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8 DESCENDING CONTROL OF NEUROPATHIC PAIN: INHIBITORY OR FACILITATORY?
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Invited Presentations / Plenary Session / European Journal of Pain 11(S1) (2007) S1–S57
Morgello, S., Estanislao, L., Simpson, D., et al. (2004). HIVassociated distal sensory polyneuropathy in the era of highly active antiretroviral therapy: The Manhattan HIV Brain Bank. Arch Neurol, 61, 546–551. Simpson, D. M., Olney, R., McArthur, J. C., et al. (2003). Lamotrigine in the treatment of painful HIV-associated peripheral neuropathy: a randomized, placebo-controlled trial. Neurology, 60, 1508–1514. McArthur, J. C., Yiannoutsos, C., & Simpson, D. M.The ACTG Clinical Trials Group Team 291. (2000). A phase II trial of recombinant human nerve growth factor for sensory neuropathy associated with HIV infection. Neurology, 54, 1080–1088. Kieburtz, K., & Simpson, D. M.The ACTG 242 Study Team. (1998). A randomized trial of amitriptiline and mexiletine for painful neuropathy in HIV infection. Neurology, 51, 1682–1688. Schifitto, G., McDermott, M. P., McArthur, J. C., et al. (2005). Markers of immune activation and viral load in HIV-associated sensory neuropathy. Neurology, 64, 842–848. Simpson, D., Evans, S., & Kitch, D.The A5117 Team. (2006). HIV neuropathy natural history cohort study: assessment measures and risk factors. Neurology, 66, 1679–1687. Schifitto, G., Yiannoutsos, C., & Simpson, D.The ACTG 301 Study Team. (2006). A placebo-controlled study of memantine for the treatment of HIV-associated sensory neuropathy. J Neurovirol, 12(4), 328–331. doi:10.1016/j.ejpain.2007.03.021
Plenary Session: MODULATORY INFLUENCES ON NEUROPATHIC PAIN
8 DESCENDING CONTROL OF NEUROPATHIC PAIN: INHIBITORY OR FACILITATORY? M.H. Ossipov Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA Enhanced abnormal pain associated with peripheral nerve injury depends in part on a sensitized spinal cord. Enhanced afferent drive immediately after injury may promote spinal sensitization. Spinal sensitization is associated with enhanced responsiveness of dorsal horn neurons to sensory stimuli, increased expression and internalization of NK1 receptors, increased release of PGE2 and upregulation of spinal dynorphin. We recently reported that dynorphin may promote nociception and transmitter release through an interaction with the bradykinin receptors. These pronociceptive changes lead to an increase in nociceptive signals that are transmitted to supraspinal pain processing sites. Converging evidence indicates that the sustained increased afferent inputs may provoke neuroplastic changes at medullary sites that serve to maintain a state of spinal sensitization and enhanced pain. Studies with animal models of neuropathic pain showed that the rostralventromedial medulla (RVM) shows evidence of increased activity of descending pain facilitatory pathways to the
spinal cord. These projections from the RVM enhance the sensitivity of dorsal horn neurons to afferent input and also promote the release of excitatory neurotransmitters from primary afferent terminals. Pharmacologic and surgical manipulations that disrupt descending pain facilitatory systems also abolish the maintenance of the behavioral signs of enhanced abnormal pain as well as upregulation of spinal dynorphin, enhanced transmitter release and internalization of the NK1 receptor in the spinal cord. It is suggested that neuropathic pain may be maintained by a spinal–supraspinal–spinal loop that provides a ‘‘feed-back’’ to constantly maintain abnormal pain. These processes and how they relate to neuropathic pain will be discussed. doi:10.1016/j.ejpain.2007.03.022
9 THE PLACEBO EFFECT: FROM MECHANISMS TO CLINICAL IMPLICATIONS F. Benedetti Department of Neuroscience, University of Turin Medical School, Italy The placebo effect is a rapidly growing research field, whereby sophisticated neurobiological research tools have recently been applied, such as neuropharmacology, brain imaging, in vivo receptor binding, and single-neuron recording in awake humans. These techniques have allowed a better understanding of the mechanisms underlying the placebo effect, with the most secure and promising results in the field of pain and analgesia. Both placebo analgesia and nocebo hyperalgesia have been investigated and the underlying biochemical mechanisms have been identified. It is fundamental to understand that the study of placebo and nocebo effects is basically the study of the psychosocial context around the patient and the treatment, and has immediate clinical implications that embrace both clinical trials methodology and clinical practice. For example, as placebos induce opioid release in the brain, any drug may potentially interact with these placebo-activated endogenous opioids, thus confounding the interpretation of clinical trials. Likewise, nocebos may activate cholecystokinin through the induction of anticipatory anxiety. A key question is whether the loss of these placebo mechanisms may represent a point of vulnerability for the expression and maintenance of a pathological condition and for the response to its therapeutic intervention. To answer this question, the disruption of placebo-related mechanisms has recently been obtained experimentally by means of
