Histaminergic Regulation of Brain Functions:

We have identified the brain histaminergic neurons in humans and other species, and found that the system innervates essentially the whole brain and could be in key position to regulate crucial brain functions. Our studies have shown that this system is altered in Parkinson's disease, and in animal models of dopamine deficiency, and may be involved in brain plasticity following the degeneration of dopaminergic neurons. Histamine H3 receptor also seems to be an important link for the cross talk between the other monoaminergic systems in the brain. Recent data from our animal model studies also suggests involvement of brain histamine in addiction. Several isoforms of histamine H3 receptor were identified, and their differential expression in the rat brain suggests versatile ways of regulation of brain functions. At least one of the isoforms is coupled to the MAPK pathway, and displays transient activation after neurotoxic damage. Current studies aim at identification of the mechanisms which regulate the cooperation of histaminergic and dopaminergic systems. A zebrafish model is being established to integrate the molecular mechanisms involved with behavioral responses after neurotoxic brain lesions, which together with the available mutants provides novel tools to study integrated functions. Parallel studies are carried out in mammals using knock-out techniques.

Significance of RFamide Peptides in Sensory Regulation

Neuropeptide FF (NPFF) was the first identified mammalian RFamide neuropeptide. It regulates endocrine, limbic, autonomic and sensory functions. Cloning of the NPFF gene revealed a well-conserved structure of a peptide precursor giving rise to two active peptides in several species. Recent identification of several related peptide genes and G-protein coupled receptors for them indicates that the group is potentially important in several CNS functions. Characterization of the NPFF gene promoter region revealed multiple transcription initiation sites, promoter activity related to levels of endogenous peptide mRNA, and NGF-induced upregulation of NPFF mRNA. NPFF appeared to regulate not only acute pain but also inflammatory and neuropathic pain, which are often resistant to treatment. We showed that increased activity of the spinal cord pain-sensitive neurons is due to dysfunction of the descending pain-inhibiting pathway, which could be restored by application of NPFF. Through a brain stem mechanism, NPFF was effective in neuropathic pain. NPFF and related peptides may thus be useful in treatment of both inflammatory and neuropathic pain.

Histaminergic Regulation of Brain Functions:

• Development of zebrafish brain aminergic systems
• Behavioral significance of zebrafish dopaminergic and histaminergic systems
• The role of histamine in plasticity induced by neuronal damage in the brain
• Molecular genetics of human histamine H3 receptor
• Characterization of HDC and histamine receptor KO-models

Significance of RFamide Peptides in Sensory Regulation:

• characterization of the NPFF knock-out mouse phenotype
• association of NPFF gene mutations with human disease
• identification of novel signalling mechanisms of RFamide peptides
• RFamide peptide mechanisms in neuropathic and inflammatory pain
• the role of RFamide peptides in interactions with morphine and morphine tolerance
• RFamide peptides in immune system

Histaminergic Regulation of Brain Functions:

• K. Karlstedt, M. Nissinen, K. Michelsen, and P. Panula, P. Multiple sites of expression of L-histidine carbcoxylase suggest novel functions for histamine in mouse development. Dev Dynamics 221: 81-91, 2001.
  
  PubMed - abstract

• G. Drutel, N. Peitsaro, K. Karlstedt, K. Wieland, M.J. Smit, H. Timmerman, P. Panula, and R. Leurs. Identification of rat H3 receptor subtypes with different brain expression and signaling properties. Mol Pharmacol 59: 1-8, 2001.
  
  PubMed - abstract

• M. Lintunen, P. Hyytiä, T. Lozada, K. Karlstedt, L. Tuomisto, R. Leurs, K. Kiianmaa, E.R. Korpi, and P. Panula. Increased brain histamine in an alcohol-preferring rat line and modulation of alcohol consumption by H3 receptor mechanisms. FASEB J 10.1096/fj.00-0545fje., 2001.
  
  PubMed - abstract

• O.V. Anichtchik, N. Peitsaro, J.O. Rinne, H. Kalimo, and P. Panula. Distribution and modulation of histamine H3 receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson's disease. Neurobiol Dis 8: 707-716, 2001.
  
  PubMed - abstract

• J. Kaslin, and P. Panula. Comparative anatomy of the zebrafish brain histaminergic system and other aminergic systems. J Comp Neurol 440: 342-377, 2001.
  
  PubMed - abstract

• C.Y. Jin, H. Kalimo, and P. Panula. The histaminergic system in human thalamus: correlation of innervation to receptor expression. Eur J Neurosci, 15: 1125-1138, 2002.
  
  PubMed - abstract

Significance of RFamide Peptides in Sensory Regulation:

• F.S. Vilim, A.A. Aarnisalo, M-L. Nieminen, M. Lintunen, K. Karlstedt, V. Kontinen, E. Kalso, B. States, P. Panula, and E. Ziff. Gene for pain modulatory neuropeptide NPFF: Induction in spinal cord by noxious stimuli. Mol Pharmacol, 55: 804-811, 1999.
  
  PubMed - abstract

• P. Panula, E. Kalso, M-L. Nieminen, V.K. Kontinen, A. Brandt, and A. Pertovaara. Neuropeptide NPFF and modulation of pain. Brain Res, 848: 191-196, 1999.
  
  PubMed - abstract

• M-L. Nieminen, A. Brandt, P. Pietilä, and P. Panula. Expression of mammalian RF-amide peptides, neuropeptide FF (NPFF), prolactin-releasing peptide (PrRP) and the PrRP receptor in the peripheral tissues of the rat. Peptides 21: 1695-1701, 2000.
  
  PubMed - abstract

• A. Pertovaara, U. Keski-Vakkuri, J. Kalmari, H. Wei, and P. Panula. Response properties of neurons in the rostroventrolateral medulla of neuropathic rats: attempted modulation of responses by [1Dme]NPYF, a neuropeptide FF analogue. Neuroscience 105: 457-468, 2001.
  
  PubMed - abstract

• J.M. Westerlund, A.M. Brandt, J. Mandelin, F.S. Vilim, E.B. Ziff, and P. Panula. Analysis of human neuropeptide FF gene expression. J Neurochem In Press.
  
  PubMed - abstract

Doctoral Theses

Histaminergic Regulation of Brain Functions:

• Histamine and histidine decarboxylase in embryonic development with special reference to the oxyntic mucosa. Markku Nissinen, 1995
• Histaminergic regulation of the nigrostriatal system in Parkinson's disease and a rat model of Parkinsonism. Oleg Anichtchik, 2001
• Brain histamine in alcohol-related behaviours and experimental epilepsy. Minnamaija Lintunen, 2001
• Development of central and peripheral histamine synthesis and receptor expression. Kaj Karlstedt, 2001

Significance of RFamide Peptides in Sensory Regulation:

• Neuropeptide FF: Neural Systems and Hypothalamic Functions. Antti A. Aarnisalo, 1998.