Gary J Bennett

McGill University, Montréal, Quebec, Canada

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Publications (123)545.08 Total impact

  • Gary J Bennett, Timothy Doyle, Daniela Salvemini
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    ABSTRACT: Chronic distal symmetrical sensory peripheral neuropathy is a common neurological complication of cancer chemotherapy, HIV treatment and diabetes. Although aetiology-specific differences in presentation are evident, the clinical signs and symptoms of these neuropathies are clearly similar. Data from animal models of neuropathic pain suggest that the similarities have a common cause: mitochondrial dysfunction in primary afferent sensory neurons. Mitochondrial dysfunction is caused by mitotoxic effects of cancer chemotherapeutic drugs of several chemical classes, HIV-associated viral proteins, and nucleoside reverse transcriptase inhibitor treatment, as well as the (possibly both direct and indirect) effects of excess glucose. The mitochondrial injury results in a chronic neuronal energy deficit, which gives rise to spontaneous nerve impulses and a compartmental neuronal degeneration that is first apparent in the terminal receptor arbor-that is, intraepidermal nerve fibres-of cutaneous afferent neurons. Preliminary data suggest that drugs that prevent mitochondrial injury or improve mitochondrial function could be useful in the treatment of these conditions.
    Nature Reviews Neurology 05/2014; · 15.52 Impact Factor
  • Mark A Ware, Gary J Bennett
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    ABSTRACT: We describe a young woman who had suffered from treatment refractory Complex Regional Pain Syndrome (CRPS) for 6 years before receiving antibiotic treatment with cefadroxil (a cephalosporin derivative) for a minor infection. Cefadroxil reduced the patient's pain and motor dysfunction (dystonia and impaired voluntary movement) within days, the pain and motor disorder returned when cefadroxil was discontinued, and both again abated when cefadroxil was re-instituted. The patient has now had symptom relief for over 3 years on continuing cefadroxil therapy. We discuss this case in the context of previous reports of antibiotic treatment relieving neuropathic pain in experimental animals.
    Pain 03/2014; · 5.64 Impact Factor
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    ABSTRACT: This case report describes the remarkable recovery of a patient with very long-standing, medically intractable and disabling, lower limb, complex regional pain syndrome type II following the resection, crushing and relocation of sensory nerves.
    Pain 02/2014; · 5.64 Impact Factor
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    ABSTRACT: Alpha1-adrenoceptor expression on nociceptors may play an important role in sympathetic-sensory coupling in certain neuropathic pain syndromes. The aim of this study was to determine whether α1-adrenoceptor expression was up-regulated on surviving peptidergic, non-peptidergic and myelinated nerve fiber populations in the skin after chronic constriction injury of the sciatic nerve in rats. Seven days after surgery, α1-adrenoceptor expression was up-regulated in the epidermis and on dermal nerve fibres in plantar skin ipsilateral to the injury, but not around blood vessels. This α1-adrenoceptor up-regulation in the plantar skin was observed on all nerve fiber populations examined. However, α1-adrenoceptor expression was unaltered in dorsal hind paw skin after the injury. The increased expression of α1-adrenoceptors on cutaneous nociceptors in plantar skin after chronic constriction injury suggests that this may be a site of sensory-sympathetic coupling that increases sensitivity to adrenergic agonists after nerve injury. In addition, activation of up-regulated α1-adrenoceptors in the epidermis might cause release of factors that stimulate nociceptive signalling. Our findings indicate that peripheral nerve injury provokes up-regulation of α1-adrenoceptors on surviving nociceptive afferents and epidermal cells in the skin. This might contribute to sympathetically maintained pain in conditions such as complex regional pain syndrome, painful diabetic neuropathy and post-herpetic neuralgia.
    The journal of pain: official journal of the American Pain Society 11/2013; · 4.22 Impact Factor
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    ABSTRACT: Peroxynitrite contributes to chemotherapy-induced neuropathic pain via post-translational nitration and inactivation of mitochondrial superoxide dismutase ultimately leading to ATP depletion within peripheral nerve sensory axons.
    Pain 07/2013; · 5.64 Impact Factor
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    ABSTRACT: Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α(2)-adrenergic (α(2)A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α(2)A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α(2)A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain. PERSPECTIVE: This article presents the synergistic antiallodynic effects of combinations of α(2)A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas.
