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.
"However, other mechanisms should also be considered, because in addition to the LC, other brain regions, which are involved in nociceptive processing, and have been shown to respond to BK and/or express B2 receptors, could also be accessed easily by Thr 6 -BK from the lateral ventricle. For example, BK produces antinociception when injected into the periaqueductal grey (PAG), one of the main sites, which integrates the endogenous descending pain modulation (Burdin et al., 1992). The PAGmediated effect could include neurons with perikarya located in the amygdala, because injection of the m-opioid agonist, DAMGO, into the basolateral part of the amygdala that expresses B2 receptors in high density inhibits the tail-flick reflex through the PAG (Helmstetter et al., 1998; Chen et al., 2000), and easily accessible for drugs from the lateral ventricle. "
[Show abstract][Hide abstract] ABSTRACT: While the role of the brain kallikrein-kinin system in the development of various pathological processes, such as oedema formation following brain injury or induction of central hypertonia has generated major interest, the possible role of this system in nociceptive processing has received little attention. In their present paper, Mortari et al. (2007) show that bradykinin B2 receptor activation in the brain by the bradykinin analogue, Thr(6)-bradykinin, isolated from the venom of the social wasp, Polybia occidentalis potently reduces acute, noxious heat-evoked reflex responses in naive rats. The unknown underlying mechanism of this powerful antinociceptive effect reminds us that the supraspinal antinociceptive system is still a "black box" in many aspects and awaits thorough investigation.
British Journal of Pharmacology 08/2007; 151(6):721-2. DOI:10.1038/sj.bjp.0707274 · 4.84 Impact Factor
"It is worth noting that antinociceptive effects have also been reported following spinal (Launeville et al. 1989, 1988) or intracerebral injections of bradykinin (Ribeiro and Rocha e Silva 1973). The periaqueductal and periventricular grey regions were suggested as possible sites for this effect (Clark 1979; Couto et al. 1995), and the release of endogenous opioids may account for the analgesia, as the bradykinin-mediated elevation of nociceptive thresholds was inhibited by intraperitoneal injections of naloxone (Burdin et al. 1992). In the spinal cord, however, stimulation of descending noradrenergic nerve terminals has been implicated in the antinociceptive effect of kinins (Laneuville and Couture 1987; Laneuville et al. 1989). "
[Show abstract][Hide abstract] ABSTRACT: Kinins (bradykinin, kallidin) are produced at sites of injury and inflammation and serve a critical role in signaling tissue distress as well as organising tissue responsiveness to injury. The acute activation and prolonged sensitization of fine afferents, to produce pain and hyperalgesia, are important in the protective responses that occur to minimize further tissue injury. These effects occur via activation of B2 receptors present on sensory neurons, resulting in a change of membrane excitability and altered cellular neurochemistry. B2 receptor activation of a variety of tissues including postganglionic sympathetic fibres stimulates the production of several proinflammatory mediators, including prostanoids and cytokines, which interact with kinins and contribute to inflammation and hyperalgesia. Increased expression of B1 receptors plays a prominent role in inflammatory hyperalgesia, but further characterization of the cellular mechanism is required. A role for kinins and kinin receptors in central pathophysiologies (trauma, ischemia, infection) needs examination. The evidence for modulation of nociception and central pain generation is compelling, as central bradykinin administration causes hyperalgesia, whereas B2 antagonists are antinociceptive. The basis for these effects should be urgently investigated. Such data will add further support to the utilization of bradykinin receptor antagonists for the treatment of peripheral and central pain.
Canadian Journal of Physiology and Pharmacology 07/1997; 75(6):704-12. DOI:10.1139/cjpp-75-6-704 · 1.77 Impact Factor
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