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The objective of this dissertation was to explore if kisspeptins have a more wide- spread function in the CNS then the regulation of the reproductive axis. Kisspeptin, a member of the RF-amide family, is an endogenous neurohormone responsible for the organisation of the HPG axis. As the product of the Kiss-1 gene it is present in four biologically active forms consisting of 54, 14, 13 and 10 amino acids. Both the distribution data of the peptides and its cognant receptor, both the already well- established function of related RF-amide peptides in nociception and neuroendocrine processes, as well as the emerging evidence associating kisspeptins with metabolic integration underlies the need for further studies. Therefore, we have investigated if centrally injected kisspeptin has any role in the organisation of the stress response and stress-associated behaviours, general activity and thermoregulation. We have also sought to know whether kisspeptin, similarly to other RF-amide peptides can modulate pain sensitivity and can impact the acute actions of morphine on nocicep- tion. KP-13 was administered icv. in different doses to adult male Sprague-Dawley rats, the behaviour of which was then observed by means of telemetry, OF and EPM tests. Additionally, plasma concentrations of corticosterone were measured in order to assess the influence of KP-13 on the HPA system. The effects on core temperature were monitored continuously via telemetry. To assess the mediation of KP’s effect on EPM behaviour AVP1R or KISS1R antagonists were administered 30 min before peptide treatment, whereas in the corticosterone measurements AVP1R antagonist and α-helical CRF(9-41) pretreatments were applied. In another set of experiments antidepressant-like effects of KP-13 were studied and the potential involvement of the adrenergic, serotonergic, cholinergic, dopaminergic and gabaergic receptors in its antidepressant-like effects was investigated in a modified FST in mice. The mice were pretreated with a non-selective α-adrenergic receptor (AR) antagonist, phenoxybenzamine, an α1/α2β-AR antagonist, prazosin, an α2-AR antagonist, yohimbine, a α-AR antagonist, propranolol, a mixed 5 − HT1/5 − HT2 serotonergic receptor antagonist, methysergide, a nonselective 5 − HT2 serotonergic receptor antagonist, cyproheptadine, a nonselective muscarinic acetylcholine receptor antagonist, atropine, a D2, D3, D4 dopamine receptor antagonist, haloperidol, or a γ-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline. Finally, in the third study we have endeavoured to shed light on the possible interaction of kisspeptin with morphine on nociception in adult male mice. Following the icv. administration of KP-13, the pain sensitivity was measured by a heat-radiant tail flick test. To assess the effect of KP-13 on acute morphine analgesia, the most effective dose was injected 30 minutes before a single subcutaneous dose of morphine Page 46 (2.4 mg/kg). Furthermore, acute morphine tolerance was evaluated by giving a bolus injection of morphine (60 mg/kg) 24 h before the pain sensitivity to a challenge dose of morphine (4 mg/kg) was measured. To evaluate if KP-13 has an effect on withdrawal signs, 3 h after the development of acute morphine tolerance naloxone- precipitated withdrawal was inducted and stereotyped jumping behaviour, weight and body temperature changes were observed. Our results demonstrated that KP-13 stimulated the horizontal locomotion in the OF test and decreased the number of entries into and the time spent in the open arms during the EPM tests, which was blocked by both the AVP1R and KISS1R antagonists. The peptide also caused marked elevations in the spontaneous locomotor activity and the core temperature recorded by the telemetric system, and significantly increased the basal corticosterone level, the last of which was prevented by again the AVP1R blocker. The FST revealed that KP-13 reversed the immobility, climbing and swimming times, suggesting antidepressant-like effects. Phenoxybenzamine, yohimbine and cyproheptadine prevented the effects of KP-13 on the immobility, climbing and swim- ming times, whereas prazosin, propranolol, methysergide, atropine, haloperidol and bicuculline did not modify the effects of KP-13. Furthermore, our results showed that KP-13 significantly decreased the pain threshold. Peptide treatment also depressed the acute nociceptive effect of morphine and attenuated the development of morphine tolerance. In the withdrawal experi- ment KP-13 was found to exacerbate withdrawal signs, however our results were not significant. In conclusion, our data indicate that icv. administered KP-13 stimulates the HPA axis through the release of AVP, induces hyperthermia, activates motor behaviour and causes anxiety in rats by the activation of KISS1R and by AVP secretion. Our results also demonstrate that the antidepressant-like effects of KP-13 in a modified mouse FST are mediated, at least in part, by an interaction of the α2-adrenergic and 5 − HT2 serotonergic receptors. Finally, our data underlies kisspeptin’s hyperalgesic effect and suggest that central KP-13 administration can modify the acute effects of morphine.

Kisspeptin modulates the activity of the stress system and associated behaviours, the body temperature and nociception