Taking the sting out of pain

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, Thr⁶-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.

Mortari et al. (2007) report in this issue that injection of Thr⁶-bradykinin (Thr⁶-BK), which is the active peptide in the venom of the social wasp, Polybia occidentalis, into the lateral ventricle of naive rats reduces noxious heat-evoked responses both in tail-flick and hot plate tests. The authors also report that the Thr⁶-BK-evoked antinociceptive effect is mediated through the bradykinin (BK) B2 receptor, and it was superior to, or comparable with the antinociceptive effects produced by intracerebroventricular injection of BK or morphine, respectively. The powerful antinociceptive effect of Thr⁶-BK, and in fact BK itself, could be surprising to many, because BK and its analogues are most often associated with peripheral events, such as inflammation and damage of the peripheral tissues, and the induction of pain through the activation of a sub-population of nociceptive primary sensory neurons (Walker et al., 1995; Raidoo and Bhoola, 1998; Moreau et al., 2005). The finding that Thr⁶-BK and BK reduce noxious heat-evoked behavioural responses could even look controversial, because the pain sensation BK evokes in the periphery is heat hyperalgesia.

Members of the kallikrein–kinin system, including tissue kallikrein, the enzyme which cleaves BK analogues, BK itself, the BK B2 receptor and the kininases that hydrolyze kinins, have all been found in various areas of the brain, including the cortex, cerebellum, hypothalamus, brain stem and the pituitary gland (Raidoo and Bhoola, 1998; Chen et al., 2000; Moreau et al., 2005). Accordingly, BK and the B2 receptor have been implicated in a series of pathological processes, including the development of post-traumatic and inflammatory brain oedema, Alzheimer's disease and central hypertonia (Raidoo and Bhoola, 1998; Moreau et al., 2005). The effect of BK on nociceptive processing in the brain has, however, received little attention. Thus, the mechanism involved in the Thr⁶-BK-evoked antinociceptive effect remains elusive.

Mortari and her co-workers suggest that Thr⁶-BK produces antinociception by activating the descending adrenergic pathways through presynaptic B2 receptors. This hypothesis is based on earlier findings that BK injected into the locus coeruleus (LC) or the principal spinal trigeminal nucleus, which receives projection from the LC, produces powerful antinociception that is abolished when noradrenaline is depleted in the LC (Couto et al., 1998, 2006). 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 Thr⁶-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 PAG-mediated effect could include neurons with perikarya located in the amygdala, because injection of the μ-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. Alternatively, BK and its analogues could activate neurons indirectly, through inducing the release of substances from B2 receptor-expressing ependyma cells, oligodendrocytes or astrocytes (Raidoo and Bhoola, 1998; Chen et al., 1996).

Regardless of the underlying mechanisms, findings by Mortari et al. (2007) and other authors show that the kallikrein–kinin system, particularly via the B2 receptor, is very much a part of the endogenous antinociceptive system. At this time, there are more questions than answers about this supraspinal pain control and it is too early to consider the exploitation of this system for pain control. First, we should elucidate whether the kallikrein–kinin system is able to reduce pathological pain sensations, such as heat/cold hyperalgesia and mechanical allodynia associated with acute and chronic diseases. Furthermore, we should identify the mechanism(s), through which the BK-evoked antinociceptive effect is produced. It is also essential to investigate the possibility of the release of any endogenous B2 receptor agonists, which could selectively activate B2 receptors in areas and nuclei involved in nociceptive processing, because B2 receptor activation is involved in a series of pathological events (Raidoo and Bhoola, 1998; Moreau et al., 2005). Nevertheless, the present and previous findings of Mortari et al., indicate that the reward might be worth the effort, because, while wasps buzzing over our heads are a nuisance, they could offer more than a sting.

Abbreviations

BK

bradykinin

LC

locus coeruleus

PAG

periaqueductal grey

Thr⁶-BK

Thr⁶-bradykinin