Pain Research Center

The Pain Research Center is staffed by 6 Principal Investigators, 3 Senior Research Associates, 3 Visiting Professors (anesthesia), 5 Postdoctoral Fellows and 5 support staff, and its work is supported by 12 NIH-funded grants.
 

Peter Gerner, M.D.

Local anesthetics may cause severe adverse effects due to local toxicity (from temporary nerve degeneration to permanent paraplegia). Of even greater importance is that depending on the type of surgery, up to 70% of patients develop a chronic pain syndrome after otherwise successful surgery. Dr. Gerner’s long-term objective is to definine the underlying pathophysiological mechanisms, with the goal of decreasing both the toxicity of local anesthetics and the incidence of chronic post-operative pain. The hypothesis is that toxicity of local anesthetics can be minimized by exploiting specific pharmacological interactions that modulate the function of the cellular signaling pathways activated by local anesthetics and surgery/pain. Dr. Gerner’s laboratory demonstrated that local toxicity can be minimized by the use of neuroprotective drugs that prevent apoptotic changes induced locally by local anesthetics (e.g., the p38 MAPK inhibitor SB203580). Similarly, the same class of drugs has been shown to be effective for the therapy of chronic pain in various animal models.

The overall specific aim (to decrease the incidence of postoperative chronic pain by co-administration of local anesthetics and MAPK inhibitors) will test in an established chronic pain model (rat thoracotomy model) the hypothesis that the intrathecal co-administration of local anesthetic and apoptosis inhibitors should not only decrease neurotoxicity, but also allodynia/hyperalgesia.

We believe that, in addition to improving the safety of currently used local anesthetics and decreasing the incidence of post-operatve chronic pain, in-depth knowledge of the mechanisms gained from these studies will ultimately be essential in designing new generations of local anesthetics.

Publications:

Amir R, Argoff CE, Bennett GJ, Cummins TR, Durieux ME, Gerner P, Gold MS, Porreca F, Strichartz GR. The role of sodium channels in chronic inflammatory and neuropathic pain. J Pain 2006; 7:S1-29.

Haller I, Hausott B, Tomaselli B, Keller C, Klimaschewski L, Gerner P, Lirk P. Neurotoxicity of Lidocaine Involves Specific Activation of the p38 Mitogen-activated Protein Kinase, but Not Extracellular Signal-regulated or c-jun N-Terminal Kinases, and Is Mediated by Arachidonic Acid Metabolites. Anesthesiology 2006; 105:1024-1033.

Lirk P, Haller I, Myers RR, Klimaschewski L, Kau YC, Hung YC, Gerner P. Mitigation of direct neurotoxic effects of lidocaine and amitriptyline by inhibition of p38 mitogen-activated protein kinase in vitro and in vivo. Anesthesiology 2006; 104:1266-1273.

Lirk P, Haller I, Hausott B, Ingorokva S, Deibl M, Gerner P, Klimaschewski L. The neurotoxic effects of amitriptyline are mediated by apoptosis and are effectively blocked by inhibition of caspase activity. Anesth Analg 2006; 102:1728-1733.

Zhuang ZY, Gerner P, Woolf CJ, Ji RR. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005.
 

Robert N. Jamison, Ph.D.
Pain Management Center, Department of Anesthesia, BWH

Activities and Goals:
Over the past few years the focus of Dr. Jamison’s clinical research efforts have been directed toward three areas of study: 1) Development and implementation of computer and information technology in the assessment and treatment of chronic pain patients; 2) Assessment of addiction risk potential among patients prescribed opioids for pain; and 3) Examination of psychopathology and personality differences as predictors of treatment outcome among chronic pain patients.

Areas of Research:
Dr. Jamison is a licensed clinical psychologist with over 25 years’ experience working with persons with chronic pain. As an Associate Professor at Harvard Medical School with appointments in the Departments of Anesthesiology, Perioperative and Pain Medicine, Psychiatry, and Physical Medicine and Rehabilitation, he has enjoyed balancing clinical duties with research and teaching. His primary clinical responsibility is as Chief Psychologist at the Pain Management Center of Brigham and Women’s Hospital. His duties include assessment and treatment of new patients referred to the Pain Center. He also screens for candidacy for opioid therapy and implantable devices and offers behavioral medicine services to patients and their families. Dr. Jamison has many related areas of research that have included 1) developing valid and reliable electronic data entry software for pain patients, 2) establishing valid screening tools for addiction risk in chronic opioid therapy, and 3) creating computerized dynamic assessment of quality of life assessment of persons with chronic pain. He has also been an investigator on studies of 1) disease management for chronic pain, 2) neuropsychological effects of long-term opioid use in chronic pain patients, 3) the association between psychopathology and placebo analgesia in patients with discogenic low back pain and 4) use of cannabinoids for chronic pain patients. He has collaborated with many of the staff members in the Pain Management Center including Ed Ross, MD, Ed Michna, MD JD, David Janfaza, MD, Sanjeet Narang, MD, Srdjan Nedeljkovic, MD, Diane Palombi, RN, and Ajay Wasan, MD as well as colleagues from other academic and private institutions.

