Results 1 to 7 of 7

Thread: New treatment may relieve chronic pain

  1. #1

    New treatment may relieve chronic pain

    Monday, April 01, 2002
    New treatment may relieve chronic pain, as reported in the 19 November issue of Science
    American Association for the Advancement of Science

    Washington, DC - In a study that could lead to new treatments for chronic pain, scientists have relieved pain in rats by dispatching molecular "smart bombs" to selectively destroy certain nerve cells in the spinal cord. Because this approach targets just those nerve cells, or neurons, that send pain messages to the brain, it shouldn't cause the side effects of drugs such as morphine or the complications of surgery. The study appears in the 19 November issue of Science.

    Thus far, the scientists' method kills the pain-signaling neurons, so its uses may be limited to stopping the extreme pain of terminally ill patients. However, designing a less drastic variation that would temporarily silence the neurons should now be "a very do-able thing," according to Patrick Mantyh, of the University of Minnesota and the Veterans Affairs Medical Center in Minneapolis, who led the research team.

    The team of scientists also includes Michael L. Nichols, Brian J. Allen, Scott D. Rogers, Joseph R. Ghilardi, Prisca Honore, Nancy M. Luger, and Matthew P. Finke, from the University of Minnesota and the Veterans Affairs Medical Center in Minneapolis; Jun Li and Donald A. Simone, from the University of Minnesota, in Minneapolis; and Douglas A. Lappi, from Advanced Targeting Systems, in San Diego.

    Chronic pain is an extremely common affliction that occurs in a variety of forms, from the specific pain of a migraine headache to the mysterious all-over body pain of fibromyalgia. In all of its incarnations, chronic pain seems to be the result of faulty signaling by a small group of neurons in the spinal cord. These signals can either make patients hypersensitive to stimuli that are minimally painful (such as a pinprick), or they can cause patients to feel pain in response to stimuli that are not painful at all (a warm shower, for example).

    The group of neurons responsible for these inappropriate responses transmit electrical signals to each other with the help of a chemical messenger called "substance P." These neurons, which collectively make up less than five percent of all the neurons in the spinal cord, wear a receptor protein on their surface that serves as the docking point for a substance P molecule as it jumps from one neuron to the other. Once substance P binds with the receptor, the neuron then envelops both molecules into its interior.

    Mantyh and his colleagues targeted these particular neurons using a Trojan horse-type strategy. They linked together molecules of a potent neurotoxin with molecules of substance P, and injected the hybrid pairs into the spinal cords of rats. When the substance P bound with the receptor on certain neurons, the cells brought about their own destruction by ushering these molecules and their neurotoxin companions inside.

    A short while later, the rats became far less sensitive to stimuli that caused two key types of pain: inflammatory pain due to an injury and "neuropathic" pain caused when the neural signaling process itself goes awry-with no tissue damage required.

    The rats' loss of sensitivity appeared to be permanent. In contrast, earlier efforts to treat chronic pain by surgically severing part of the spinal cord only provided temporary relief. In these cases, the pain probably returned because the surgeons cut through hundreds of other neurons in addition to those that expressed the substance P receptor. The damage to these additional neurons could have induced the brain to experience pain even without a real stimulus.

    "That's the beautiful thing about this technique," said Mantyh. "We can pick out the neurons expressing substance P receptors and leave the other neurons intact."

    Another important advantage of the scientists' approach is that it doesn't interfere with the mechanism by which morphine works. Physicians who wanted to administer this type of treatment to their patients should therefore find it reassuring that they could still use morphine as a standby.

    Mantyh and his colleagues believe that it should also be possible to attach other molecules to substance P that would quiet--but not kill--the neurons after sneaking inside. One possible candidate might be a molecule known to temporarily shut down the neurons' powerhouses, the mitochondria.