    The journal of pain: official journal of the American Pain Society 01/2013; 14(1):66-78. · 4.22 Impact Factor
  • Gary J Bennett
    The journal of pain: official journal of the American Pain Society 10/2012; 13(10):934-5. · 4.22 Impact Factor
  • H Zheng, W H Xiao, G J Bennett
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    ABSTRACT: Many of the most effective anti-cancer drugs induce a dose-limiting peripheral neuropathy that compromises therapy. Evidence from animal models of chemotherapy-induced painful peripheral neuropathy produced by the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin, indicate that they produce neuropathy via a common mechanism-a toxic effect on the mitochondria in primary afferent sensory neurons. Bortezomib is from the proteasome-inhibitor class of chemotherapeutics. It also produces a dose-limiting peripheral neuropathy, but its effects on neuronal mitochondria are unknown. To investigate this, we developed a model of bortezomib-induced painful peripheral neuropathy in the rat and assessed mitochondrial function (respiration and ATP production) in sciatic nerve samples harvested at two time points: day 7, which is three days after treatment and before pain appears, and day 35, which is one month post-treatment and the time of peak pain severity. We found significant deficits in Complex I-mediated and Complex II-mediated respiration, and in ATP production at both time points. Prophylactic treatment with acetyl-l-carnitine, which has previously been shown to prevent paclitaxel- and oxaliplatin-induced mitochondrial dysfunction and pain, completely blocked bortezomib's effects on mitochondria and pain. These results suggest that mitotoxicity may be the core pathology for all chemotherapy-induced peripheral neuropathy and that drugs that protect mitochondrial function may be useful chemotherapy adjuncts.
    Experimental Neurology 08/2012; 238(2):225-234. · 4.62 Impact Factor
  • Zheng H, Xiao WH, Bennett GJ
    Experimental Neurology 08/2012; 238:225-234. · 4.62 Impact Factor
  • Gary J Bennett
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    ABSTRACT: Spontaneous pain is often discussed in the context of both chronic inflammatory and neuropathic pain conditions, and it has been suggested that spontaneous pain, rather than stimulus-evoked pain, may be the more significant clinical problem. The following issues are discussed here. First, it is suggested that the concept of spontaneous pain makes no sense when the pain is the result of an ongoing inflammatory reaction. Evidence is reviewed that indicates that spontaneous pain is present in patients with neuropathic pain, but perhaps only in a subset of such patients. Second, it is suggested that in the presence of allodynia and hyperalgesia, stimulation from the activities of daily life occurs very many times a day and that these stimulus-evoked pains may summate to give a fluctuating level of daily pain that both patients and investigators mistake for spontaneous pain. PERSPECTIVE: Which is more important-stimulus-evoked pain or spontaneous pain? This review suggests that to answer the question we will need to distinguish neuropathic spontaneous pain from inflammatory ongoing pain and to differentiate both from summated allodynic and hyperalgesic pains caused by the stimuli of daily life.
    The journal of pain: official journal of the American Pain Society 07/2012; 13(10):921-9. · 4.22 Impact Factor
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    Wen Hua Xiao, Gary J Bennett
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    ABSTRACT: The dose-limiting side effect of taxane, platinum-complex, and other kinds of anticancer drugs is a chronic, distal, bilaterally symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Work with animal models of these conditions suggests that the neuropathy is a consequence of toxic effects on mitochondria in primary afferent sensory neurons. If this is true, then additional mitochondrial insult ought to make the neuropathic pain worse. This prediction was tested in rats with painful peripheral neuropathy due to the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin. Rats with established neuropathy were given 1 of 3 mitochondrial poisons: rotenone (an inhibitor of respiratory Complex I), oligomycin (an inhibitor of adenosine triphosphate synthase), and auranofin (an inhibitor of the thioredoxin-thioredoxin reductase mitochondrial antioxidant defense system). All 3 toxins significantly increased the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia while having no effect on the mechano-sensitivity of chemotherapy-naïve rats. Chemotherapy-evoked painful peripheral neuropathy is associated with an abnormal spontaneous discharge in primary afferent A fibers and C fibers. Oligomycin, at the same dose that exacerbated allodynia and hyperalgesia, significantly increased the discharge frequency of spontaneously discharging A fibers and C fibers in both paclitaxel-treated and oxaliplatin-treated rats, but did not evoke any discharge in naïve control rats. These results implicate mitochondrial dysfunction in the production of chemotherapy-evoked neuropathic pain and suggest that drugs that have positive effects on mitochondrial function may be of use in its treatment and prevention.