Importance of Research Contributions:
Dr. Jamison has been predominantly involved in clinical trials that have practical application for pain patients and their clinicians. His research efforts have been clinically based with direct applicability in the assessment and management of persons with chronic pain. He has gained recognition for his contribution in the creation of screening tools and software programs for use by busy practitioners. The universal acceptance of the Screener and Opioid Assessment for Patients with Pain (SOAPP) and the Current Opioid Misuse Measure (COMM) in pain management centers has added to his notoriety. He has also co-developed and validated the Interactive Computerized Quality of Life (ICQOL) and the Pain Electronic Calendar (PEC) programs. He is currently co-editing a special issue of Pain Medicine entitled “Computer and Information Technology in the Assessment and Management of Patients with Pain” designed to inform clinicians of new modalities to advance the treatment of pain patients. Dr. Jamison is committed to remaining active in clinical studies with the goal of continuing to improve the overall quality and outcomes of pain management among persons with acute and chronic pain.

Publications:

Michna E, Ross EL, Hynes WL, Nedeljkovic SS, Soumekh S, Janfaza D, Palombi D, Jamison RN. Predicting problems with opioids in chronic pain patients. J Pain Symptom Manage 2004;28:250-258.

Jamison RN, Fanciullo GJ, Baird JC. Computerized Dynamic Assessment of Pain: Comparison of Chronic Pain Patients and Healthy Controls. Pain Medicine 2004;5(2):168-177.

Butler SF, Budman SH, Fernandez K, Jamison RN. Validation of a screener and opioid assessment measure for patients with chronic pain. Pain 2004;112:65-75.

Jamison RN, Fanciullo GJ, Baird JC. Usefulness of pain drawings in identifying real or imagined pain: accuracy of pain professionals, nonprofessionals, and a decision model. J Pain 2004;5:476-482.

Wasan AD, Gudarz D, Jamison RN. The association between negative affect and opioid analgesia in patients with discogenic low back pain. Pain 2005;117:450-461.

Jamison RN, Raymond SA, Slawsby EA, McHugo GJ, Baird JC. Pain assessment in patients with low back pain: comparison of weekly recall and momentary assessment of pain. J Pain 2006;7:192-199.

Ru-Rong Ji, Ph.D.
Intracellular signaling and neural-glial interaction for chronic pain sensitization

Chronic pain, such as neural injury-associated neuropathic pain, is a major public health problem worldwide. Current treatment for this pain only has limited success due to our incomplete understanding of the mechanisms underlying the induction and maintenance of chronic pain. It is generally believed that chronic pain is an expression of neural plasticity in the pain pathway. Although pain was regarded as “neuron-mediated”, recent evidence suggests that glial cells in the spinal cord play an important role in the development and maintenance of chronic pain. We found that the intracellular signaling molecules MAP kinases (mitogen activated protein kinases) are activated in spinal glial cells (microglia or astrocytes) after nerve injury, which is essential for neuropathic pain sensitization. We are investigating how neural-glial interaction contributes to chronic pain development. The following questions are addressed: (1) how neural signals (e.g., electrical activity, release of chemokines and proteinases) in damaged primary sensory neurons are conveyed to glial cells in the spinal cord after peripheral axonal injury, and (2) how inflammatory mediators (e.g., cytokines and growth factors), which are typically produced by peripheral immune cells, are produced in spinal glial cells, and (3) how glial signals (e.g., release of the inflammatory mediators) feedback to spinal neurons enhancing synaptic transmission in spinal neurons. We are using histochemical, biochemical, imaging, electrophysiological, and behavioral approaches in intact animals or in isolated spinal cord slices to answer these questions. I believe our studies will shed light on the molecular and cellular mechanisms underlying chronic pain and lead to novel therapies for the management of chronic pain.

