MAPK family consists of three major members: extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinase (JNK), which represent three separate signal...

The endogenous peptide endothelin-1 (ET-1), originally identified as a potent vasoconstrictor, plays a role in a number of painful conditions. In this review article we discuss the mechanisms that are essential for local sensitization by subcutaneously administered ET-1, and report evidence of ET-1's ability to sensitize distant regions of the body...

Functional blockade of peripheral nerves is the primary objective of local anesthesia, and it is often desirable to have a persistent blockade, sustained throughout and beyond a surgical procedure. Current local anesthetics give effective analgesia for <8-12 h after a single bolus injection. We report on an implantable, controlled-release drug deli...

Unlabelled: The endogenous endothelin (ET) peptides participate in a remarkable variety of pain-relatedprocesses. Pain that is elevated by inflammation, by skin incision, by cancer, during a Sickle Cell Disease crisis and by treatments that mimic neuropathic and inflammatory pain and are all reduced by local administration of antagonists of endoth...

This review considers the ion channels that underlie transduction of nociceptive energies in the periphery, that are involved in impulse initiation and propagation in peripheral sensory neurones, and that participate in pre- and post-synaptic actions in the spinal cord dorsal horn, in light of their susceptibility to local anaesthetics. Although th...

Resiniferatoxin (RTX) is a potent agonist of the transient receptor potential vanilloid 1 channel (TRPV1) found in peripheral nociceptors. RTX causes cellular excitation first, followed by a long-lasting refractory state, which has suggested its therapeutic use for pain control. RTX's effect could result from specific actions on TRPV1 channels, but...

Characterization of the Saxitoxin Receptor in Drosophila MelanogasterMutant AnalysisExplanation of the napts PhenotypesDiscussion and Future ProspectsReferencesDiscussionReferences

The contribution of endothelin-1 (ET-1), acting via endothelin-A receptors (ET(A)), on post-incisional pain was examined in a rat model of incision through the hairy skin of the lumbar dorsum. Post-incisional mechanical hyperesthesia was evaluated by cutaneous trunci muscle reflexes (CTMR) of subcutaneous muscles responding to stimulation with von...

Interactions of the local anesthetic tetracaine with unilamellar vesicles made of dimyristoyl or dipalmitoyl phosphatidylcholine (DMPC or DPPC), the latter without or with cholesterol, were examined by following changes in the drug's fluorescent properties. Tetracaine's location within the membrane (as indicated by the equivalent dielectric constan...

Sandhoff disease is an inherited lysosomal storage disease caused by a mutation in the gene for the beta-subunit (Hexb gene) of beta-hexosaminidase A (alphabeta) and B (beta beta). The beta-subunit together with the GM2 activator protein catabolize ganglioside GM2. This enzyme deficiency results in GM2 accumulation primarily in the central nervous...

Local anesthetics are used broadly to prevent or reverse acute pain and treat symptoms of chronic pain. This chapter, on the analgesic aspects of local anesthetics, reviews their broad actions that affect many different molecular targets and disrupt their functions in pain processing. Application of local anesthetics to peripheral nerve primarily r...

Subcutaneous endothelin-1 (ET-1; 200 microM, 2 nmoles/paw) injected into the rat hind paw, has been shown to cause robust hind paw flinching (HPF) and paw licking, and to induce impulses selectively in primary nociceptors. Here we report that a much lower [ET-1] sensitizes the paw to a nocifensive withdrawal response to tactile stimulation (by von...

Clinical and experimental data indicate that changes in the expression of voltage-gated sodium channels play a key role in the pathogenesis of neuropathic pain and that drugs that block these channels are potentially therapeutic. Clinical and experimental data also suggest that changes in voltage-gated sodium channels may play a role in inflammator...

Central terminals of primary nociceptors release neurotransmitters glutamate and substance P, which bind to ionotropic or metabotropic receptors on spinal neurons to induce cellular responses. Extracellular signal-regulated kinases are activated by these receptors and are important modulators of pain at the dorsal horn. The authors investigated the...

Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GFAP-expressing astrocytes in the spinal cord. In contrast...