    The team's findings also provide researchers the opportunity to investigate what causes chronic pain to begin with. Scientists can now compare normal neurons expressing substance P receptors with those that are sending inappropriate pain signals. They can search, for example, for genes that are "turned on" in the misfiring neurons. It may then be possible someday to use gene therapy to correct the problem.

    For the moment, Mantyh and his colleagues are planning a toxicology study to learn whether the neurotoxin they used in the rats would be safe to use the same way in terminally ill humans who are desperate for pain relief.

  2. #2

    Where to Find an Update?

    Seneca, I saw this article first on pain.com about 3 - 4 years ago and they re-ran it recently. Trouble is I haven't seen any kind of an update on it. I'd really like to know what the status of the research is now, but don't know how to find out. Any ideas?

    Calico

  3. #3
    I don't know Calico, maybe David Berg would know?

  4. #4
    seneca,

    I appreciate the implied vote of confidence, but I don't have any further information. I can tell you that the November 19 issue of Science mentioned in the article was published in 1999. I even took a look at Patrick Mantyh's webpage at the University of Minnesota. His publications are listed but either he hasn't published much lately or his webpage is badly out of date.

    Wise has better search tools available, so perhaps he can turn something up from Mantyh that's later than '99.

    It's a promising line of research and I'd love to hear whether anything more has come of it.

    David Berg

  5. #5
    Here are all the abstracts by Mantyh on pain:


    • Honor P, Menning PM, Rogers SD, Nichols ML, Basbaum AI, Besson JM and Mantyh PW (1999). Spinal substance P receptor expression and internalization in acute, short-term, and long-term inflammatory pain states. J Neurosci. 19 (17): 7670-8. Summary: Inflammatory pain involves the sensitization of both primary afferent and spinal cord neurons. To explore the neurochemical changes that contribute to inflammatory pain, we have examined the expression and ligand-induced internalization of the substance P receptor (SPR) in the spinal cord in acute, short-term, and long-term inflammatory pain states. These inflammatory models included unilateral injection of formalin (8-60 min), carrageenan (3 hr), and complete Freund's adjuvant (CFA; 3 d) into the rat hindpaw as well as adjuvant-induced polyarthritis (21 d). In acute inflammatory pain there is ongoing release of substance P (SP) as measured by SPR internalization in lamina I neurons at both 8 and 60 min after formalin injection. Although there is no tonic release of SP in short-term inflammatory pain, at 3 hr after carrageenan injection, SP is released in response to both noxious and non-noxious somatosensory stimulation with SPR internalization being observed in neurons located in both laminae I and III-IV. In long-term inflammatory pain models (CFA and polyarthritis) the same pattern of SP release and SPR activation occurs as is observed in short-term inflammation with the addition that there is a significant upregulation of the SPR in lamina I neurons. These results suggest that SPR internalization might serve as a marker of the contribution of ongoing primary afferent input in acute and persistent pain states. These stereotypical neurochemical changes suggest that there are unique neurochemical signatures for acute, short-term, and long-term inflammatory pain. Neurosystems Center, Department of Preventive Sciences, Psychiatry and Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
    <http://www.jneurosci.org/cgi/content/full/19/17/7670
    http://www.jneurosci.org/cgi/content...act/19/17/7670
    medline

    • Honore P, Luger NM, Sabino MA, Schwei MJ, Rogers SD, Mach DB, O'Keefe P F, Ramnaraine ML, Clohisy DR and Mantyh PW (2000). Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med. 6 (5): 521-8. Summary: Bone cancer pain is common among cancer patients and can have a devastating effect on their quality of life. A chief problem in designing new therapies for bone cancer pain is that it is unclear what mechanisms drive this distinct pain condition. Here we show that osteoprotegerin, a secreted 'decoy' receptor that inhibits osteoclast activity, also blocks behaviors indicative of pain in mice with bone cancer. A substantial part of the actions of osteoprotegerin seems to result from inhibition of tumor-induced bone destruction that in turn inhibits the neurochemical changes in the spinal cord that are thought to be involved in the generation and maintenance of cancer pain. These results demonstrate that excessive tumor-induced bone destruction is involved in the generation of bone cancer pain and that osteoprotegerin may provide an effective treatment for this common human condition. Neurosystems Center and Departments of Preventive Sciences, Psychiatry, Neuroscience, and Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
    <http://www.nature.com/cgi-taf/DynaPa...m0500_521.html
    http://www.nature.com/cgi-taf/DynaPa...m0500_521.html
    medline