Publications:

Jin SX, Zhuang ZY, Woolf CJ, and Ji RR. p38 MAPK is activated after spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. Journal of Neuroscience 2003; 23:4017-4022.

Ji RR. Mitogen-activated protein kinases as potential targets for pain killers. Current Opinion in Investigating Drugs, 2004, 5:71-75.

Ji RR, Strichartz G. Cell signaling and the genesis of neuropathic pain. Science’ STKE. 2004, 252:reE14.

Zhuang ZY, Gerner P, Woolf CJ, Ji RR. ERK is sequentially activated in neurons, microglia, and astroglia by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain, 2005, 114:149-59.

Zhuang ZY, Wen YR, Zhang DR, Tiziana B, Christhophe B, Strichartz GR, Decosterd I, Ji RR. A peptide JNK inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. Journal of Neuroscience, 2006; 26:3551-3560.

Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Zhang YQ. Protein kinases as potential targets for the treatment of pathological pain. Handbook of Experimental Pharmacology, 2007; 177:359-389.

Igor Kissin M.D., Ph.D.
Neurobehavioral Pharmacology of Anesthetics and Analgesics

My laboratory is focused on experimental analysis of findings obtained in our clinical studies or on investigation of laboratory findings that can be applied to the clinical practice. For these aims we mostly use the methods of neurobehavioral pharmacology.

One area of our investigations is preemptive analgesia. Preemptive analgesia is a treatment that prevents establishment of the altered sensory processing that amplifies post-operative pain. The treatment should cover the entire duration of high-intensity noxious stimulation that can lead to establishment of central (and peripheral) sensitization caused by incisional or inflammatory injuries (during surgery and the initial postoperative period). Two approaches have been used to reveal preemptive analgesia. One of them is to demonstrate a reduction in pain intensity and/or in analgesic use beyond the drug presence in the biophase. This approach is based on a study design comparing preoperative treatment and nontreatment groups (PRE versus NO). The other approach is to prove that a treatment applied before surgery is more effective than the same treatment provided at the end of surgery (PRE versus POST). The present direction of our investigations is to prove that full potential of preemptive analgesia can be revealed only with PRE versus NO approach. The other condition is the completeness of interventions suppressing C and Aδ fibers central input.

One of our projects is based on the idea to use vanilloid agonists for the blockade of peripheral nerves. Vanilloids bind to the transient receptor potential type channels (TRPV1) and cause nerve desensitization. We have shown that vanilloids can provide selective (C fibers and A? fibers) and long-lasting (days) neural blockade. Extension of the traditional local anesthetic blockade into the postoperative period presents a problem for early mobilization (rehabilitation) after surgery and when protective sensation is required. Vanilloid agonists have an advantage in this regard. They do not affect non-painful sensation to touch and pressure or motor function. Our experiments demonstrated that perineural resiniferatoxin (vanilloid agonist) prevents hyperalgesia in a rat model of postoperative pain. Our electron microscopy study in rats demonstrated that resiniferatoxin-induced sciatic nerve blockade may lead to morphological changes in C fibers but to a much smaller degree than those with the use of local anesthetics. This result may indicate a new direction in the treatment of pain — peripheral analgesia.

Publications:

Kissin I, Davison N, Bradley EL Jr. Perineural resiniferatoxin prevents hyperalgesia in a rat model of postoperative pain. Anesth Analg. 2005;100:774-80

Kissin I. Tolerance to opioid analgesia: why do we differ from rats? Anesth Analg 2005;101:1727-9

Kissin EY, Freitas CF, Kissin I. The effects of intraarticular resiniferatoxin in experimental knee-joint arthritis. Anesth Analg 2005;101:1433-9

Kissin I. Preemptive analgesia at the crossroad. Anesth Analg 2005;100:754-6

Kissin I, Freitas CF, Bradley EL Jr. Memory of pain: the effect of perineural resiniferatoxin. Anesth Analg 2006;103:721-8.
 

Gary R. Strichartz, Ph.D.
Principal Investigator
Director, Pain Research Center
Peripheral Neuropharmacology for Chronic Pain

The Strichartz lab is interested in two areas of chronic pain, the role of receptors for endothelin-1 (ET-1) in persistent pain, especially cancer pain, and the mechanisms of chronic post-operative pain.

