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57 Topical Seminar Summary: VISCERAL PAIN: BASIC AND CLINICAL ASPECTS
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European Journal of Pain 2006, Vol 10 (suppl S1)
of a TNFa blocker reduces the intensity and duration of pain, probably by reducing the inflammatory response, and hence local oedema, around a prolapsed disc. 56 GENE MICROARRAYS – IDENTIFYING NEW ANALGESIC TARGETS M. Costigan ° . Anesthesia, MGH and Harvard Medical School, Boston, MA, USA In recent years differential gene expression analysis using oligonucleotide microarrays has expanded at a greater than exponential rate. We are actively using this technology to analyze the transcriptional response of primary sensory and second order dorsal horn neurons in the spinal cord to peripheral nerve damage and chronic inflammation. Global gene expression patterns in these tissues with these conditions will be discussed. The immense power of whole genome gene expression screens can simultaneously be their weakness – such screens often result in many hundreds of candidate genes. Which of these genes are key to the disease? Methods for zeroing in on a few fundamental genes will be discussed. We are presently analyzing several gene hits identified in this way and functional descriptions of these will be given. Including one new target system, whose inhibition results in profound analgesia in neuropathic pain, better, in our hands, than any other drug we have ever tested.
Topical Seminar: VISCERAL PAIN – BASIC AND CLINICAL ASPECTS 57 Topical Seminar Summary: VISCERAL PAIN: BASIC AND CLINICAL ASPECTS M.A. Giamberardino1 ° , U. Wesselmann2 , K.J. Berkley3 . 1 Ce.S.I., “G. D’Annunzio” Foundation, Chieti, Italy, 2 Johns Hopkins University School of Medicine, Dept. of Neurology, Baltimore, MD; 3 Program in Neuroscience, Florida State University, Tallahassee, FL, USA Background and Aims: In recent decades it has become increasingly acknowledged that the clinical experience of visceral pain is very often the result of complex interactions between sensory inputs from different internal organs as well as somatic areas. In some cases these interactions lead to an enhancement of pain perception, the so-called phenomenon of viscero-visceral hyperalgesia, which can be very difficult to handle therapeutically, while in others they produce a reduction of pain symptoms, potentially responsible for a delayed diagnosis of the underlying pathologic processes. In spite of their enormous clinical importance, these phenomena still lack an appropriate appreciation regarding both their prompt recognition in patients and their pathophysiologic interpretation. Based on these premises, the three speakers of this topical seminar will focus on current research, both clinical and experimental, about viscero-viscero-somatic interactions, also addressing therapeutic implications. Methods and Results: Human and animal studies will be reported. In patients with concomitant algogenic conditions in two viscera with partially overlapping sensory projection (gallbladder/heart, uterus/colon, uterus/urinary tract) the typical pain symptoms from both districts are enhanced (viscero-visceral hyperalgesia) and the reduction of the sensory input from one viscus by specific treatment significantly improves symptoms from the other. Psychophysical studies in women also show how pain from the gynecologic area may create dysfunction in the urinary tract and vice-versa. In the female rat, bladder inflammation reduces uterine contractions while uterine inflammation reduces the effects of cannabinoids on the bladder. Both colon and uterine inflammation produce signs of inflammation in the bladder. These results imply clinically that: if a woman develops a uterine or colon inflammation, she might show signs of an inflamed bladder; if a person is being treated with a drug for a disorder of the uterus and then develops a bladder infection the efficacy of the
Abstracts, 5th EFIC Congress, Invited Presentations drug’s action on the uterus could be affected. Sham endometriosis in the female rat reduces pain reactivity to a urinary stone, while endometriosis produces vaginal hyperalgesia, increases the reactivity to a urinary stone and also reduces bladder micturition threshold. This latter finding may explain why women with endometriosis often present interstitial cystitis, a disabling chronic condition characterized by extreme urinary urgency and frequency, and sometimes severe pelvic pain. Conclusions: Clinical and experimental studies show numerous complex interactions between different viscera, whose pathophysiology will be addressed. Throughout the nervous system convergences between sensory inputs from different internal organs (as well as from somatic structures) are observed, e.g., neurons responsive to stimulation of the reproductive tract also respond to stimulation of skin and other internal organs, in a manner modifiable by reproductive status and peripheral pathophysiology. This dynamic physiological convergence may reflect extensive anatomical divergence of and interconnections between pathways entering the CNS via gateways through the spinal cord, dorsal column nuclei, and solitary nucleus. The convergence also indicates the existence of extensive crosssystem, viscero-visceral interactions within the CNS, that, while organized for coherent bodily functioning, serves as a substrate by which pathophysiology in one organ can influence physiology and responses to pathophysiology in other organs. 