Most DRG neurons supplying the visceral organs of rodents contain substance P and neuro-kinin A, and tachykinin NKX, NK2, and NK3 receptors are expressed at many levels of the gut-brain axis (242-244). A double-blind pilot study has shown that the tachykinin NKj
Table 4 Effects of Tachykinin Receptor Blockade or Deletion In Experimental Models of Visceral Hyperalgesia and Pain
Beneficial effects of NK1 receptor blockade or deletion Cardiovascular pain response to peritoneal irritation and jejunal distension in rats Visceromotor pain response to colonic distension in rats Mechanical hyperalgesia caused by repeated noxious colonic distension in rats Stress-induced hypersensitivity to noxious colonic distension in rats Cardiovascular pain response to colonic irritation by capsaicin or acetic acid in mice Mechanical hyperalgesia in irritated colon of mice Inflammation-induced hypersensitivity to noxious colonic distension in rabbits Beneficial effects of NK2 receptor blockade Cardiovascular pain response to peritoneal irritation and jejunal distension in rats Visceromotor pain response to gastric and colorectal distension in rats
Enhanced c-fos expression in spinal cord after trinitrobenzene sulphonic acid-induced irritation of rat colon Inflammation- and stress-induced hypersensitivity to noxious rectal distension in rats Enhanced firing of lumbosacral afferents after distension of inflamed rat colon Infection-induced hypersensitivity to noxious jejunal distension in rats Beneficial effects of NK3 receptor blockade Visceromotor pain response to colorectal distension in rats Inflammation-induced hypersensitivity to noxious colorectal distension in rats Mechanical hyperalgesia caused by repeated noxious colonic distension in rats receptor antagonist CJ-11,974 reduces IBS symptoms and attenuates the emotional response to rectosigmoid distension (245). These observations are in keeping with preclinical studies that attest to a role of tachykinin receptors in visceral pain and hyperalgesia (Table 4) (242-244). For instance, genetic deletion of NKj receptors in mice prevents intracolonic acetic acid and cap-saicin from inducing primary mechanical hyperalgesia in the colon and referred mechanical hyperalgesia in the abdominal skin (246). In addition, NKX receptor-deficient mice fail to respond to intracolonic acetic acid and capsaicin with cardiovascular responses indicative of pain, whereas the reaction to distension is normal (246).
Experimental studies with selective tachykinin receptor antagonists indicate that all three tachykinin receptors play a role in visceral nociception and inflammation-induced hyperalgesia (242-244). The visceromotor pain response to gastric and colorectal distension in the rat is inhibited by NK2 and NK3 receptor antagonists but left unaltered by NKX receptor antagonists (247-252). In contrast, the inflammation- or stress-induced colonic hypersensitivity to colorectal distension in the rabbit, rat, and guinea pig is reduced by NKj receptor antagonists (253-256). The cardiovascular reaction to jejunal distension in the absence of intestinal infection and the analogous reaction to peritoneal irritation are attenuated by both NKj and NK2 receptor antagonists (238,257,258). The inflammation- and stress-induced hypersensitivity to rectal distension is largely prevented by an NK2 receptor antagonist (249), and the cardiovascular reaction to jejunal distension, which is exaggerated in rats infected with Nippostrongylus brasiliensis, is likewise normalized by an NK2 receptor antagonist (259).
Tachykinin receptor antagonists may target multiple relays in the nociceptive pathways from the periphery to the brain. One site of action is within the spinal cord where tachykini-nergic transmission from primary afferents is interrupted. This appears to be true for the antihyperalgesic effect of the NKX receptor antagonist TAK-637 in the rabbit and guinea pig (253,255). One study reports that the visceromotor pain response to colorectal distension in rats and the hypersensitivity caused by repeated distension is blocked by intrathecal administration of an NKX or NK3, but not NK2, receptor antagonist (260). In another study, it has been found that the inflammation-induced hypersensitivity to noxious colorectal distension in rats is inhibited by the intrathecal administration of an NK3 receptor antagonist or a combination of an NKX and NK2 receptor antagonist, whereas NKX and NK2 receptor antagonists given singly are without effect (261). These observations point to a site of action within the spinal cord and, in addition, suggest that the antinociceptive efficacy of multi-/pan-tachykinin receptor antagonists is superior to that of monoreceptor antagonists. Similarly, the afferent signaling of a noxious acid stimulus from the stomach to the rat brain stem is attenuated only by simultaneous administration of an NKX, an NK2, and a ionotropic NMDA-type glutamate receptor antagonist (229). Further consistent with a central site of the antinociceptive action of NKX receptor antagonists is the finding that experimental colitis or cystitis in the rat leads to an upregulation and de novo expression of NK receptors in the dorsal horn of the spinal cord (262-264).
Apart from blocking tachykininergic transmission in the spinal cord, NK1 and NK2 receptor antagonists may be antihyperalgesic by a peripheral site of action on nociceptive afferents. Although the expression of tachykinin receptors by primary afferent nerve fibers remains to be clarified (243), the NK2 receptor antagonist nepadutant has been observed to inhibit the enhanced firing, which lumbosacral afferent neurons exhibit after distension of the experimentally inflamed rat colon (250). Since the activity in pelvic and somatic afferent neurons is not affected, nepadutant has been proposed to be antihyperalgesic by a peripheral action on hypersensitive afferents supplying the colon (250). In addition, peripheral nepadu-tant suppresses the effect of acute irritation of the colon with TNBSA, but not non-noxious colorectal distension, to stimulate neurons in the spinal cord as visualized by c-fos expression (265). The effect of intraperitoneally injected tachykinin receptor agonists to elicit visceromotor pain reactions (238,266) and to increase vagal afferent nerve acticity via an NK1 receptor-mediated mechanism (267) also point to an action on peripheral axons of afferent neurons. Part of these pronociceptive actions of tachykinins in the periphery may be indirect and due to their ability to modify GI motility and secretion and to promote inflammatory processes (243,244). This is true for tachykinin actions mediated by NK and NK2 receptors and, possibly, for those brought about by NK3 receptors. The available evidence indicates that NK3 receptor antagonists are antihyperalgesic both by a peripheral and by a central site of action. On the one hand, intrathecal administration of an NK3 receptor antagonist effectively inhibits the visceromotor response to noxious distension of the inflamed or sensitized rat colon (260,261). On the other hand, systemic administration of the non—brain-penetrant NK3 receptor antagonist SB-235375 is able to inhibit the visceromotor reaction to painful colorectal distension in rats without affecting colonic motility (252,268). Since mechanonociception in the skin is not affected, it has been proposed that NK3 receptor antagonists exhibit intestine-specific antino-ciceptive activity (252).
Taken all experimental findings together, tachykinin receptor antagonists appear to have potential for the treatment of visceral pain and FBDs (Table 4) (242-244). This may, in particular, apply to IBS and other disorders where the tachykinin system is deranged in several ways. By correcting hyper- or hypomotility, hypersecretion and inflammation, tachykinin receptor antagonists may reduce the sensory gain of extrinsic afferents in the GI tract and, in addition, block tachykininergic transmission in the spinal cord. Furthermore, the effects of brain-penetrant NKj receptor antagonists at the level of the gut and afferent system may favorably combine with their inhibitory actions on emesis, anxiety, depression, and stress reactions in the brain (269,270). In extrapolating these preclinical observations to the development of effective drugs for visceral pain, it needs to be clarified which types of tachykinin receptors are most relevant in the initiation and/or maintenance of visceral pain syndromes in humans.
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