The G-protein coupled receptors for ET-1, an endogenous peptide, appear to be involved in several forms of acute and chronic pain. Our work has shown that injection of ET-1 in the paw or application directly on peripheral nerve causes immediate and transient pain behavior in rats, induces spontaneous action potentials selectively in peripheral nociceptors and causes increases in cellular [Ca⁺²] in and in the opening probability of a type of voltage-gated Na⁺ channel found exclusively in nociceptors; all these effects are mediated by ET_A receptors for ET-1. In addition, ET-1 enhances the amount of both glutamate and CGRP in the epidermis, accounting for a rapid phase of nociceptor sensitization, and also enhances the expression of the transducing receptor TRPV-1, a molecule that senses noxious heat and the elevated [H⁺] that accompanies inflammation. The ET_B receptor sub-type, in contrast, makes two different contributions to pain; ET_B receptors on neurons are pro-algesic and sensitize nociceptors to mechanical stimuli to elevate pain behavior, whereas ET_B receptors on keratinocytes, in the skin’s epidermis, are anti-hyperalgesic, countering the effects of pain stimuli and sensitizers, by the release of the opioid peptide β-endorphin from the keratinocytes that synthesize and store it. The ultimate likelihood that a nociceptor will generate afferent impulses to signal pain is substantially dependent on the dynamic interactions between pro-algesic neuronal ET_A and ET_B receptors and the anti-algesic ET_B receptors on keratinocytes, a balance which changes after injury and inflammation.

Chronic post-operative pain is an important clinical problem for many procedures, including thoracotomies, mastectomies, gynecological surgery, obstetrical surgery and most forms of amputation. Our laboratory has begun to study this problem by developing new animal models that mimic surgical procedures. Using the hairy skin of the rat we have found that skin incisions through the dorso-lumbar region cause both primary and secondary mechanical allodynia, but that this elevated pain can be prevented by pre-emptive application of local and systemic local anesthetics, apparently through an action on the CNS/spinal cord. Incisions through the medial thigh, followed by an hour-long retraction of the skin and muscle that entraps the saphenous nerve, leads to a profound and long-lasting (3-5 week) tactile allodynia of the ipsilateral plantar paw surface, a striking example of secondary hyperalgesia since this region is not directly innervated by the saphenous nerve. Ongoing studies to document the absence of nerve damage at the retraction site and to examine the anatomical changes in the plantar skin, at the stimulation site, and of the DRG and spinal cord that process signals from nerves of the retraction and test sites will allow the identification of cells and structures involved in this prolonged hyperalgesia.

Publications:

Houck CS, Khodorova A, Reale A, Strichartz GR, Davar G. Sensory fibers resistant to the actions of tetrodotoxin mediate nocifensive responses to local administration of endothelin-1 in rats. Pain 2004, 110: 719-726.

Ji RR, Strichartz G. Cell signaling and the genesis of neuropathic pain Science 2004, 252:STKE re 14,

Duarte AM, Pospisilova E, Reilly E, Mujenda F, Hamaya Y, Strichartz, GR. Reduction of post-incisional allodynia by subcutaneous bupivacaine: Findings with a new model in the hairy skin of the rat. Anesthesiol. 2005, 103: 113-25.

Yanagidate F and Strichartz, GR. Bupivacaine inhibits activation of neuronal spinal extracellular receptor activated kinase through selective effects on ionotropic receptors. Anesthesiology 2006, 104: 805-814.

Balonov K, Khodorova A, Strichartz, GR. Tactile allodynia initiated by local subcutaneous endothelin-1 is prolonged by activation of TRPV-1 receptors. Exp Biol Med 2006, 231:1165-70.

Amir R, Argoff CE, Bennett GJ, Cummins TR, Durieux ME, Gerner P, Gold MS, Porreca F, Strichartz GR.  The role of sodium channels in chronic inflammatory and neuropathic pain.  J Pain 2006, 7 (Supplement 3): S1-S29.

Flatters S and Strichartz G. Characterization of a new model of post-operative pain evoked by skin/muscle incision and retraction (SMIR). Ann Mtg Soc Neurosci. 2006.

Khodorova A,Vasko MR, Ritcher JA and Strichartz GR. NMDA receptors favor tactile allodynia induced by injection of low concentrations of endothelin-1 into the rat’s hindpaw. Ann Mtg Soc Neurosci. 2006.