    • Honore P, Menning PM, Rogers SD, Nichols ML and Mantyh PW (2000). Neurochemical plasticity in persistent inflammatory pain. Prog Brain Res. 129: 357-63. Summary: Department of Preventive Sciences, University of Minnesota, Minneapolis 55455, USA.
    <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=11098703>

    • Honore P, Rogers SD, Schwei MJ, Salak-Johnson JL, Luger NM, Sabino MC, Clohisy DR and Mantyh PW (2000). Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience. 98 (3): 585-98. Summary: The aim of this investigation was to determine whether murine models of inflammatory, neuropathic and cancer pain are each characterized by a unique set of neurochemical changes in the spinal cord and sensory neurons. All models were generated in C3H/HeJ mice and hyperalgesia and allodynia behaviorally characterized. A variety of neurochemical markers that have been implicated in the generation and maintenance of chronic pain were then examined in spinal cord and primary afferent neurons.Three days after injection of complete Freund's adjuvant into the hindpaw (a model of persistent inflammatory pain) increases in substance P, calcitonin gene-related peptide, protein kinase C gamma, and substance P receptor were observed in the spinal cord. Following sciatic nerve transection or L5 spinal nerve ligation (a model of persistent neuropathic pain) significant decreases in substance P and calcitonin gene-related peptide and increases in galanin and neuropeptide Y were observed in both primary afferent neurons and the spinal cord. In contrast, in a model of cancer pain induced by injection of osteolytic sarcoma cells into the femur, there were no detectable changes in any of these markers in either primary afferent neurons or the spinal cord. However, in this cancer-pain model, changes including massive astrocyte hypertrophy without neuronal loss, increase in the neuronal expression of c-Fos, and increase in the number of dynorphin-immunoreactive neurons were observed in the spinal cord, ipsilateral to the limb with cancer.These results indicate that a unique set of neurochemical changes occur with inflammatory, neuropathic and cancer pain in C3H/HeJ mice and further suggest that cancer induces a unique persistent pain state. Determining whether these neurochemical changes are involved in the generation and maintenance of each type of persistent pain may provide insight into the mechanisms that underlie each of these pain states. Neurosystems Center and Departments of Preventive Sciences, Psychiatry, Neuroscience, and Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
    <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=10869852>

    • Honore P, Schwei J, Rogers SD, Salak-Johnson JL, Finke MP, Ramnaraine ML, Clohisy DR and Mantyh PW (2000). Cellular and neurochemical remodeling of the spinal cord in bone cancer pain. Prog Brain Res. 129: 389-97. Summary: Department of Preventive Sciences, University of Minnesota, Minneapolis 55455, USA.
    <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=11098706>

    • Hunt SP and Mantyh PW (2001). The molecular dynamics of pain control. Nat Rev Neurosci. 2 (2): 83-91. Summary: Pain is necessary for survival, but persistent pain can result in anxiety, depression and a reduction in the quality of life. The discriminative and affective qualities of pain are both thought to be regulated in an activity-dependent fashion. Recent studies have identified cells and molecules that regulate pain sensitivity and the parallel pathways that distribute nociceptive information to limbic or sensory areas of the forebrain. Here, we emphasize the cellular and neurobiological consequences of pain, especially those that are involved in the generation and maintenance of chronic pain. These new insights into pain processing will significantly alter our approach to pain control and the development of new analgesics. Department of Anatomy and Developmental Biology, Medawar Building, University College London, Gower Street, London WC1E 6BT, UK. hunt@ucl.ac.uk.
    <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=11252998>

