- Email: [email protected]
72 LABORATORY MODELS OF NEUROPATHIC PAIN AND THEIR APPLICATION IN DEVELOPING NEW ANALGESICS
Invited Presentations / Workshop – Mechanisms And Translational Research 3 / European Journal of Pain 11(S1) (2007) S1–S57
workshop, we will give an update on new developments in our understanding of small fiber neuropathy from basic science to the clinic. Susan Fleetwood–Walker will report on some neuropathic pain models and subgroups of sensory nerve fibers with specific receptors, which may be able to modulate sensitized nociceptive input. One such receptor is the TRPM8 cool receptor, which may be a target for new analgesic drugs. John Griffin will talk about the diagnostic value of intraepidermal nerve fiber measurements in small fiber neuropathies of different etiologies, for example prediabetic and autonomic neuropathies. He will also report on follow-up and measures of regeneration in these diseases. Claudia Sommer will relate findings on painful small fiber neuropathies, in particular how systemic and local cytokine production may contribute to pain. doi:10.1016/j.ejpain.2007.03.085
S29
of this in which we have demonstrated the analgesic effectiveness of Na+ channel blockers, NMDA receptor blockers and gabapentin. We have taken a quite novel approach to analgesic design for neuropathic pain, considering whether sub-groups of non-nociceptive afferents may be able to gate out sensitised nociceptive inputs. Striking analgesic effects (limited to the sensitised state) were observed following activation of the TRPM8 cool receptor (also selectively activated by chemicals such as menthol and icilin), pointing to a new, independent strategy for therapeutic analgesia in neuropathic pain. doi:10.1016/j.ejpain.2007.03.086
73 CUTANEOUS INNERVATION IN SMALL FIBER NEUROPATHIES J.W. Griffin Johns Hopkins University, Baltimore, USA
72 LABORATORY MODELS OF NEUROPATHIC PAIN AND THEIR APPLICATION IN DEVELOPING NEW ANALGESICS S.M. Fleetwood-Walker *,a, C.J. Proudfoot a, E.M. Garry a, D.F. Cottrell a, R. Rosie a, H. Anderson a, A. Delaney a, D.C. Robertson a, R. Mitchell b a
Centre for Neuroscience Research, Division of Veterinary Biomedical Sciences, School of Biomedical Sciences, University of Edinburgh, UK b Centre for Integrative Physiology (Membrane Biology Group), School of Biomedical Sciences, University of Edinburgh, UK Chronic pain states resulting from injury to primary sensory afferents are maintained by hypersensitivity of spinal neurons. Thermal hyperalgesia, mechanical and cold allodynia ensue and are difficult to treat with current analgesics at doses that do not cause side effects. We work extensively with the sciatic nerve chronic constriction injury (CCI) model of clinical nerve damage which produces an outcome of both injured and uninjured afferents with the same sensory ganglia. Nerve injury produces characteristic phenotypic changes in both small and large afferents and consequent changes in the central processing of afferent inputs. The CCI pain state is dependent on spinal NMDA receptors and their assembly with receptor-interacting proteins such as PSD-95, AMPA receptors and their protein:protein interactions as well as receptors for phenotypically induced afferent mediators like vasoactive intestinal polypeptide (VIP) and their intracellular signalling pathways. Small fibre neuropathy with therapeutically intransigent pain is commonly found after varicella zoster infection, so we generated a laboratory rodent model
Disease of small sensory fibers, including C fiber nociceptors innervating the epidermis, is implicated in some painful neuropathies. In man several lines of evidence have found that most patients with painful sensory neuropathies have reduced intraepidermal nerve fiber densities in distal sites. Even in more proximal sites, where IENF density may be normal, the work of Polydefkis and others has identified defective regenerative and collateral regeneration. To make clinical trials of agents that protect axons or promote regeneration more realistic, we have defined features that are associated with rapid progression and that should favor measurable regeneration. The dermal and epidermal nociceptors include a group that express the Ret receptor and respond to artemin or GDNF and an NGF-responsive group that express TrkA. We have found that impairment or blockade of TrkA function in TrkAF592A knockin mice markedly reduces inflammatory and neuropathic pain behaviors, providing further evidence for a role for NGF-responsive fibers in these settings. doi:10.1016/j.ejpain.2007.03.087
74 PAIN IN SMALL FIBER NEUROPATHIES: SKIN BIOPSY FINDINGS AND MEASURES OF INFLAMMATION C. Sommer *,a, E. Vlckova b, W. Kafke a, N. Ueceyler a a