58 CLINICAL ASPECTS OF VISCERO-VISCERAL HYPERALGESIA M.A. Giamberardino ° . Ce.S.I., “G. D’Annunzio” Foundation, Chieti, Italy Background and Aims: Viscero-visceral hyperalgesia is defined as an enhancement of pain symptoms due to the interaction between algogenic conditions of two different internal organs sharing at least part of their central sensory projection, for instance gallbladder and heart (T5), colon and uterus (T10-L1), urinary tract and uterus (T10-L1). This phenomenon is of great clinical importance as concomitant algogenic conditions are increasingly encountered in patients; its prompt recognition is furthermore of marked potential impact on treatment. The aim of this presentation is to illustrate paradigmatic examples of viscero-visceral hyperalgesia in terms of clinical characterization and therapeutic implications. Methods: Studies will be reported on patients affected with: coronary artery disease and gallbladder calculosis, dysmenorrhea and irritable bowel syndrome (IBS), urinary calculosis and dysmenorrhea. They will address the spontaneous painful symptomatology and the referred hyperalgesia (evaluated via measurement of pain thresholds to pressure and electrical stimulation in parietal tissues) as compared to symptoms recorded in patients with one condition only. Studies will also be reported on the effects of treatment of one painful condition on typical symptoms of the other. Results: Patients with coronary heart disease plus gallbladder calculosis present more anginal attacks and biliary colics than patients with one condition only in comparable periods of time and also show more pronounced muscle pain/hyperalgesia in the referred chest/abdominal pain areas. Women with dysmenorrhea and IBS complain of more menstrual pain, intestinal pain and referred abdominal/pelvic hyperalgesia than women with dysmenorrhea or IBS only. Patients with dysmenorrhea/endometriosis plus urinary calculosis have increased menstrual pain, urinary colic pain and referred abdominal/lumbar hyperalgesia than patients with one condition only. The interdependence of these phenomena is indirectly shown by the fact that suppression/reduction of the sensory input from one visceral domain may significantly improve typical symptoms from the other. A significant reduction of biliary pain is, in fact, obtained after cardiac revascularization in patients with concomitant coronary artery disease. Similarly, a decrease in urinary pain is observed after hormonal treatment of dysmenorrhea or in menstrual pain after urinary stone elimination following lithotripsy. Conclusions: The interaction between different internal organs may lead to problematic clinical pain pictures of viscero-visceral hyperalgesia. Mechanisms behind this phenomenon are still incompletely known, but probably involve sensitization of viscero-viscero-somatic convergent neurons in the
European Journal of Pain 2006, Vol 10 (suppl S1)
of a TNFa blocker reduces the intensity and duration of pain, probably by reducing the inflammatory response, and hence local oedema, around a prolapsed disc. 56 GENE MICROARRAYS – IDENTIFYING NEW ANALGESIC TARGETS M. Costigan ° . Anesthesia, MGH and Harvard Medical School, Boston, MA, USA In recent years differential gene expression analysis using oligonucleotide microarrays has expanded at a greater than exponential rate. We are actively using this technology to analyze the transcriptional response of primary sensory and second order dorsal horn neurons in the spinal cord to peripheral nerve damage and chronic inflammation. Global gene expression patterns in these tissues with these conditions will be discussed. The immense power of whole genome gene expression screens can simultaneously be their weakness – such screens often result in many hundreds of candidate genes. Which of these genes are key to the disease? Methods for zeroing in on a few fundamental genes will be discussed. We are presently analyzing several gene hits identified in this way and functional descriptions of these will be given. Including one new target system, whose inhibition results in profound analgesia in neuropathic pain, better, in our hands, than any other drug we have ever tested.