    • Luger NM, Honore P, Sabino MA, Schwei MJ, Rogers SD, Mach DB, Clohisy DR and Mantyh PW (2001). Osteoprotegerin diminishes advanced bone cancer pain. Cancer Res. 61 (10): 4038-47. Summary: Bone cancer pain most commonly occurs when tumors originating in breast, prostate, or lung metastasize to long bones, spinal vertebrae, and/or pelvis. Primary and metastatic cancers involving bone account for approximately 400,000 new cancer cases per year in the United States alone, and >70% of patients with advanced breast or prostate cancer have skeletal metastases. Whereas pain resulting from bone cancer can dramatically impact an individual's quality of life, very little is known about the mechanisms that generate and maintain this pain. To begin to define the mechanisms that give rise to advanced bone cancer pain, osteolytic 2472 sarcoma cells or media were injected into the intramedullary space of the femur of C3H/HeJ mice, and the injection hole was sealed using dental amalgam, confining the tumor cells to the bone. Twelve days after injection of 2472 tumor cells, animals showed advanced tumor-induced bone destruction of the injected femur, bone cancer pain, and a stereotypic set of neurochemical changes in the spinal cord dorsal horn that receives sensory inputs from the affected femur. Administration of osteoprotegerin, a naturally secreted decoy receptor that inhibits osteoclast maturation and activity and induces osteoclast apoptosis, or vehicle was begun at 12 days, when significant bone destruction had already occurred, and administration was continued daily until day 21. Ongoing pain behaviors, movement-evoked pain behaviors, and bone destruction were assessed on days 10, 12, 14, 17, and 21. The neurochemistry of the spinal cord was evaluated at days 12 and 21. Results indicated that osteoprotegerin treatment halted further bone destruction, reduced ongoing and movement-evoked pain, and reversed several aspects of the neurochemical reorganization of the spinal cord. Thus, even in advanced stages of bone cancer, ongoing osteoclast activity appears to be involved in the generation and maintenance of ongoing and movement-evoked pain. Blockade of ongoing osteoclast activity appears to have the potential to reduce bone cancer pain in patients with advanced tumor-induced bone destruction. Neurosystems Center, Department of Orthopedic Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
    <http://cancerres.aacrjournals.org/cg...ull/61/10/4038
    http://cancerres.aacrjournals.org/cg...act/61/10/4038
    medline

    • Mantyh PW and Yaksh TL (2001). Sensory neurons are PARtial to pain. Nat Med. 7 (7): 772-3. Summary: Department of Preventive Science, Neuroscience and Psychiatry, University of Minnesota, Minneapolis, MN, USA. manty001@tc.umn.edu.
    <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=11433334>

    • Nichols ML, Allen BJ, Rogers SD, Ghilardi JR, Honore P, Luger NM, Finke MP, Li J, Lappi DA, Simone DA and Mantyh PW (1999). Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science. 286 (5444): 1558-61. Summary: Substance P receptor (SPR)-expressing spinal neurons were ablated with the selective cytotoxin substance P-saporin. Loss of these neurons resulted in a reduction of thermal hyperalgesia and mechanical allodynia associated with persistent neuropathic and inflammatory pain states. This loss appeared to be permanent. Responses to mildly painful stimuli and morphine analgesia were unaffected by this treatment. These results identify a target for treating persistent pain and suggest that the small population of SPR-expressing neurons in the dorsal horn of the spinal cord plays a pivotal role in the generation and maintenance of chronic neuropathic and inflammatory pain. Department of Preventive Sciences, University of Minnesota, Minneapolis, MN 55455, USA.
    <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=10567262>