An incision of hairy skin of the rat's back provides a new model for postincisional pain to determine the importance of cutaneous anesthesia. Male Sprague-Dawley rats were anesthetized with sevoflurane and given a 0.6-ml subcutaneous injection of bupivacaine (0.25%) under the incision site or the medial lumbar dorsum or at the nuchal midline, 30 mi...

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 senso...

Endothelin-1 (ET-1) applied to the sciatic nerve or injected into the plantar hindpaw of rats induces pain behavior (ipsilateral hindpaw flinching) and selective excitation of nociceptors by activation of endothelin-A (ET(A)) receptors. To determine the pharmacological profile of the sensory fibers that mediate this pain behavior, we administered l...

1. The interaction of veratridine (VTD), a Na+ channel activator, scorpion α-toxin (LQ), an open state Na+ channel stabilizer, and the local anesthetic, lidocaine (LID), a channel inhibitor, at the neuronal sodium channel was assessed by measuring VTD-dependent slow depolarizations of frog sciatic nerve using the sucrose-gap method. 2. The slow dep...

The adjustment of local anesthetic dosage for peripheral nerve block must meet two basic requirements: a drug concentration sufficient to inhibit Na+ channels to the point of impulse failure and a volume of drug sufficient to expose a length of nerve longer than the "critical length" for propagation failure. This study examines the lidocaine dosage...

Endothelin-1 (ET-1) is a newly described pain mediator that is involved in the pathogenesis of pain states ranging from trauma to cancer. ET-1 is synthesized by keratinocytes in normal skin and is locally released after cutaneous injury. While it is able to trigger pain through its actions on endothelin-A (ET(A)) receptors of local nociceptors, it...

Ropivacaine and levobupivacaine, both single S- enantiomers, are being promoted as safer alternatives to racemic bupivacaine. To determine whether levobupivacaine produces a more potent and longer lasting peripheral nerve block than ropivacaine, we compared functional blockade of sciatic nerve in the rat at several doses with these 2 agents. Percut...

Systemic lidocaine can relieve various forms of neuropathic pain that develop after nerve injury. Mechanical allodynia, defined by a significant drop in paw withdrawal threshold force following spinal nerve ligation (L5-L6) in rats, can be reversed by one 30min lidocaine infusion at a constant plasma concentration as low as 1-2 microg/ml, an effect...

Adding epinephrine to lidocaine solutions for peripheral nerve block potentiates and prolongs the action, but by incompletely understood mechanisms. In an effort to discriminate the pharmacokinetic from the pharmacodynamic effects of epinephrine, the authors measured the lidocaine content of peripheral nerve over the course of block produced by 0.5...

Understanding the interaction of local anesthetics (LAs) with plasma proteins is essential to understanding their systemic pharmacology and toxicology. The molecular determinants of LA binding to the major variant (F1*S) of human alpha1-acid glycoprotein (AGP) were therefore investigated spectrofluorometrically using whole AGP and a novel, F1*S var...

Abnormal impulses caused by very slowly inactivating Na channels of peripheral nerve have been proposed to play a critical role in neuropathic pain. Low concentrations of local anesthetics, often effective in treating experimental and clinical neuropathic pain, are also known to potently suppress the long after-depolarizations induced by these pers...

We showed previously that subcutaneous injection of the injury-associated peptide mediator endothelin-1 (ET-1) into the rat plantar hindpaw produces pain behavior and selective excitation of nociceptors, both through activation of ET(A) receptors likely on nociceptive terminals. The potential role of ET(B) receptor activation in these actions of ET...

Endothelin-1 (ET-1) causes pain through activation of nociceptors, by either direct depolarization or increased excitability. Here we examined the effect of ET-1 on nociceptor-associated tetrodotoxin-resistant (TTX-R) sodium currents using whole-cell voltage clamp of acutely dissociated rat dorsal root ganglion (DRG) neurons. DRG neurons that respo...

The theoretical bases for therapeutic and toxic differences between chiral drug molecules are presented, and examples of local anesthetics, volatile anesthetics, and the intravenous anesthetic ketamine are critically reviewed.