Angiotensin (5-8) modulates nociception at the rat periaqueductal gray via the NO-sGC pathway and an endogenous opioid.

Angiotensins (Angs) modulate blood pressure, hydro-electrolyte composition, and antinociception. Although Ang (5-8) has generally been considered to be inactive, we show here that Ang (5-8) was the smallest Ang to elicit dose-dependent responses and receptor-mediated antinociception in the rat ventrolateral periaqueductal gray matter (vlPAG). Ang (5-8) antinociception seems to be selective, because it did not alter blood pressure or act on vascular or intestinal smooth muscle cells. The non-selective Ang-receptor (Ang-R) antagonist saralasin blocked Ang (5-8) antinociception, but selective antagonists of Ang-R types I, II, IV, and Mas did not, suggesting that Ang (5-8) may act via an unknown receptor. Endopeptidase EP 24.11 and amastatin-sensitive aminopeptidase from the vlPAG catalyzed the synthesis (from Ang II or Ang III) and inactivation of Ang (5-8), respectively. Selective inhibitors of neuronal-nitric oxide (NO) synthase, soluble guanylyl cyclase (sGC) and a non-selective opioid receptor (opioid-R) inhibitor blocked Ang (5-8)-induced antinociception. In conclusion, Ang (5-8) is a new member of the Ang family that selectively and strongly modulates antinociception via NO-sGC and endogenous opioid in the vlPAG.

Effect of gonadal steroid hormones on formalin-induced temporomandibular joint inflammation.

We have recently demonstrated that gonadal steroid hormones decrease formalin-induced temporomandibular joint nociception in rats. Given that the attenuation of inflammation is a potential mechanism underlying this antinociceptive effect, we evaluated the effect of gonadal steroid hormones on formalin-induced temporomandibular joint inflammation. Plasma extravasation, a major sign of acute inflammation, and neutrophil migration, an important event related to tissue injury, were evaluated. Formalin induced significantly lower temporomandibular joint plasma extravasation and neutrophil migration in proestrus females than in males and in diestrus females. Since estradiol serum level is high in proestrus females and low in diestrus females and in males, these findings suggest that the high physiological level of estradiol decreases temporomandibular joint inflammation. Estradiol but not progesterone administration in ovariectomized females significantly decreased formalin-induced plasma extravasation and neutrophil migration, an effect that was blocked by the estrogen receptor antagonist ICI 182780. Plasma extravasation and neutrophil migration were not affected by orchiectomy, but testosterone or estradiol administration in orchidectomized males significantly decreased them. The androgen receptor antagonist flutamide blocked the anti-inflammatory effect of testosterone while ICI 182780 blocked that of estradiol in males. Previous intravenous administration of a nonspecific selectin inhibitor significantly decreased formalin-induced temporomandibular joint nociception and neutrophil migration in males, revealing a potent and positive correlation between temporomandibular joint nociception and inflammation. Taken together, these findings demonstrate a pronounced anti-inflammatory effect of estradiol and testosterone in the temporomandibular joint region and suggest that this effect may mediate, at least in part, the antinociceptive effect of these hormones.

Angiotensin III modulates the nociceptive control mediated by the periaqueductal gray matter.

Endogenous angiotensin (Ang) II and/or an Ang II-derived peptide, acting on Ang type 1 (AT(1)) and Ang type 2 (AT(2)) receptors, can carry out part of the nociceptive control modulated by periaqueductal gray matter (PAG). However, neither the identity of this putative Ang-peptide, nor its relationship to Ang II antinociceptive activity was clarified. Therefore, we have used tail-flick and incision allodynia models combined with an HPLC time course of Ang metabolism, to study the Ang III antinociceptive effect in the rat ventrolateral (vl) PAG using peptidase inhibitors and receptor antagonists. Ang III injection into the vlPAG increased tail-flick latency, which was fully blocked by Losartan and CGP 42,112A, but not by divalinal-Ang IV, indicating that Ang III effect was mediated by AT(1) and AT(2) receptors, but not by the AT(4) receptor. Ang III injected into the vlPAG reduced incision allodynia. Incubation of Ang II with punches of vlPAG homogenate formed Ang III, Ang (1-7) and Ang IV. Amastatin (AM) inhibited the formation of Ang III from Ang II by homogenate, and blocked the antinociceptive activity of Ang II injection into vlPAG, suggesting that aminopeptidase A (APA) formed Ang III from Ang II. Ang III can also be formed from Ang I by a vlPAG alternative pathway. Therefore, the present work shows, for the first time, that: (i) Ang III, acting on AT(1) and AT(2) receptors, can elicit vlPAG-mediated antinociception, (ii) the conversion of Ang II to Ang III in the vlPAG is required to elicit antinociception, and (iii) the antinociceptive activity of endogenous Ang II in vlPAG can be ascribed preponderantly to Ang III.