    • Pomonis JD, Rogers SD, Peters CM, Ghilardi JR and Mantyh PW (2001). Expression and localization of endothelin receptors: implications for the involvement of peripheral glia in nociception. J Neurosci. 21 (3): 999-1006. Summary: The endothelins (ETs) are peptides that have a diverse array of functions mediated by two receptor subtypes, the endothelin A receptor (ET(A)R) and the endothelin B receptor (ET(B)R). Pharmacological studies have suggested that in peripheral tissues, ET(A)R expression may play a role in signaling acute or neuropathic pain, whereas ET(B)R expression may be involved in the transmission of chronic inflammatory pain. To begin to define the mechanisms by which ET can drive nociceptive signaling, autoradiography and immunohistochemistry were used to examine the distribution of ET(A)R and ET(B)R in dorsal root ganglia (DRG) and peripheral nerve of the rat, rabbit, and monkey. In DRG and peripheral nerve, ET(A)R-immunoreactivity was present in a subset of small-sized peptidergic and nonpeptidergic sensory neurons and their axons and to a lesser extent in a subset of medium-sized sensory neurons. However, ET(B)R-immunoreactivity was not seen in DRG neurons or axons but rather in DRG satellite cells and nonmyelinating ensheathing Schwann cells. Thus, when ETs are released in peripheral tissues, they could act directly on ET(A)R-expressing sensory neurons and on ET(B)R-expressing DRG satellite cells or nonmyelinating Schwann cells. These data indicate that ETs can have direct, nociceptive effects on the peripheral sensory nervous system and that peripheral glia may be directly involved in signaling nociceptive events in peripheral tissues. Departments of Preventive Science, Neuroscience, and Psychiatry, University of Minnesota, Minneapolis, Minnesota 55455, USA.
    <http://www.jneurosci.org/cgi/content/full/21/3/999
    http://www.jneurosci.org/cgi/content/abstract/21/3/999
    medline

    • Sabino MA, Honore P, Rogers SD, Mach DB, Luger NM and Mantyh PW (2002). Tooth extraction-induced internalization of the substance P receptor in trigeminal nucleus and spinal cord neurons: imaging the neurochemistry of dental pain. Pain. 95 (1-2): 175-86. Summary: Although pains arising from the craniofacial complex can be severe and debilitating, relatively little is known about the peripheral and central mechanisms that generate and maintain orofacial pain. To better understand the neurons in the trigeminal complex and spinal cord that are activated following nociceptive stimuli to the orofacial complex, we examined substance P (SP) induced internalization of substance P receptors (SPR) in neurons following dental extraction in the rat.Unilateral gingival reflection or surgical extraction of a rat maxillary incisor or molar was performed and tissues harvested at various time points post-extraction. Immunohistochemical analysis of brainstem and cervical spinal cord sections was performed using an anti-SPR antibody and confocal imaging. Both the number and location of neurons showing SPR internalization was dependent on the location and extent of tissue injury. Whereas extraction of the incisor induced internalization of SPR in neurons bilaterally in nucleus caudalis and the spinal cord, extraction of the molar induced strictly unilateral internalization of SPR-expressing neurons in the same brain structures. Minor tissue injury (retraction of the gingiva) activated SPR neurons located in lamina I whereas more extensive and severe tissue injury (incisor or molar extraction) induced extensive SPR internalization in neurons located in both laminae I and III-V. The rostrocaudal extent of the SPR internalization was also correlated with the extent of tissue injury. Thus, following relatively minor tissue injury (gingival reflection) neurons showing SPR internalization were confined to the nucleus caudalis while procedures which cause greater tissue injury (incisor or molar extraction), neurons showing SPR internalization extended from the interpolaris/caudalis transition zone through the C7 spinal level. Defining the population of neurons activated in orofacial pain and whether analgesics modify the activation of these neurons should provide insight into the mechanisms that generate and maintain acute and chronic orofacial pain. Department of Preventive Sciences, University of Minnesota, 18-208 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA.
    <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&li st_uids=11790480>