Neurologische Klinik Der Universitaet Wuerzburg, Germany b Department of Neurology, University Hospital Brno, Czech Republic
workshop, we will give an update on new developments in our understanding of small fiber neuropathy from basic science to the clinic. Susan Fleetwood–Walker will report on some neuropathic pain models and subgroups of sensory nerve fibers with specific receptors, which may be able to modulate sensitized nociceptive input. One such receptor is the TRPM8 cool receptor, which may be a target for new analgesic drugs. John Griffin will talk about the diagnostic value of intraepidermal nerve fiber measurements in small fiber neuropathies of different etiologies, for example prediabetic and autonomic neuropathies. He will also report on follow-up and measures of regeneration in these diseases. Claudia Sommer will relate findings on painful small fiber neuropathies, in particular how systemic and local cytokine production may contribute to pain. doi:10.1016/j.ejpain.2007.03.085
S29
of this in which we have demonstrated the analgesic effectiveness of Na+ channel blockers, NMDA receptor blockers and gabapentin. We have taken a quite novel approach to analgesic design for neuropathic pain, considering whether sub-groups of non-nociceptive afferents may be able to gate out sensitised nociceptive inputs. Striking analgesic effects (limited to the sensitised state) were observed following activation of the TRPM8 cool receptor (also selectively activated by chemicals such as menthol and icilin), pointing to a new, independent strategy for therapeutic analgesia in neuropathic pain. doi:10.1016/j.ejpain.2007.03.086
73 CUTANEOUS INNERVATION IN SMALL FIBER NEUROPATHIES J.W. Griffin Johns Hopkins University, Baltimore, USA
72 LABORATORY MODELS OF NEUROPATHIC PAIN AND THEIR APPLICATION IN DEVELOPING NEW ANALGESICS S.M. Fleetwood-Walker *,a, C.J. Proudfoot a, E.M. Garry a, D.F. Cottrell a, R. Rosie a, H. Anderson a, A. Delaney a, D.C. Robertson a, R. Mitchell b a
Centre for Neuroscience Research, Division of Veterinary Biomedical Sciences, School of Biomedical Sciences, University of Edinburgh, UK b Centre for Integrative Physiology (Membrane Biology Group), School of Biomedical Sciences, University of Edinburgh, UK Chronic pain states resulting from injury to primary sensory afferents are maintained by hypersensitivity of spinal neurons. Thermal hyperalgesia, mechanical and cold allodynia ensue and are difficult to treat with current analgesics at doses that do not cause side effects. We work extensively with the sciatic nerve chronic constriction injury (CCI) model of clinical nerve damage which produces an outcome of both injured and uninjured afferents with the same sensory ganglia. Nerve injury produces characteristic phenotypic changes in both small and large afferents and consequent changes in the central processing of afferent inputs. The CCI pain state is dependent on spinal NMDA receptors and their assembly with receptor-interacting proteins such as PSD-95, AMPA receptors and their protein:protein interactions as well as receptors for phenotypically induced afferent mediators like vasoactive intestinal polypeptide (VIP) and their intracellular signalling pathways. Small fibre neuropathy with therapeutically intransigent pain is commonly found after varicella zoster infection, so we generated a laboratory rodent model
Disease of small sensory fibers, including C fiber nociceptors innervating the epidermis, is implicated in some painful neuropathies. In man several lines of evidence have found that most patients with painful sensory neuropathies have reduced intraepidermal nerve fiber densities in distal sites. Even in more proximal sites, where IENF density may be normal, the work of Polydefkis and others has identified defective regenerative and collateral regeneration. To make clinical trials of agents that protect axons or promote regeneration more realistic, we have defined features that are associated with rapid progression and that should favor measurable regeneration. The dermal and epidermal nociceptors include a group that express the Ret receptor and respond to artemin or GDNF and an NGF-responsive group that express TrkA. We have found that impairment or blockade of TrkA function in TrkAF592A knockin mice markedly reduces inflammatory and neuropathic pain behaviors, providing further evidence for a role for NGF-responsive fibers in these settings. doi:10.1016/j.ejpain.2007.03.087
74 PAIN IN SMALL FIBER NEUROPATHIES: SKIN BIOPSY FINDINGS AND MEASURES OF INFLAMMATION C. Sommer *,a, E. Vlckova b, W. Kafke a, N. Ueceyler a a
Neurologische Klinik Der Universitaet Wuerzburg, Germany b Department of Neurology, University Hospital Brno, Czech Republic