The spinal cord dorsal horn plays an important role in nociceptive transmission, as it represents the site where the first synapse in the pain system is located and where extensive processing of the nociceptive information occurs. An important example of this proceesing in the dorsal horn is hyperalgesia and allodynia, i.e. the increased sensitivity for pain or touch that occurs after substantial damage has occurred. This increased sensitivity persists even after the damage, that caused it, has disappeared, thus representing a sort of “pain memory” in the spinal cord. At the cellular level this phenomenon, which is termed sensitization, is reflected in an increased sensitivity of spinal nocicptive cells to afferent stimuli. Sensitization is induced by a strong afferent C-fiber input, and lasts much longer than the original impulse that induced it. An importanr goal of this project is to identify the transmitters, receptors and second messengers that are involved in the process of sensitization. Sensitization is also associated with the development of neuropathic pain, a pathological pain state, characterized by allodynia and hyperalgesia as well as spontaneous pains, often occurring after an extensive nerve lesion (e.g. phantom limb pain and scar pain). Neuropathic pain is very resistant to pain treatment and its mechanisms are still largely unclear.

This project is focussed on the role of neurotrophic factors in pain transmission and the induction of sensitization. Initially based on morphological findings (see picture), the hypothesis was developed that brain derived neurotrophic factor (BDNF) and glial cell-line derived neurotrophic factor (GDNF) act as a transmitters in primary afferent nociceptive fibers, which terminate in the dorsal horn of the spinal cord. With respect to BDNF, this hypothesis was tested using electrophysiological and behavioral studies, and showed the involvement of BDNF in the sensitization of dorsal horn neurons, a process underlying hyperalgesia. We are presently investigating the effects of growth factors on second messengers and various immediate early genes.

In addition to the role of growth factors in adult nociceptive transmission, a separate project was recently started in collaboration with Dr. Dies Meyer (Dept of Genetics), involving the role of neurotrophic factors in regeneration and myelination of peripheral nerves.

Selected recent publications

• Jaarsma D, Rognoni F, van Duijn W, Verspaget HW, Haasdijk ED, Holstege JC. CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol 102 (2001) 293-305. (Pubmed)
• Jaarsma D, Haasdijk ED, Grashorn JA, Hawkins R, van Duijn W, Verspaget HW, London J, Holstege JC. Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1. Neurobiol Dis. 7 (2000) 623-643. (Pubmed)
• Mannion RJ, Costigan M, Decosterd I, Amaya F, Ma QP, Holstege JC, Ji RR, Acheson A, Lindsay RM, Wilkinson GA, Woolf CJ. Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc Natl Acad Sci U S A. 96 (1999) 9385-9390. (Pubmed)
• Jongen JL, Dalm E, Vecht CJ, Holstege JC. Depletion of GDNF from primary afferents in adult rat dorsal horn following peripheral axotomy. Neuroreport. 10 (1999) 867-871. (Pubmed)
• Holstege JC, Jongen JL, Kennis JH, van Rooyen-Boot AA, Vecht CJ. Immunocytochemical localization of GDNF in primary afferents of the lumbar dorsal horn. Neuroreport. 9 (1998) 2893-2897. (Pubmed)