    • Schwei MJ, Honore P, Rogers SD, Salak-Johnson JL, Finke MP, Ramnaraine ML, Clohisy DR and Mantyh PW (1999). Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci. 19 (24): 10886-97. Summary: The cancer-related event that is most disruptive to the cancer patient's quality of life is pain. To begin to define the mechanisms that give rise to cancer pain, we examined the neurochemical changes that occur in the spinal cord and associated dorsal root ganglia in a murine model of bone cancer. Twenty-one days after intramedullary injection of osteolytic sarcoma cells into the femur, there was extensive bone destruction and invasion of the tumor into the periosteum, similar to that found in patients with osteolytic bone cancer. In the spinal cord, ipsilateral to the cancerous bone, there was a massive astrocyte hypertrophy without neuronal loss, an expression of dynorphin and c-Fos protein in neurons in the deep laminae of the dorsal horn. Additionally, normally non-noxious palpation of the bone with cancer induced behaviors indicative of pain, the internalization of the substance P receptor, and c-Fos expression in lamina I neurons. The alterations in the neurochemistry of the spinal cord and the sensitization of primary afferents were positively correlated with the extent of bone destruction and the growth of the tumor. This "neurochemical signature" of bone cancer pain appears unique when compared to changes that occur in persistent inflammatory or neuropathic pain states. Understanding the mechanisms by which the cancer cells induce this neurochemical reorganization may provide insight into peripheral factors that drive spinal cord plasticity and in the development of more effective treatments for cancer pain. Neurosystems Center, Department of Preventive Sciences, Minneapolis, Minnesota 55455, USA.
    <http://www.jneurosci.org/cgi/content/full/19/24/10886
    http://www.jneurosci.org/cgi/content...ct/19/24/10886
    medline

    • Trafton JA, Abbadie C, Marchand S, Mantyh PW and Basbaum AI (1999). Spinal opioid analgesia: how critical is the regulation of substance P signaling? J Neurosci. 19 (21): 9642-53. Summary: Although opioids can reduce stimulus-evoked efflux of Substance P (SP) from nociceptive primary afferents, the consequences of this reduction on spinal cord nociceptive processing has not been studied. Rather than assaying SP release, in the present study we examined the effect of opioids on two postsynaptic measures of SP release, Fos expression and neurokinin-1 (NK-1) receptor internalization, in the rat. The functional significance of the latter was first established in in vitro studies that showed that SP-induced Ca(2+) mobilization is highly correlated with the magnitude of SP-induced NK-1 receptor internalization in dorsal horn neurons. Using an in vivo analysis, we found that morphine had little effect on noxious stimulus-evoked internalization of the NK-1 receptor in lamina I neurons. However, internalization was reduced when we coadministered morphine with a dose of an NK-1 receptor antagonist that by itself was without effect. Thus, although opioids may modulate SP release, the residual release is sufficient to exert maximal effects on the target NK-1 receptors. Morphine significantly reduced noxious stimulus-induced Fos expression in lamina I, but the Fos inhibition was less pronounced in neurons that expressed the NK-1 receptor. Taken together, these results suggest that opioid analgesia predominantly involves postsynaptic inhibitory mechanisms and/or presynaptic control of non-SP-containing primary afferent nociceptors. Department of Anatomy, University of California San Francisco, San Francisco, California 94143, USA.
    <http://www.jneurosci.org/cgi/content/full/19/21/9642
    http://www.jneurosci.org/cgi/content...act/19/21/9642
    medline

  6. #6
    Banned
    Join Date
    Oct 2007
    Location
    Central Pennsylvania, USA
    Posts
    3
    Hi Everyone!
    Just wanted to say that this is amazing information!
    Thx,
    Ravenblanc

  7. #7
    oh also they told me to bring in the rest of the suboxone tomorrow, what are they going to buy it back from me?? and if they are trying to acuse me of just looking for drugs its fairly obvious, but i have my whole damed count.minus what i was supposed to take

Posting Permissions

  • You may not post new threads
  • You may not post replies
  • You may not post attachments
  • You may not edit your posts
  •