Neuropeptides and spinal antinociception : studies on galanin, nociceptin and endomorphin

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 ones 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.

List of scientific papers

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. Eur J Pharmacol. 370(1): 17-22.
https://pubmed.ncbi.nlm.nih.gov/10323275

II. Xu IS, Grass S, Calo G, Guerrini R, Wiesenfeld-Hallin Z, Xu XJ (2002). Intrathecal [Nphe1]nociceptin( 1-13)NH2 selectively reduces the spinal inhibitory effect of nociceptin. Life Sci. 70(10): 1151-7.
https://pubmed.ncbi.nlm.nih.gov/11848299

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(2): 339-44.
https://pubmed.ncbi.nlm.nih.gov/10854766

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. Neurosci Lett. 324(3): 197-200.
https://pubmed.ncbi.nlm.nih.gov/12009522

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(3): 827-35.
https://pubmed.ncbi.nlm.nih.gov/9639276

VI. Grass S, Crawley JN, Xu XJ, Wiesenfeld-Hallin Z (2003). Reduced spinal cord sensitization to C-fibre stimulation in mice over-expressing galanin. Eur J Neurosci. 17(9): 1829-32.
https://pubmed.ncbi.nlm.nih.gov/12752782

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.