- Email: [email protected]
35 TARGETING TRP CHANNELS FOR PAIN RELIEF: TRPV1 AND BEYOND
TOPICAL SEMINAR SUMMARIES / European Journal of Pain Supplements 5 (2011) 5–14
9
35 TARGETING TRP CHANNELS FOR PAIN RELIEF: TRPV1 AND BEYOND A. Szallasi1 *, M.M. Moran2 , M.J. Fischer3 , S. Bevan4 . 1 Monmouth Medical Center and Drexel University College of Medicine, Long Branch, NJ, 2 Hydra Biosciences, Cambridge, MA, USA; 3 University of Cambridge, Cambridge, 4 King’s College London, London, UK
The topical seminar on oxidative stress covers all its main aspects involving use of free radicals in pain evaluation, involvement of oxidative stress in the mechanisms of neuropathic and inflammatory pain, and subsequences of oxidative stress of pain origin in newborns.
The capsaicin (vanilloid) receptor TRPV1, the archetypal transient receptor potential (TRP) channel, was discovered in 1997. It took less than a decade from channel cloning to preclinical proof-ofconcept and clinical trials. The focus of current drug discovery efforts are TRPA1, TRPV3 and TRPM8. Clinical indications for compounds targeting TRP channels range from chronic neuropathic pain (including diabetic neuropathy and cancer pain) through migraine, inflammatory bowel disease and overactive bladder to chronic cough, asthma, and, possibly, endocrine (e.g. diabetes and obesity) as well as neurological and psychiatric disorders. Although no TRP channel antagonist other than TRPV1 has reached Phase II clinical trials, this field is rapidly advancing. TRPA1 antagonists (e.g. AP18 and HC0300331) show promising activity in animal models of inflammatory and neuropathic pain. TRPM8 agonists were reported to reverse chronic constriction injury-induced thermal and mechanical hyperalgesia. Moreover, TRPM8 antagonists are beneficial in a guinea pig model of urinary incontinence. The TRPV3 antagonist GRC15300 has entered Phase I clinical trials in the UK with an eye towards pain indications. Chaired and moderated by Arpad Szallasi (an Attending Physician at Monmouth Medical Center and Adjunct Professor at Drexel University College of Medicine), this workshop composed of 4 lectures delivered by World experts on TRP channels both from pharmaceutical industry and academia will bring together researchers involved in drug discovery, development and preclinical studies of compound targeting TRP channels with clinicians conducting clinical trials with TRP antagonists.
37 NON-INVASIVE BRAIN STIMULATION FOR CHRONIC PAIN: ARE WE THERE YET? D. Ciampi de Andrade *. Pain Evaluation and Treatment Group, Instituto do Cˆ ancer do Estado de S˜ ao Paulo, S˜ ao Paulo, Brazil
Disclosure: Dr. Moran is the Vice President of Biology at Hydra Biosciences which is involved in TRP channel research
36 THE EFFECTS OF OXIDATIVE STRESS ON PAIN PROCESSING S. Vaculin1 *, M. Franek1 , J. Fricova1 , P. Stopka1 , M. Vejrazka1 , R. Rokyta1 , T. Pufe2 , A. Fragoulis2 , C. Wruck2 , C. Bellieni3 , G. Buonocore3 , L. Luongo4 , C. Giordano4 , S. Maione4 . 1 Charles University in Prague, Third Medical Faculty, Prague, Czech Republic; 2 RWTH Aachen University, Aachen, Germany; 3 University Hospital, Siena, Siena, 4 The Second University of Naples, Naples, Italy Oxidative stress has been widely described both in animals and men. Oxidative stress is the result of an imbalance between increased free radical production and reduced degradation. It has been known for a long time that lipoperoxidation can impair nerve tissue structure and function by decreasing Na/K ATP-ase activity. Oxidative stress also plays a key role in the events leading to caspase activation and glial activation. Painful procedures are well recognized conditions leading to free radicals generation. On the other hand, growing evidences show that oxidative stress itself plays a role in pain mechanisms, especially in neuropathic and inflammatory pain, and antioxidants have been used as anti-nociceptive agens in several studies. Concerning pain mechanism, reactive oxygen species have been shown in animal studies to play an important role in allodynia and hyperalgesia mainly through central sensitization, as well as in the pathogenesis of rheumatoid arthritis. Consequently, antioxidant and free radical scavengers have been demonstrated to reduce both neuropathic pain, and cartilage damage. Recently it was shown that oxidative stress is evoked by even routine pain procedures in newborns and that the developing tissues are particularly susceptible to free radicals toxicity.