Topical Seminar: VISCERAL PAIN – BASIC AND CLINICAL ASPECTS 57 Topical Seminar Summary: VISCERAL PAIN: BASIC AND CLINICAL ASPECTS M.A. Giamberardino1 ° , U. Wesselmann2 , K.J. Berkley3 . 1 Ce.S.I., “G. D’Annunzio” Foundation, Chieti, Italy, 2 Johns Hopkins University School of Medicine, Dept. of Neurology, Baltimore, MD; 3 Program in Neuroscience, Florida State University, Tallahassee, FL, USA Background and Aims: In recent decades it has become increasingly acknowledged that the clinical experience of visceral pain is very often the result of complex interactions between sensory inputs from different internal organs as well as somatic areas. In some cases these interactions lead to an enhancement of pain perception, the so-called phenomenon of viscero-visceral hyperalgesia, which can be very difficult to handle therapeutically, while in others they produce a reduction of pain symptoms, potentially responsible for a delayed diagnosis of the underlying pathologic processes. In spite of their enormous clinical importance, these phenomena still lack an appropriate appreciation regarding both their prompt recognition in patients and their pathophysiologic interpretation. Based on these premises, the three speakers of this topical seminar will focus on current research, both clinical and experimental, about viscero-viscero-somatic interactions, also addressing therapeutic implications. Methods and Results: Human and animal studies will be reported. In patients with concomitant algogenic conditions in two viscera with partially overlapping sensory projection (gallbladder/heart, uterus/colon, uterus/urinary tract) the typical pain symptoms from both districts are enhanced (viscero-visceral hyperalgesia) and the reduction of the sensory input from one viscus by specific treatment significantly improves symptoms from the other. Psychophysical studies in women also show how pain from the gynecologic area may create dysfunction in the urinary tract and vice-versa. In the female rat, bladder inflammation reduces uterine contractions while uterine inflammation reduces the effects of cannabinoids on the bladder. Both colon and uterine inflammation produce signs of inflammation in the bladder. These results imply clinically that: if a woman develops a uterine or colon inflammation, she might show signs of an inflamed bladder; if a person is being treated with a drug for a disorder of the uterus and then develops a bladder infection the efficacy of the
Abstracts, 5th EFIC Congress, Invited Presentations drug’s action on the uterus could be affected. Sham endometriosis in the female rat reduces pain reactivity to a urinary stone, while endometriosis produces vaginal hyperalgesia, increases the reactivity to a urinary stone and also reduces bladder micturition threshold. This latter finding may explain why women with endometriosis often present interstitial cystitis, a disabling chronic condition characterized by extreme urinary urgency and frequency, and sometimes severe pelvic pain. Conclusions: Clinical and experimental studies show numerous complex interactions between different viscera, whose pathophysiology will be addressed. Throughout the nervous system convergences between sensory inputs from different internal organs (as well as from somatic structures) are observed, e.g., neurons responsive to stimulation of the reproductive tract also respond to stimulation of skin and other internal organs, in a manner modifiable by reproductive status and peripheral pathophysiology. This dynamic physiological convergence may reflect extensive anatomical divergence of and interconnections between pathways entering the CNS via gateways through the spinal cord, dorsal column nuclei, and solitary nucleus. The convergence also indicates the existence of extensive crosssystem, viscero-visceral interactions within the CNS, that, while organized for coherent bodily functioning, serves as a substrate by which pathophysiology in one organ can influence physiology and responses to pathophysiology in other organs. 58 CLINICAL ASPECTS OF VISCERO-VISCERAL HYPERALGESIA M.A. Giamberardino ° . Ce.S.I., “G. D’Annunzio” Foundation, Chieti, Italy Background and Aims: Viscero-visceral hyperalgesia is defined as an enhancement of pain symptoms due to the interaction between algogenic conditions of two different internal organs sharing at least part of their central sensory projection, for instance gallbladder and heart (T5), colon and uterus (T10-L1), urinary tract and uterus (T10-L1). This phenomenon is of great clinical importance as concomitant algogenic conditions are increasingly encountered in patients; its prompt recognition is furthermore of marked potential impact on treatment. The aim of this presentation is to illustrate paradigmatic examples of viscero-visceral hyperalgesia in terms of clinical characterization and therapeutic implications. Methods: Studies will be reported on patients affected with: coronary artery disease and gallbladder calculosis, dysmenorrhea and irritable bowel syndrome (IBS), urinary calculosis and dysmenorrhea. They will address the spontaneous painful symptomatology and the referred hyperalgesia (evaluated via measurement of pain thresholds to pressure and electrical stimulation in parietal tissues) as compared to symptoms recorded in patients with one condition only. Studies will also be reported on the effects of treatment of one painful condition on typical symptoms of the other. Results: Patients with coronary heart disease plus gallbladder calculosis present more anginal attacks and biliary colics than patients with one condition only in comparable periods of time and also show more pronounced muscle pain/hyperalgesia in the referred chest/abdominal pain areas. Women with dysmenorrhea and IBS complain of more menstrual pain, intestinal pain and referred abdominal/pelvic hyperalgesia than women with dysmenorrhea or IBS only. Patients with dysmenorrhea/endometriosis plus urinary calculosis have increased menstrual pain, urinary colic pain and referred abdominal/lumbar hyperalgesia than patients with one condition only. The interdependence of these phenomena is indirectly shown by the fact that suppression/reduction of the sensory input from one visceral domain may significantly improve typical symptoms from the other. A significant reduction of biliary pain is, in fact, obtained after cardiac revascularization in patients with concomitant coronary artery disease. Similarly, a decrease in urinary pain is observed after hormonal treatment of dysmenorrhea or in menstrual pain after urinary stone elimination following lithotripsy. Conclusions: The interaction between different internal organs may lead to problematic clinical pain pictures of viscero-visceral hyperalgesia. Mechanisms behind this phenomenon are still incompletely known, but probably involve sensitization of viscero-viscero-somatic convergent neurons in the