    Pain 03/2012; 153(3):704-9. · 5.64 Impact Factor
  • Pain 02/2012; 153(4):934-5; author reply 935-6. · 5.64 Impact Factor
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    ABSTRACT: The dose-limiting side effect of the anti-neoplastic agent, paclitaxel, is a chronic distal symmetrical peripheral neuropathy that produces sensory dysfunction (hypoesthesia and neuropathic pain) but little or no distal motor dysfunction. Similar peripheral neuropathies are seen with chemotherapeutics in the vinca alkaloid, platinum-complex, and proteasome inhibitor classes. Studies in rats suggest that the cause is a mitotoxic effect on axonal mitochondria. If so, then the absence of motor dysfunction may be due to mitotoxicity that affects sensory axons but spares motor axons. To investigate this, paclitaxel exposure levels in the dorsal root, ventral root, dorsal root ganglion, peripheral nerve, and spinal cord were measured, and the ultrastructure and the respiratory function of mitochondria in dorsal roots and ventral roots were compared. Sensory and motor axons in the roots and nerve had comparably low exposure to paclitaxel and exposure in the spinal cord was negligible. However, sensory neurons in the dorsal root ganglion had a very high and remarkably persistent (up to 10 days or more after the last injection) exposure to paclitaxel. Paclitaxel evoked a significant increase in the incidence of swollen and vacuolated mitochondria in the myelinated and unmyelinated sensory axons of the dorsal root (as seen previously in the peripheral nerve) but not in the motor axons of the ventral root. Stimulated mitochondrial respiration in the dorsal root was significantly depressed in paclitaxel-treated animals examined 2-4 weeks after the last injection, whereas respiration in the ventral root was normal. We conclude that the absence of motor dysfunction in paclitaxel-evoked peripheral neuropathy may be due to the absence of a mitotoxic effect in motor neuron axons, whereas the sensory dysfunction may be due to a mitotoxic effect resulting from the primary afferent neuron's cell body being exposed to high and persistent levels of paclitaxel.
    Neuroscience 12/2011; 199:461-9. · 3.33 Impact Factor
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    W H Xiao, H Zheng, G J Bennett
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    ABSTRACT: Anti-neoplastic agents in the platinum-complex, taxane, vinca alkaloid, and proteasome-inhibitor classes induce a dose-limiting, chronic, distal, symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Clinical descriptions suggest that these conditions are very similar, but clinical data are insufficient to determine the degree of similarity and to determine if they share common pathophysiological mechanisms. Animal models do not have the limitations of clinical studies and so we have characterized a rat model of chronic painful peripheral neuropathy induced by a platinum-complex agent, oxaliplatin, in order to compare it with a previously characterized model of chronic painful peripheral neuropathy induced by a taxane agent, paclitaxel. The oxaliplatin model evokes mechano-allodynia, mechano-hyperalgesia, and cold-allodynia that have a delayed onset, gradually increasing severity, a distinct delay to peak severity, and duration of about 2.5 months. There is no effect on heat sensitivity. Electron microscopy (EM) analyses found no evidence for axonal degeneration in peripheral nerve, and there is no upregulation of activating transcription factor-3 in the lumbar dorsal root ganglia. There is a statistically significant loss of intraepidermal nerve fibers in the plantar hind paw skin. Oxaliplatin treatment causes a significant increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons, but not in their Schwann cells. Nerve conduction studies found significant slowing of sensory axons, but no change in motor axons. Single fiber recordings found an abnormal incidence of A- and C-fibers with irregular, low-frequency spontaneous discharge. Prophylactic dosing with two drugs that are known to protect mitochondria, acetyl-l-carnitine and olesoxime, significantly reduced the development of pain hypersensitivity. Our results are very similar to those obtained previously with paclitaxel, and support the hypothesis that these two agents, and perhaps other chemotherapeutics, produce very similar conditions because they have a mitotoxic effect on primary afferent neurons.