Disclosure: None declared
Non-Invasive Brain Stimulation (NIBS) techniques have been tested to control chronic pain in the last fifteen years. Two main modalities were used: repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS). A large number of randomized, sham-controlled studies have evaluated their analgesic effects in different pain syndromes. Despite the different stimulation parameters and types of chronic pain syndromes evaluated, positive results have been found in fibromyalgia and in both central and peripheral neuropathic pain. Recently, new studies have broadened our current knowledge on the mechanisms of action of NIBS, such as its effect on endogenous opioid system and changes in cortical excitability. These data may help to further improve the clinical effect of such techniques in the near future. The analgesic effect of a single session of both tDCS and rTMS is short lasting, being significant for a couple of days in general. Recent studies have suggested that repetitive sessions of NIBS could prolong its effect for several days, opening the possibility to use this technique in the clinical setting. Although tempting, this approach is still hampered by some limitations such as a small number of studies using repetitive sessions of stimulation and cost. Disclosure: None declared
38 NEUROPATHIC VS. CANCER PAIN: SHARED MECHANISM AND DIFFERENCES R. Rolke1 *, M.I. Bennett2 , O. Wilder-Smith3 . 1 Department of Palliative Medicine, University of Bonn, Bonn, Germany; 2 St Gemma’s Hospice, Palliative Medicine, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK; 3 Department of Anaesthesiology, Radboud University Nijmegen, Nijmegen, The Netherlands Pain is a common feature during the course of cancer proliferation. If cancer itself or associated therapies such as surgery, radiotherapy or chemotherapy also affect neural structures of the somatosensory system, pain intensity and quality may change due to an additional neuropathic pain component. Whereas in neuropathic pain various verbal descriptors are established and validated in different questionnaires to distinguish pain stemming from predominantly nociceptive vs. neuropathic origin, the use of such questionnaires is limited in cancer patients. Obviously a rather tight stratification is hardly possible comparing pure cancer vs. mixed cancer pain including a neuropathic component. In pure cancer pain activation of the nociceptive system is driven by tumour associated inflammation presenting with tissue acidosis, and nociceptive receptor activation by substances such as prostaglandins, bradykinin, or NGF. The resulting peripheral nociceptive sensitization may give rise to a possible secondary sensitization. In the case of cancer related axonal damage to the somatosensory system ectopic discharge may drive central sensitization. The somatosensory phenotype as measured using quantitative sensory testing differs between pure cancer and cancer related neuropathic pain in the way that in the latter symptoms and signs of sensory loss are predominant. Other signs of neural damage such as reflex deficits or motor weakness accompany this neuropathic pain.
9
35 TARGETING TRP CHANNELS FOR PAIN RELIEF: TRPV1 AND BEYOND A. Szallasi1 *, M.M. Moran2 , M.J. Fischer3 , S. Bevan4 . 1 Monmouth Medical Center and Drexel University College of Medicine, Long Branch, NJ, 2 Hydra Biosciences, Cambridge, MA, USA; 3 University of Cambridge, Cambridge, 4 King’s College London, London, UK
The topical seminar on oxidative stress covers all its main aspects involving use of free radicals in pain evaluation, involvement of oxidative stress in the mechanisms of neuropathic and inflammatory pain, and subsequences of oxidative stress of pain origin in newborns.
The capsaicin (vanilloid) receptor TRPV1, the archetypal transient receptor potential (TRP) channel, was discovered in 1997. It took less than a decade from channel cloning to preclinical proof-ofconcept and clinical trials. The focus of current drug discovery efforts are TRPA1, TRPV3 and TRPM8. Clinical indications for compounds targeting TRP channels range from chronic neuropathic pain (including diabetic neuropathy and cancer pain) through migraine, inflammatory bowel disease and overactive bladder to chronic cough, asthma, and, possibly, endocrine (e.g. diabetes and obesity) as well as neurological and psychiatric disorders. Although no TRP channel antagonist other than TRPV1 has reached Phase II clinical trials, this field is rapidly advancing. TRPA1 antagonists (e.g. AP18 and HC0300331) show promising activity in animal models of inflammatory and neuropathic pain. TRPM8 agonists were reported to reverse chronic constriction injury-induced thermal and mechanical hyperalgesia. Moreover, TRPM8 antagonists are beneficial in a guinea pig model of urinary incontinence. The TRPV3 antagonist GRC15300 has entered Phase I clinical trials in the UK with an eye towards pain indications. Chaired and moderated by Arpad Szallasi (an Attending Physician at Monmouth Medical Center and Adjunct Professor at Drexel University College of Medicine), this workshop composed of 4 lectures delivered by World experts on TRP channels both from pharmaceutical industry and academia will bring together researchers involved in drug discovery, development and preclinical studies of compound targeting TRP channels with clinicians conducting clinical trials with TRP antagonists.
