Title

 

Authors

R. Russo, G. La Rana, G. D’Agostino, R. Meli and A. Calignano

Department of Experimental Pharmacology, University of Naples ‘‘Federico II’’, via D. Montesano 49, 80131 Naples, Italy.

 

Abstract

The present study investigates the effect of oxytocin (OXT) on carrageenan-induced pain response. Oxytocin (OXT)is a nonapeptide synthesized in the paraventricular (PVN) and the supraoptical (SON) nuclei in the hypothalamus, its receptors are widely distribute in the CNS, including cortex, olfactory system, basal gangalia, limbic system, thalamus, hypothalamus, brain stem, and dorsal horn of the spinal cord [1].OXT performs its biological functions through OXT receptor functionally coupled to Gq/11α class GTP binding proteins that stimulate together with G β/γ, the activity of phospholipase C-β isoforms [1]. Several studies have reported that OXT modulates analgesia or nociception [2; 3], and that the endogenous opioid system may be involved [4]. Moreover, a series of physiological and pharmacological studies have shown that OXT acts on autoreceptors to elevate intracellular Ca²⁺ [5; 6]. Although many authors have reported and are in agreement on analgesic action of OXT, the mechanism has not been well elucidated. Some studies suggest in fact, that OXT has no effect on nociception [7] and attribute the OXT increased latency responses on the hot plate test to the sedative and vasoconstrictive effects of this peptide [8]. In this study animals received carrageenan in the hindpaw, and at 0.5-24 h following administration, we have valuated paw oedema and hyperalgesia. Intracerebroventricular (icv) administration of oxytocin (30ng/mouse), but neither intraperitoneal and intraplantar, decreased withdrawal latency but did not modified oedema, suggesting a central role on hyperalgesia. OXT effect (30ng/mouse, icv) was significantly reduced by co-injection of atosiban (1μg/mouse), a specific oxytocin-receptor antagonist. On the other hand, several manuscripts suggest that OXT-induce analgesia or nociception could be due to the interaction with opioid system [9; 4]. Indeed, Miranda-Cardenas and co-worker [10] have show that the endogenous released OXT induced by electrical stimulation of the paraventricular nucleus of hypothalamus or direct application of OXT on the spinal cord produced a clear analgesic effect, which was reduced significantly using naloxone (it) [10]. In agreement of this hypothesis we demonstrated using a selective μ-opioid receptor antagonist, β-funaltrexamine (1μg/mouse, icv), and a selective k-opioid receptor antagonist nor-binaltorphimine (10 nmol/mouse, icv) that the analgesic effect of nanopeptide was significantly reduced; whereas no modification observed using naltrindole (10nmol/mouse, icv), a selective delta-opioid receptor antagonist. Recently, an interesting hypothesis suggest that OXT releases from presynaptic cell may activate local Ca²⁺ stores[5; 6] producing a secondmolecule such as endocannabinoid [11; 12], whichin turn then function as retrograde transmitter [13]. Our results showed that oxytocin-induced antihyperalgesic effect was reversed by central administration of a PLD inhibitor, suramin (1μg/mouse, icv), and by a specific CB1 antagonist receptor, SR141617A, (1μg/mouse, icv). Taken together our results show that (i) OXT plays a important role in modulation of hyperalgesic pain (ii) opioid system are involved, and in particular μ- and k-receptors, and (iii) we produce evidence that support the involve of cannabinoid CB1-receptor, in OXT-induced antihyperalgesic effect.
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