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Nociceptin/Orphanin FQ Is the Endogenous Ligand of the Orphan Opioid-Receptor-Like Receptor (ORL1)

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Nociceptin/Orphanin FQ Is the Endogenous Ligand of the Orphan Opioid-Receptor-Like Receptor (ORL1) From the Department of Laboratory Medicine, Division of Clinical Neurophysiology, Karolinska Institutet, Stockholm, Sweden Neuropeptides and spinal antinociception: studies on galanin, nociceptin and endomorphin by Stefan Grass Stockholm 2003 © Stefan Grass, 2003. Printed in Stockholm by REPRO PRINT AB ISBN 91-7349-580-8 To Maria About doing research and becoming an expert: “An expert is one who knows more and more about less and less until he knows absolutely everything about nothing.” (Murphy's Law of Super Speciality). Abstract Nociception and/or the sensation of pain is essential for the survival of the organism. Just as important are the antinociceptive mechanisms that reduce the nociceptive input and perceived pain. Without such mechanisms, it would be impossible to turn one’s focus away from even the most minor painful stimulus. The balance between excitatory and inhibitory functions in nociception is intricate and complex and some of the modulators involved may be important for future drug development for treating pain states. This work has tried to highlight some of the neuropeptides involved in the endogenous antinociceptive mechanism. Endomorphin-1 and endomorphin-2 are peptides that have high selectivity and affinity to the µ-opioid receptor, the receptor mediating the effect morphine. Intrathecal (i.t.) application of endomorphin-1 and –2 produced a dose-dependent short lasting depression of the spinal nociceptive flexor reflex in normal rats with comparable potency. The inhibitory effect of endomorphin-1 was significantly longer than that of endomorphin-2, suggesting a possible difference in enzymatic degradation. The reflex depressive effect of endomorphin-2 was maintained in rats after inflammation and in axotomized rats that did not exhibit neuropathic pain-like behavior (autotomy). However, in rats exhibiting autotomy behavior after nerve section, the effect of endomorphin-2 was significantly reduced. These results suggest that the presence of neuropathic pain decreases the antinociceptive potency of endomorphin-2, which is similar to what is observed with morphine. Nociceptin/orphanin FQ is the endogenous ligand of the orphan opioid-receptor-like receptor (ORL1). We now verified that the nociceptin analogue [Nphe1]nociceptin(1-13)NH2 is a selective antagonist of nociceptin in rat spinal cord. We have also systematically evaluated the effect of i.t. nociceptin on the flexor reflex in normal, inflamed and nerve injured rats. It was observed that nociceptin produced comparable depression of the flexor reflex in normal and inflamed rats and the effect of nociceptin was not reduced and if anything increased in rats with nerve injury. The results showed that nociceptin agonists may be useful analgesics in neuropathic pain. Galanin is a well documented inhibitory peptide in nociception. The work presented in this thesis provides further evidence for an inhibitory role of this peptide after inflammation. Moreover, we have developed a protocol to study flexor reflex in mice and studies on mice over-expressing galanin suggested that increased level of galanin is effective in reduced spinal hyperexcitability after repetitive C-fiber stimulation. However, we did not obtain evidence that galanin GAL-R1 receptor is tonically involved in inhibiting nociceptive input under normal condition in studies on mice lacking the GAL-R1 receptor. Key words: endomorphin, flexor reflex, galanin, knock-out mice, neuropathic pain, nociceptin, orphanin FQ, transgenic mice List of papers The thesis is based on the following list of paper and will be referred in the text according to their roman numerals: I. Xu IS., Grass S., Wiesenfeld-Hallin Z., Xu XJ. (1999). “Effects of intrathecal orphanin FQ on a flexor reflex in the rat after inflammation or peripheral nerve section.” European Journal of Pharmacology 370: 17-22. II. Xu IS., Grass S., Calo G., Guerini R., Wiesenfeld-Hallin, Z., Xu XJ. (2002). “Intrathecal [Nphe1]nociceptin(1-13)NH2 selectively reduces the spinal inhibitory effect of nociceptin.” Life Sciences 70: 1151-1157. III. Grass S., Wiesenfeld-Hallin Z., Xu XJ. (2000). “The effect of intrathecal endomorphin-2 on the flexor reflex in normal, inflamed and axotomized rats: reduced effect in rats with autotomy.” Neuroscience 98: 339-344. IV. Grass S., Xu, IS., Wiesenfeld-Hallin Z., Xu XJ. (2002). “Comparison of the effect of intrathecal endomorphin-1 and endomorphin-2 on spinal cord excitability in rats.” Neuroscience Letters 324: 197-200. V. Xu IS., Grass S., Xu XJ., Wiesenfeld-Hallin Z. (1998). “On the role of galanin in mediating spinal flexor reflex excitability in inflammation.” Neuroscience 85: 827-835. VI. Grass S., Crawley JN., Xu XJ., Wiesenfeld-Hallin Z. (2003). “Reduced spinal cord sensitization to C-fiber stimulation in mice over-expressing galanin.” European J of Neuroscience (in press). VII. Grass S., Jacoby AS., Ismaa TP., Crawley JN., Xu XJ., Wiesenfeld-Hallin Z. (2003) “Flexor reflex excitability in mice lacking galanin receptor GAL-R1.” Neuroscience Letters (in press). Contents Contents Abbreviations 10 Introduction 11 Background...........................................................................................................................11 The concept of pain...............................................................................................................11 Pain pathway.........................................................................................................................12 The nociceptive flexor reflex................................................................................................13 Wind-up and central sensitization.........................................................................................13 Peptide transmission .............................................................................................................13 Peptides, nerve injury and inflammation ..............................................................................14 Nociceptin/orphanin FQ .......................................................................................................15 Galanin..................................................................................................................................16 Galanin receptors ............................................................................................................16 Function of galanin during hyperexcitability..................................................................17 Endomorphin-1 and -2..........................................................................................................18 Pharmacolgoy..................................................................................................................18 Distribution .....................................................................................................................18 Function...........................................................................................................................18 Animals studies of pain.........................................................................................................19 Behavioral studies ...........................................................................................................19 Physiological studies.......................................................................................................19 Other methods .................................................................................................................19 Genetically modified mice ..............................................................................................20 Aims of the study 21 Materials and methods 22 Animals.................................................................................................................................22 Rats..................................................................................................................................22 Mice.................................................................................................................................22 Electrophysiology .................................................................................................................23 Rats..................................................................................................................................23 Mice.................................................................................................................................23 Wind-up ................................................................................................................................24 Nerve injury ..........................................................................................................................24 Inflammation.........................................................................................................................25 Peptides.................................................................................................................................25 Statistics................................................................................................................................25 8 Contents Results 26 Study I...................................................................................................................................26 Summary .........................................................................................................................26 Normal rats......................................................................................................................26
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