    Neuroscience 12/2011; 203:194-206. · 3.33 Impact Factor
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    ABSTRACT: Provoked vestibulodynia, the most common form of vulvodynia (unexplained pain of the vulva), is a prevalent, idiopathic pain disorder associated with a history of recurrent candidiasis (yeast infections). It is characterized by vulvar allodynia (painful hypersensitivity to touch) and hyperinnervation. We tested whether repeated, localized exposure of the vulva to a common fungal pathogen can lead to the development of chronic pain. A subset of female mice subjected to recurrent Candida albicans infection developed mechanical allodynia localized to the vulva. The mice with allodynia also exhibited hyperinnervation with peptidergic nociceptor and sympathetic fibers (as indicated by increased protein gene product 9.5, calcitonin gene-related peptide, and vesicular monoamine transporter 2 immunoreactivity in the vaginal epithelium). Long-lasting behavioral allodynia in a subset of mice was also observed after a single, extended Candida infection, as well as after repeated vulvar (but not hind paw) inflammation induced with zymosan, a mixture of fungal antigens. The hypersensitivity and hyperinnervation were both present at least 3 weeks after the resolution of infection and inflammation. Our data show that infection can cause persistent pain long after its resolution and that recurrent yeast infection replicates important features of human provoked vulvodynia in the mouse.
    Science translational medicine 09/2011; 3(101):101ra91. · 14.41 Impact Factor
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    Huaien Zheng, Wen Hua Xiao, Gary J Bennett
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    ABSTRACT: Cancer chemotherapeutics like paclitaxel and oxaliplatin produce a dose-limiting chronic sensory peripheral neuropathy that is often accompanied by neuropathic pain. The cause of the neuropathy and pain is unknown. In animal models, paclitaxel-evoked and oxaliplatin-evoked painful peripheral neuropathies are accompanied by an increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons. It has been proposed that mitochondrial swelling and vacuolation are indicative of a functional impairment and that this results in a chronic axonal energy deficiency that is the cause of the neuropathy's symptoms. However, the significance of mitochondrial swelling and vacuolation is ambiguous and a test of the hypothesis requires a direct assessment of the effects of chemotherapy on mitochondrial function. The results of such an assessment are reported here. Mitochondrial respiration and ATP production were measured in rat sciatic nerve samples taken 1-2 days after and 3-4 weeks after induction of painful peripheral neuropathy with paclitaxel and oxaliplatin. Significant deficits in Complex I-mediated and Complex II-mediated respiration and significant deficits in ATP production were found for both drugs at both time points. In addition, prophylactic treatment with acetyl-l-carnitine, which inhibited the development of paclitaxel-evoked and oxaliplatin-evoked neuropathy, prevented the deficits in mitochondrial function. These results implicate mitotoxicity as a possible cause of chemotherapy-evoked chronic sensory peripheral neuropathy.
    Experimental Neurology 08/2011; 232(2):154-61. · 4.62 Impact Factor
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    ABSTRACT: Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e.g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.
    BMC Neurology 05/2011; 11:61. · 2.49 Impact Factor
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    F Y Zheng, W-H Xiao, G J Bennett
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    ABSTRACT: Painful peripheral neuropathies produced by nerve trauma are accompanied by substantial axonal degeneration and by a response in spinal cord microglia that is characterized by hypertrophy and increased expression of several intracellular and cell-surface markers, including ionizing calcium-binding adapter molecule 1 (Iba1) and Cd11b (a complement receptor 3 antigen recognized by the OX42 antibody). The microglia response has been hypothesized to be essential for the pathogenesis of the neuropathic pain state. In contrast, the painful peripheral neuropathies produced by low doses of cancer chemotherapeutics do not produce degeneration of axons in the peripheral nerve, although they do cause partial degeneration of the sensory axons' distal-most tips, that is the intraepidermal nerve fibers that form the axons' terminal receptor arbors. The question thus arises as to whether the relatively minor and distal axonal injury characterizing the chemotherapy-evoked neuropathies is sufficient to evoke the microglial response that is seen after traumatic nerve injury. We examined the lumbar spinal cord of rats with painful peripheral neuropathies due to the anti-neoplastic agents, paclitaxel, vincristine, and oxaliplatin, and the anti-retroviral agent, 2',3'-dideoxycytidine (ddC), and compared them to rats with a complete sciatic nerve transection and the partial sciatic nerve injury produced in the chronic constriction injury model (CCI). As expected, microglia hypertrophy and increased expression of Iba1 were pronounced in the nerve transection and CCI animals. However, there was no microglia hypertrophy or increased Iba1 staining in the animals treated with paclitaxel, vincristine, oxaliplatin, or ddC. These results suggest that the mechanisms that produce neuropathic pain after exposure to chemotherapeutics may be fundamentally different than those operating after nerve trauma.
