Research

Group Zeilhofer
Within the last ten years, the research of my group has centered at the mechanisms of pathological pain with a particular focus on the cellular and molecular basis of nociceptive processing in the spinal dorsal horn and with the long-term goal to identify novel strategies for the treatment of chronic pain. Central to our research is the investigation of neural plasticity in the spinal dorsal horn, the sensory part of the spinal cord. We routinely use whole-cell patch-clamp recordings and imaging techniques in slices of the spinal cord prepared from normal and genetically modified mice to unravel molecular and synaptic pathways behind chronic pain syndromes. Conventional and inducible knock-out and knock-in technologies are employed to correlate cellular and molecular processes with changes in pain behavior.
Early work in our group has focused on the spinal N/OFQ neuropeptide system and its role in pain processing. We were among the first to demonstrate that N/OFQ possesses spinal analgesic properties and identified the cellular and molecular mechanism of this analgesia (Liebel et al., Br. J. Pharmacol. 1997; Zeilhofer et al., J Neurosci 2000; Ahmadi et al., Mol. Pharmacol 2001; Ahmadi et al., Eur J Pharmacol 2001; Depner et al., Eur J Neurosci 2003; reviewed in Zeilhofer & Calo, JPET 2003). Although controversial at the time of discovery, this concept has meanwhile been further developed by other groups and is now close to entering clinical trials (e.g. Ko et al., Neuropsychopharmacol 2009).

In more recent years, our research has concentrated on the control of pain transmission by dorsal horn inhibitory interneurons. Although, a critical role of dorsal horn inhibitory interneurons in spinal pain control has been proposed in Melzack and Wall’s gate-control theory as early as 1965, a significant contribution of diminished synaptic inhibition to chronic inflammatory or neuropathic pain could only be demonstrated recently by our group and by other leading groups in the field. Our group has identified key mechanisms behind the loss of inhibitory neurotransmission in inflammatory pain states in a series of well-recognized publications (Ahmadi et al., Nat Neurosci 2002; Harvey et al., Science 2004; Reinold et al., J Clin Invest 2005; Hösl et al., Pain 2006; reviewed in Zeilhofer, CMLS 2005 and Zeilhofer & Brune, TiPS 2006). In ongoing studies we are now addressing the mechanisms of homo- and heterosynaptic pain plasticity in the spinal dorsal horn circuits. In these studies we discovered an unexpected role for endocannabinoids and CB₁ receptors as mediators of activity-dependent heterosynaptic pain plasticity. Most recently, our research addressed the question whether a pharmacological restoration of dorsal horn synaptic inhibition could normalize pathological pain hypersensitivity. Using a series of GABA_A receptor point-mutated mice, we identified specific GABA_A receptor subtypes, which can be targeted by GABA_A receptor ligands to reverse pathologic pain of inflammatory or neuropathic origin (Knabl et al., Nature 2008; Knabl et al., Pain 2009; reviewed in Zeilhofer et al., J Mol Med 2009; Zeilhofer et al., TiPS 2009).