Brain sites involved in the antinociceptive effect of bradykinin in rats.

The localization of brain sites where bradykinin (BK) induces its antinociceptive effect in rats, was studied using as index the threshold for the jaw-opening reflex elicited by the dental pulp electrical stimulation test (DPEST). The microinjection of BK into the lateral or fourth cerebral ventricles induced an antinociceptive effect, with Index of Antinociception (IA) of 0.51+/-0.03 and 0.68+/-0.05, respectively. However, microinjections of the peptide into the third ventricle induced a less marked antinociception (IA = 0.28+/-0.08). The brain sites where the microinjection of BK caused an antinociceptive effect were: locus coeruleus, principal nucleus, oral part of the spinal sensorial trigeminal nucleus, and the sensory root of the trigeminal nerve. The antinociceptive effect was more intense when BK (4-16 nmol) was injected into the locus coeruleus. Microinjection of BK (4 nmol) into the fourth ventricle, but not into the locus coeruleus, induced an increase in blood pressure. The microinjection of the peptide into the nucleus tractus solitarius, a site that is also involved in the pressor effect of BK, did not induce an antinociceptive effect. These results indicate that the antinociceptive effect of BK is not related to blood pressure changes. The microinjection of BK into some of the sites involved in the mechanisms of analgaesia, including the periaqueductal gray matter (dorsal, lateral and ventrolateral) and the dorsal raphe nucleus did not induce an antinociceptive effect. The results suggest that the most likely brain sites involved in the antinociceptive effect of BK are the locus coeruleus and the principal sensory trigeminal nucleus. The present results did not exclude the involvement of other brain sites surrounding the lateral and the third ventricles.

Antinociceptive action of bradykinin and related kinins of larger molecular weights by the intraventricular route.

1. It was shown previously that bradykinin (Bk) when given intraventricularly increases the threshold of electrical stimulation of dental pulp in the rabbit.2. Bradykinin derivatives with increasing molecular weights (lysyl-Bk (L-Bk), methionyl-lysyl-Bk (ML-Bk) and glycyl-arginyl-methionyl-lysyl-Bk (GAML-Bk)) were found to produce effects of decreasing intensity on the threshold of electrical stimulation according to the following scale: Bk (1.00)>L-Bk (0.28)>ML-Bk (0.060)>GAML-Bk (0.047).3. The four peptides had similar relative activities on the guinea-pig ileum but an inverse relationship in their effects on vascular permeability and rat blood pressure.4. The discrimination index, increase in vascular permeability/antinociceptive effect rose to values of the order of 170 to 550, taking Bk as the reference peptide (potency=1.00).5. We conclude that the increase in threshold of electrical stimulation could not be due to an increase in vascular permeability or decrease of blood pressure.

Opioid mediation of the antiaversive and hyperalgesic actions of bradykinin injected into the dorsal periaqueductal gray of the rat.

Reported evidence indicates that the dorsal region of the periaqueductal gray matter (PAG) is involved in the modulation of both pain and aversion, and that opioid mechanisms, among others, participate in their modulation. Since many central actions of bradykinin (BK) have been shown to be similar to those of morphine, the present was undertaken to measure the effects of microinjection of BK into the PAG on the thresholds of aversive electrical stimulation of the same brain area and of dental pulp electrical stimulation. Bradykinin, injected into the dorsal PAG, induced a dose-dependent increase in the aversive threshold, an effect similar to that reported by others for morphine. Also, as reported for morphine, the antiaversive effect of BK was antagonized by naloxone injected intraperitoneally. Whereas subcutaneously administered morphine induced marked analgesia, intra-PAG administration of BK caused a small but significant hyperalgesia. Similarly, morphine injected into the dorsal PAG tended to cause hyperalgesia instead of analgesia. Furthermore, the hyperalgesic effect of BK also appears to involve opioid mechanisms since it was blocked by naloxone. As in previously reported studies, intracerebroventricularly injected BK raised the pain threshold. These results indicate that BK mobilizes opioid mechanisms in the dorsal PAG that inhibit aversion but not pain.

The functional interaction of EGF and PDGF with bradykinin in the proliferation of human gingival fibroblasts.

Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)-BB are both involved in periodontal wound healing. Each of these growth factors exerts a positive proliferative effect on cells of the periodontium in vitro. However, in vivo the peptide bradykinin is one of a complex array of mediators present in addition to these growth factors. The purposes of this investigation were to: 1) evaluate bradykinin interactions with EGF and PDGF-BB altering cell proliferation in cultured human gingival fibroblasts (HGF), periodontal ligament cells (HPDL), and cells derived from alveolar bone (HOB); and 2) determine at the signal transduction level the mechanism of interaction between EGF and bradykinin in HGF. EGF and PDGF-BB stimulated DNA synthesis in a concentration-dependent manner, as measured by [3H] thymidine incorporation. Bradykinin alone did not alter significantly based DNA synthesis values; however, bradykinin in combination with EGF reduced DNA synthesis to nearly basal levels and bradykinin in combination with PDGF reduced the DNA synthesis over 50%. Examination of the interactions between bradykinin and EGF signal transduction pathways revealed that PGE2 release was increased in the presence of bradykinin and EGF (167 +/- 33% to 317 +/- 29%). The bradykinin-stimulated PGE2 release was completely abolished by indomethacin. Indomethacin also was found to block the bradykinin inhibition of EGF-induced DNA synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effects of intra-arterial and locally applied vasoactive agents on pulpal blood flow in dog canine teeth determined by laser Doppler velocimetry.

The vasoactive agents norepinephrine, 5-hydroxytryptamine, isoproterenol and bradykinin, at concentrations which changed local arterial pressure without changing systemic arterial pressure significantly, were injected intra-arterially (i.a.) into the maxillary artery or applied directly in a deep dentinal cavity on the buccal surface of canine teeth. The probe of a laser Doppler velocimeter was placed in the cavity to monitor pulpal blood flow. Bolus i.a. injections of the vasoconstrictors norepinephrine and 5-hydroxytryptamine produced a statistically significant (p less than 0.05) reduction in pulpal blood flow, 21.1 +/- 3.7 and 30.7 +/- 15.2%, and the local arterial pressure from the lateral nasal artery increased with norepinephrine but decreased with 5-hydroxytryptamine. The i.a. injections of the vasodilators isoproterenol and bradykinin were found to decrease both local arterial pressure and pulpal blood flow, 17.7 +/- 6.0 and 22.7 +/- 4.2%, respectively (p less than 0.05). However, local application of isoproterenol and bradykinin caused a biphasic response: an increase in pulpal blood flow, 8.6 +/- 1.6 and 9.4 +/- 1.1% (p less than 0.05), followed by a decrease, 19.1 +/- 11.9 and 5.3 +/- 2.1% (p greater than 0.005). Local application of norepinephrine and 5-hydroxytryptamine caused a decrease in pulpal blood flow, 23.7 +/- 5.2% (p less than 0.05) and 9.3 +/- 5.2% (p less than 0.05), respectively. These findings were in accordance with those from other reliable methods, such as injections of radioisotope-labelled 15 microns microspheres and the 133Xe washout technique, making laser Doppler flowmetry a reliable alternative. In addition, the biphasic response to the locally applied vasodilators and the reduction of pulpal blood flow after i.a. injection of vasodilators suggest that regulation of pulpal blood flow is determined by the combined effects of the low compliance environment and the stealing of perfusion to the pulp by the neighbouring tissues.

Involvement of afferent nerves in pulpal blood-flow reactions in response to clinical and experimental procedures in the cat.

A unilateral resection of the mandibular nerve (n = 20) was made 10-14 days before investigation of the contribution of afferent nerves in vasodilator reactions in the dental pulp. Lower canine teeth were subjected to various stimuli and pulp blood-flow responses monitored by laser Doppler flowmetry. An absence of response to bipolar electrical (5 impulses, 50 microA, 5 ms, 2 Hz) stimulation on the tooth surface was used to demonstrate a successful chronic nerve lesion. Local application of capsaicin (10(-4) M) in a deep dentinal cavity induced a long-lasting increase in pulpal blood flow in control teeth only. Bradykinin (10(-3) M) induced significantly larger responses in control than in denervated teeth (58.3 +/- 9.8% and 24.5 +/- 4.9%, respectively, p less than 0.005, n = 8); in addition, the onset was slower and the duration of the response significantly (60%) shorter than in control teeth. Intermittent grinding of surface dentine instantly increased flow in control teeth by 53.0 +/- 12.5% (n = 12) whereas in denervated teeth the response was delayed and significantly (70%) smaller. Deeper preparation produced responses of similar magnitude in control and denervated teeth (69 and 50%, respectively) but the onset was delayed in denervated teeth. Low-intensity ultrasonic stimulation caused vasodilation in intact teeth (38% increase) but had no effect in denervated teeth. This effect was abolished after local anaesthetic (mepivacaine) injection. Sympathectomy (n = 3) did not influence stimulation-induced blood-flow responses in the dental pulp.(ABSTRACT TRUNCATED AT 250 WORDS)

[Prophylactic use of icatibant before tracheal intubation of a patient with hereditary angioedema type III. (A literature review of perioperative management of patients with hereditary angioedema type III)]. / Uso profiláctico de icatibant en un caso de angioedema hereditario tipo III. (Revisión de la literatura sobre manejo perioperatorio en pacientes con angioedema hereditario tipo III).