    Neuroscience 03/2011; 176:447-54. · 3.33 Impact Factor
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    ABSTRACT: The antineoplastic agent paclitaxel causes a dose-limiting distal, symmetrical, sensory peripheral neuropathy that is often accompanied by a neuropathic pain syndrome. In a low-dose model of paclitaxel-evoked painful peripheral neuropathy in the rat, we have shown that the drug causes degeneration of intraepidermal nerve fibers (IENFs), i.e. the fibers which give rise to the sensory afferent's terminal receptor arbor. However, we did not find any evidence for axonal degeneration in samples taken at the mid-nerve level. Here we aimed to determine whether the absence of degenerating peripheral nerve axons was due to sampling a level that was too proximal. We used electron microscopy to study the distal-most branches of the nerves innervating the hind paw glabrous skin of normal and paclitaxel-treated rats. We confirmed that we sampled at a time when IENF degeneration was prominent. Because degeneration might be easier to detect with higher paclitaxel doses, we examined a four-fold cumulative dose range (8-32 mg/kg). We found no evidence of degeneration in the superficial subepidermal axon bundles (sSAB) that are located just a few microns below the epidermal basal lamina. Specifically, for all three dose groups there was no change in the number of sSAB per millimeter of epidermal border, no change in the number of axons per sSAB and no change in the diameter of sSAB axons. We conclude that paclitaxel produces a novel type of lesion that is restricted to the afferent axon's terminal arbor; we name this lesion 'terminal arbor degeneration'.
    European Journal of Neuroscience 03/2011; 33(9):1667-76. · 3.67 Impact Factor
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    ABSTRACT: In view of the extensive distribution in the spinal cord of primary afferent nociceptive nerve fibers from the rat hind paw, a model of regional inflammation would be useful in the study of arthritis pain. However, the subcutaneous intraplantar injection of a single low dose of Freund's complete adjuvant (CFA) has been used mostly as an inflammation model. We undertook this study to characterize this model by means of conventional radiography, microfocal computed tomography, and bone densitometry and by examining changes in pain-related behavior. Male rats were injected unilaterally with CFA or saline subcutaneously in the hind paw and killed 7, 15, and 30 days after injection. Pain-related behavior was studied using the Hargreaves, von Frey, and acetone tests. CFA-injected animals developed soft tissue inflammation and polyarthritis restricted to the joints of the injected hind paw. No signs of joint involvement were observed 7 days after CFA injection. On day 15 after CFA injection, there was widening of joint space indicative of joint effusion. By day 30 after CFA injection, there was evidence of joint damage with joint space narrowing, erosions, osteophyte formation, and joint deformity. There were no changes contralaterally or in saline-injected rats. Mechanical hyperalgesia and cold allodynia were present in the affected hind paw from day 1 through day 30. Signs of arthritis were strictly unilateral and started only 2 weeks after injection. Since the affected area has a broad representation in the spinal cord, this model has advantages over monarthritis models for the study of plastic changes in the dorsal horn of the spinal cord.
    Arthritis & Rheumatology 02/2011; 63(6):1573-81. · 7.48 Impact Factor

Publication Stats

7k Citations
545.08 Total Impact Points


  • 2003–2014
    • McGill University
      • • Department of Anesthesia
      • • Department of Pharmacology and Therapeutics
      Montréal, Quebec, Canada
    • Rehabilitation Institute of Chicago
      Chicago, Illinois, United States
  • 1998–2012
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2008
    • Hiroshima University
      • Department of Anesthesiology and Critical Care
      Hiroshima-shi, Hiroshima-ken, Japan
  • 2004
    • McGill University Health Centre
      Montréal, Quebec, Canada
  • 2002–2004
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 1979–2004
    • National Institutes of Health
      • Branch of Neurobiology
      Bethesda, MD, United States
  • 1991–1992
    • University of Minnesota Duluth
      Duluth, Minnesota, United States