Invited Presentations / Plenary Session / European Journal of Pain 11(S1) (2007) S1–S57
Morgello, S., Estanislao, L., Simpson, D., et al. (2004). HIVassociated distal sensory polyneuropathy in the era of highly active antiretroviral therapy: The Manhattan HIV Brain Bank. Arch Neurol, 61, 546–551. Simpson, D. M., Olney, R., McArthur, J. C., et al. (2003). Lamotrigine in the treatment of painful HIV-associated peripheral neuropathy: a randomized, placebo-controlled trial. Neurology, 60, 1508–1514. McArthur, J. C., Yiannoutsos, C., & Simpson, D. M.The ACTG Clinical Trials Group Team 291. (2000). A phase II trial of recombinant human nerve growth factor for sensory neuropathy associated with HIV infection. Neurology, 54, 1080–1088. Kieburtz, K., & Simpson, D. M.The ACTG 242 Study Team. (1998). A randomized trial of amitriptiline and mexiletine for painful neuropathy in HIV infection. Neurology, 51, 1682–1688. Schifitto, G., McDermott, M. P., McArthur, J. C., et al. (2005). Markers of immune activation and viral load in HIV-associated sensory neuropathy. Neurology, 64, 842–848. Simpson, D., Evans, S., & Kitch, D.The A5117 Team. (2006). HIV neuropathy natural history cohort study: assessment measures and risk factors. Neurology, 66, 1679–1687. Schifitto, G., Yiannoutsos, C., & Simpson, D.The ACTG 301 Study Team. (2006). A placebo-controlled study of memantine for the treatment of HIV-associated sensory neuropathy. J Neurovirol, 12(4), 328–331. doi:10.1016/j.ejpain.2007.03.021
Plenary Session: MODULATORY INFLUENCES ON NEUROPATHIC PAIN
8 DESCENDING CONTROL OF NEUROPATHIC PAIN: INHIBITORY OR FACILITATORY? M.H. Ossipov Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA Enhanced abnormal pain associated with peripheral nerve injury depends in part on a sensitized spinal cord. Enhanced afferent drive immediately after injury may promote spinal sensitization. Spinal sensitization is associated with enhanced responsiveness of dorsal horn neurons to sensory stimuli, increased expression and internalization of NK1 receptors, increased release of PGE2 and upregulation of spinal dynorphin. We recently reported that dynorphin may promote nociception and transmitter release through an interaction with the bradykinin receptors. These pronociceptive changes lead to an increase in nociceptive signals that are transmitted to supraspinal pain processing sites. Converging evidence indicates that the sustained increased afferent inputs may provoke neuroplastic changes at medullary sites that serve to maintain a state of spinal sensitization and enhanced pain. Studies with animal models of neuropathic pain showed that the rostralventromedial medulla (RVM) shows evidence of increased activity of descending pain facilitatory pathways to the
spinal cord. These projections from the RVM enhance the sensitivity of dorsal horn neurons to afferent input and also promote the release of excitatory neurotransmitters from primary afferent terminals. Pharmacologic and surgical manipulations that disrupt descending pain facilitatory systems also abolish the maintenance of the behavioral signs of enhanced abnormal pain as well as upregulation of spinal dynorphin, enhanced transmitter release and internalization of the NK1 receptor in the spinal cord. It is suggested that neuropathic pain may be maintained by a spinal–supraspinal–spinal loop that provides a ‘‘feed-back’’ to constantly maintain abnormal pain. These processes and how they relate to neuropathic pain will be discussed. doi:10.1016/j.ejpain.2007.03.022
9 THE PLACEBO EFFECT: FROM MECHANISMS TO CLINICAL IMPLICATIONS F. Benedetti Department of Neuroscience, University of Turin Medical School, Italy The placebo effect is a rapidly growing research field, whereby sophisticated neurobiological research tools have recently been applied, such as neuropharmacology, brain imaging, in vivo receptor binding, and single-neuron recording in awake humans. These techniques have allowed a better understanding of the mechanisms underlying the placebo effect, with the most secure and promising results in the field of pain and analgesia. Both placebo analgesia and nocebo hyperalgesia have been investigated and the underlying biochemical mechanisms have been identified. It is fundamental to understand that the study of placebo and nocebo effects is basically the study of the psychosocial context around the patient and the treatment, and has immediate clinical implications that embrace both clinical trials methodology and clinical practice. For example, as placebos induce opioid release in the brain, any drug may potentially interact with these placebo-activated endogenous opioids, thus confounding the interpretation of clinical trials. Likewise, nocebos may activate cholecystokinin through the induction of anticipatory anxiety. A key question is whether the loss of these placebo mechanisms may represent a point of vulnerability for the expression and maintenance of a pathological condition and for the response to its therapeutic intervention. To answer this question, the disruption of placebo-related mechanisms has recently been obtained experimentally by means of