Ging Kuo Wang, Ph.D.
Molecular Biology and Molecular Pharmacology of Ion Channels

The overall goals of Dr. Wang’s laboratory are (1) to map the local anesthetic receptor within the voltage-gated Na⁺ channel and (2) to identify novel drugs that may be applicable as long-acting local anesthetics for prolonged nerve block. Local anesthetics are clinic drugs that block action potentials in excitable membranes reversibly. The primary target of local anesthetics is voltage-gated Na⁺ channels, which are responsible for the generation and propagation of action potentials. Prolonged nerve block by long-acting local anesthetics is desirable for alleviating postoperative pain. Local anesthetics are also used in pain management for chronic and cancer pain but their applications appear limited because of the short blocking action.

Mammalian Na⁺ channels contain a large a-subunit (Nav1.1-1.9) and one or two small β-subunit (β1-β4). The primary structure of the a-subunit isoform consists of four homologous domains (D1-D4) each with six transmembrane segments (S1-S6). The local anesthetic receptor has been mapped to a cluster of residues at D1S6, D3S6, and D4S6 segments encircling the inner cavity of the Na⁺ channel. Dr. Wang’s laboratory is working to identify the contact points of local anesthetics with the Na⁺ channel in order to understand how the Na⁺ permeation pathway is blocked by local anesthetics. Towards this goal, Dr. Wang is also collaborating with other theorists to construct an open Na⁺ channel model for in silico local anesthetic docking within the inner cavity. Such a model will be used to reveal and/or to confirm the contact points between local anesthetics and residues within the Na⁺ channel. With this model Dr. Wang’s laboratory will be able to explore whether drugs can be identified as local anesthetics by the docking exercise and later tested in animal for their duration of nerve block.

To identify novel drugs, Dr. Wang’s laboratory is working to establish stable cell lines that express robust inactivation-deficient Na⁺ channels. Persistent late Na⁺ currents are likely the culprit that induces ecotopic high-frequency discharges in injured nerve. Such high-frequency discharges have been found as the cause for neuropathic pain. Cell lines that express robust inactivation-deficient Na+ channels are therefore valuable as screening tools to identify drugs that target persistent late Na⁺ currents. Two cell lines have now been established in Dr. Wang’s laboratory: (1) inactivation-deficient rNav1.4-WCW mutant channels and (2) inactivation-deficient hNav1.4-CW mutant channels.

Recent studies in Dr. Wang’s laboratory regarding local anesthetic block, the establishment of cell lines expressing inactivation-deficient Na⁺ channels, and the construction of the open Na⁺ channel model are listed below in the published form. Personnel in Wang’s laboratory included Dr. Peter Gerner, Dr. Thomas Edrich, Ms. Gabriella Russell, and Ms. Jane Mitchell. Dr. Peter Gerner is supported by Mentored Clinical Scientist Development Award and Dr. Thomas Edrich was supported by Harvard Anesthesia fellowship.

Publications:

Wang,G.K., C.Russell, and S.Y.Wang. 2004a. State-dependent block of voltage-gated Na⁺ channels by amitriptyline via the local anesthetic receptor and its implication for neuropathic pain. Pain 110:166-174.

Wang,S.-Y., J.Mitchell, E.Moczydlowski, and G.K.Wang. 2004b. Block of inactivation-deficient Na⁺ channels by local anesthetics in stably transfected mammalian cells: Evidence for drug binding along the activation pathway. J Gen Physiol 124:691-701.

Gerner,P., S.H.Luo, Z.Y.Zhuang, A.G.Djalali, A.M.Zizza, R.R.Myers, and G.K.Wang. 2005. Differential block of N-propyl derivatives of amitriptyline and doxepin for sciatic nerve block in rats. Reg Anesth. Pain Med. 30:344-350.

Edrich, T., S. Y. Wang, and G. K. Wang. 2005b. State-dependent block of human cardiac hNav1.5 sodium channels by propafenone. J Membr. Biol. 207:35-43.

Wang,G.K., T.Edrich, and S.Y.Wang. 2006. Time-Dependent Block and Resurgent Tail Currents Induced by Mouse b4_154-167 Peptide in Cardiac Na⁺ Channels. J Gen. Physiol 127:277-289.

Wang,S.-Y., J.Mitchell, and G.K.Wang. 2006. Preferential block of inactivation-deficient Na⁺ currents by capsaicin reveals a non-TRPV1 receptor within the Na⁺ channel. Pain (in Press; doi:10.1016/j.pain.2006.08.002).