37 NON-INVASIVE BRAIN STIMULATION FOR CHRONIC PAIN: ARE WE THERE YET? D. Ciampi de Andrade *. Pain Evaluation and Treatment Group, Instituto do Cˆ ancer do Estado de S˜ ao Paulo, S˜ ao Paulo, Brazil
Disclosure: Dr. Moran is the Vice President of Biology at Hydra Biosciences which is involved in TRP channel research
36 THE EFFECTS OF OXIDATIVE STRESS ON PAIN PROCESSING S. Vaculin1 *, M. Franek1 , J. Fricova1 , P. Stopka1 , M. Vejrazka1 , R. Rokyta1 , T. Pufe2 , A. Fragoulis2 , C. Wruck2 , C. Bellieni3 , G. Buonocore3 , L. Luongo4 , C. Giordano4 , S. Maione4 . 1 Charles University in Prague, Third Medical Faculty, Prague, Czech Republic; 2 RWTH Aachen University, Aachen, Germany; 3 University Hospital, Siena, Siena, 4 The Second University of Naples, Naples, Italy Oxidative stress has been widely described both in animals and men. Oxidative stress is the result of an imbalance between increased free radical production and reduced degradation. It has been known for a long time that lipoperoxidation can impair nerve tissue structure and function by decreasing Na/K ATP-ase activity. Oxidative stress also plays a key role in the events leading to caspase activation and glial activation. Painful procedures are well recognized conditions leading to free radicals generation. On the other hand, growing evidences show that oxidative stress itself plays a role in pain mechanisms, especially in neuropathic and inflammatory pain, and antioxidants have been used as anti-nociceptive agens in several studies. Concerning pain mechanism, reactive oxygen species have been shown in animal studies to play an important role in allodynia and hyperalgesia mainly through central sensitization, as well as in the pathogenesis of rheumatoid arthritis. Consequently, antioxidant and free radical scavengers have been demonstrated to reduce both neuropathic pain, and cartilage damage. Recently it was shown that oxidative stress is evoked by even routine pain procedures in newborns and that the developing tissues are particularly susceptible to free radicals toxicity.
Disclosure: None declared
Non-Invasive Brain Stimulation (NIBS) techniques have been tested to control chronic pain in the last fifteen years. Two main modalities were used: repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS). A large number of randomized, sham-controlled studies have evaluated their analgesic effects in different pain syndromes. Despite the different stimulation parameters and types of chronic pain syndromes evaluated, positive results have been found in fibromyalgia and in both central and peripheral neuropathic pain. Recently, new studies have broadened our current knowledge on the mechanisms of action of NIBS, such as its effect on endogenous opioid system and changes in cortical excitability. These data may help to further improve the clinical effect of such techniques in the near future. The analgesic effect of a single session of both tDCS and rTMS is short lasting, being significant for a couple of days in general. Recent studies have suggested that repetitive sessions of NIBS could prolong its effect for several days, opening the possibility to use this technique in the clinical setting. Although tempting, this approach is still hampered by some limitations such as a small number of studies using repetitive sessions of stimulation and cost. Disclosure: None declared
38 NEUROPATHIC VS. CANCER PAIN: SHARED MECHANISM AND DIFFERENCES R. Rolke1 *, M.I. Bennett2 , O. Wilder-Smith3 . 1 Department of Palliative Medicine, University of Bonn, Bonn, Germany; 2 St Gemma’s Hospice, Palliative Medicine, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK; 3 Department of Anaesthesiology, Radboud University Nijmegen, Nijmegen, The Netherlands Pain is a common feature during the course of cancer proliferation. If cancer itself or associated therapies such as surgery, radiotherapy or chemotherapy also affect neural structures of the somatosensory system, pain intensity and quality may change due to an additional neuropathic pain component. Whereas in neuropathic pain various verbal descriptors are established and validated in different questionnaires to distinguish pain stemming from predominantly nociceptive vs. neuropathic origin, the use of such questionnaires is limited in cancer patients. Obviously a rather tight stratification is hardly possible comparing pure cancer vs. mixed cancer pain including a neuropathic component. In pure cancer pain activation of the nociceptive system is driven by tumour associated inflammation presenting with tissue acidosis, and nociceptive receptor activation by substances such as prostaglandins, bradykinin, or NGF. The resulting peripheral nociceptive sensitization may give rise to a possible secondary sensitization. In the case of cancer related axonal damage to the somatosensory system ectopic discharge may drive central sensitization. The somatosensory phenotype as measured using quantitative sensory testing differs between pure cancer and cancer related neuropathic pain in the way that in the latter symptoms and signs of sensory loss are predominant. Other signs of neural damage such as reflex deficits or motor weakness accompany this neuropathic pain.