Type III hereditary angioedema is a rare familial disorder that has recently been described as a separate condition. Triggers for episodes of angioedema include surgery, dental procedures, and tracheal intubation maneuvers. Since episodes affecting the upper airway are potentially life-threatening, prophylactic treatment is recommended in these situations. The use of icatibant (Firazyr(®)), for prevention of angioedema prior to tracheal intubation, is reported in a patient with type iii hereditary angioedema. A literature review on the anesthetic management of this condition was conducted.

The Artificial Synapse Chip: a flexible retinal interface based on directed retinal cell growth and neurotransmitter stimulation.

The Artificial Synapse Chip is an evolving design for a flexible retinal interface that aims to improve visual resolution of an electronic retinal prosthesis by addressing cells individually and mimicking the physiological stimulation achieved in synaptic transmission. We describe three novel approaches employed in the development of the Artificial Synapse Chip: (i) micropatterned substrates to direct retinal cell neurite growth to individual stimulation sites; (ii) a prototype retinal interface based on localized neurotransmitter delivery; and (iii) the use of soft materials to fabricate these devices. By patterning the growth of cells to individual stimulation sites, we can improve the selectivity of stimulation and decrease the associated power requirements. Moreover, we have microfabricated a neurotransmitter delivery system based on a 5- micro m aperture in a 500-nm-thick silicon nitride membrane overlying a microfluidic channel. This device can release neurotransmitter volumes as small as 2 pL, demonstrating the possibility of chemical-based prostheses. Finally, we have fabricated and implanted an equivalent device using soft flexible materials that conform to the retinal tissue more effectively. As many of the current retinal prosthesis devices use hard materials and electrical excitation at a lower resolution, our approach may provide more physiologic retinal stimulation.

Analgesic action of amfenac Na, a non-steroidal anti-inflammatory agent.

Amfenac Na is a new non-steroidal analgesic anti-inflammatory drug which is clinically used for ailments such as rheumatoid arthritis and pain and/or inflamation after surgery. In this paper, amfenac Na is studied on the bradykinin induced-flexor reflex and the simultaneous recording of the cortical somatosensory-evoked response (SER) and the electromyogram of digastric muscle (d-EMG) evoked by a tooth pulp stimulation. Amfenac Na at doses of 0.1-1 mg/kg p.o. suppressed hindlimb flexor reflexes induced by bradykinin infusion in the rat. This effect was the most potent among the drugs used; the order of potency was as follows: amfenac Na greater than floctafenine greater than loxoprofen much greater than piroxicam = emorfazone greater than mefanamic acid. Similarly, the intravenous injection of amfenac Na completely suppressed the flexor reflex with a dose as low as 0.1 mg/kg; the potency was almost equal to that of morphine. On the SER and d-EMG evoked by tooth pulp stimulation, a high dose (100 mg/kg i.v.) of amfenac Na showed very weak inhibition, whereas morphine (10 mg/kg i.v.) suppressed those responses. These data suggest that amfenac Na showed a very potent analgesic effect comparable to morphine, and that the site of action is mainly the periphery.

Secretory and motor effects in the submaxillary gland of the rat on intraarterial administration of some polypeptides and autonomic drugs.

Bradykinin, oxytocin, physalaemin and some autonomic drugs were injected in to the common carotid artery. Physalaemin evoked secretion and a pressure rise in the submaxillary duct. A duct pressure rise could be elicited by bradykinin which did not evoke secretion. Autonomic blocking agents did not diminish secretion evoked by physalaemin and did not change pressure responses elicited by bradykinin or physalaemin. Neither secretion, nor duct pressure changes could be recorded after administration of oxytocin. In agreement with previous experiments secretion evoked by autonomic drugs was found to be mediated via cholinergic, alpha- and beta-adrenergic receptors, while motor effects were due to activation of cholinergic and alpha-adrenergic receptors.