5-HT acts on nociceptive primary afferents through an indirect mechanism to induce hyperalgesia in the subcutaneous tissue.

We have recently demonstrated that s.c.-injected 5-hydroxytryptamine (5-HT) induces nociception by an indirect action on the primary afferent nociceptor in addition to its previously described direct action. Although the mechanisms mediating hyperalgesia can be quite separate and distinct from those mediating nociception, the aim of this study was to test the hypothesis that 5-HT induces mechanical hyperalgesia by mechanisms similar to those mediating nociception. s.c. injection of 5-HT induced a dose-dependent mechanical hyperalgesia measured by the mechanical paw withdrawal nociceptive threshold test in the rat. 5-HT-induced hyperalgesia was significantly reduced by local blockade of the 5-HT(3) receptor by tropisetron, by the nonspecific selectin inhibitor fucoidan, by the cyclooxygenase inhibitor indomethacin, by guanethidine depletion of norepinephrine in the sympathetic terminals, and by local blockade of the beta(1)- or beta(2)-adrenergic receptor by atenolol or ICI 118,551, respectively. Taken together, these findings indicate that like nociception, hyperalgesia induced by the injection of 5-HT in the s.c. tissue is also mediated by an indirect action of 5-HT on the primary afferent nociceptor. This indirect hyperalgesic action of 5-HT is mediated by a combination of mechanisms involved in inflammation such as neutrophil migration and the local release of prostaglandin and norepinephrine. However, in contrast to nociception, hyperalgesia induced by 5-HT in the s.c. tissue is mediated by a norepinephrine-dependent mechanism that involves the activation of peripheral beta(2) adrenoceptors.

A novel mechanism involved in 5-hydroxytryptamine-induced nociception: the indirect activation of primary afferents.

The aim of this study was to test the hypothesis that 5-hydroxytryptamine induces nociception by an indirect action on the primary afferent nociceptor in addition to its previously described direct action. Injection of 5-hydroxytryptamine into the s.c. tissue of the hind paw of rats produced nociceptive flinch behavior and inflammatory cell migration, that were significantly reduced by the nonspecific selectin inhibitor fucoidan. 5-Hydroxytryptamine-induced nociception was also significantly reduced by local blockade of the 5-HT3 receptor by tropisetron, by the cyclooxygenase inhibitor indomethacin and by local blockade of the beta1-adrenergic receptor or of the D1 receptor by atenolol or SCH 23390, respectively. Neither guanethidine depletion of norepinephrine in the sympathetic terminals nor local blockade of the beta2-adrenergic receptor by ICI-118,551 significantly reduced 5-hydroxytryptamine-induced nociception. Taken together, these findings indicate that 5-hydroxytryptamine induces nociception by a novel, indirect and norepinephrine-independent mechanism mediated by neutrophil migration and local release of prostaglandin and dopamine. Furthermore, to test whether dopamine acts on beta1-adrenergic and/or D1 receptor to contribute to 5-hydroxytryptamine-induced nociception, dopamine was s.c. injected either alone or combined with atenolol or with SCH 23390. S.c.-injected dopamine also produced a dose-dependent nociceptive behavior that was significantly reduced by both SCH 23390 and atenolol. Based on that it is proposed that dopamine, once released, activates D1 and beta1-adrenergic receptors to contribute to 5-hydroxytryptamine-induced nociception.

A new role for the renin-angiotensin system in the rat periaqueductal gray matter: angiotensin receptor-mediated modulation of nociception.

Renin-angiotensin (Ang) system (RAS) peptides injected into the periaqueductal gray matter (PAG) elicit antinociception. Saralasin blocks Ang II-elicited antinociception. Thus, it is possible that endogenous RAS peptides could participate on the modulation of nociception in the PAG. This possibility was tested here injecting, in the PAG, the specific Ang type 1 and type 2 receptor (AT1 receptor and AT(2 receptor) antagonists losartan and CGP42,112A, respectively, either alone or before Ang II. The effects of Ang II, losartan and CGP42,112A on nociception were measured using the tail flick test and the model of incision allodynia. Ang II increased tail-flick latency, an effect inhibited by both losartan and CGP42,112A. Ang II reduced incisional allodynia. Either losartan or CGP42,112A alone increased incision allodynia, suggesting that endogenous Ang II and/or an Ang-peptide participates in the control of allodynia by the PAG. AT1 and AT2 receptors were immunolocalized in neuronal cell bodies and processes in the ventrolateral PAG. Taken together, the antinociceptive effect of Ang II injection into the ventrolateral PAG, the increase of allodynia elicited by injecting either losartan or CGP42,112A alone in the PAG, and the presence of AT1 and AT2 receptors in neurons and neuronal processes in the same region, represent the first evidence that part of the tonic nociceptive control mediated by the PAG is carried out locally by endogenous Ang II and/or an Ang-peptide acting on AT1 and AT2 receptors.