Antinociceptive activity of the tachykinin NK₁ receptor antagonist, CP‐99,994, in conscious gerbils

Abstract

1 The ability of 994, and its less active enantiomer, 263, to

Maturation of NK1 receptor involvement in the nociceptive response to formalin

“…However, both the NK1 antagonists, and the less active enantiomer CP100,263 attenuated nociceptive response in both 3-day and 21-day old subjects, suggesting that the antinociception is not specific to antagonism of the NK1 receptor, or that actions other than those at the NK1 receptor override any specific NK1 antagonism. In the adult literature, several researchers have reported that systemic administration of NK1 antagonists produces an antinociception that is not limited to the active enantiomers (Rupniak et al, 1995;Smith et al, 1994). Peripheral administration of high doses of these antagonists also attenuated both the early and the late phases of the formalin response in the adult (Seguin et al, 1995).…”

“…It is possible that these compounds produce analgesia by blocking ion channels (Rupniak et al, 1995). Several of the NK1 antagonists have been shown to bind to L-type calcium channels, and it has been proposed that the antinociception induced by systemic administration of these compounds is due to the blockade of these channels (Rupniak et al, 1995). One potential problem for this explanation is that it has been demonstrated that CP99,994 and CP100,263 have lower affinity for these calcium channels at the dihydropyridine site than other compounds such as CP-96,345 (McLean et al, 1993).…”

“…Systemic and intraplantar application of NK1 antagonists attenuate the pain response to noxious chemical stimulation, such as injection of formalin or capsaicin (Birch et al, 1992;Nagahisa et al, 1992;Rupniak et al, 1995;Santos and Calixto, 1997). However, this effect is not specific to the antagonists action on the NK1 receptor since similar levels of attenuation occur with the less active enantiomers (Nagahisa et al, 1992;Rupniak et al, 1995;Smith et al, 1994). These observations suggest that the antinociception produced by local or systemic application of NK1 antagonists is produced by mechanisms other than or in addition to those mediated by the NK1 receptor.…”

“…The results described above indicate that SP and its receptor, NK1, play a prominent role in the processing of nociceptive stimuli; however, attempts to block noxious stimulus evoked pain behaviors with NK1 antagonists have yielded mixed results. Systemic and intraplantar application of NK1 antagonists attenuate the pain response to noxious chemical stimulation, such as injection of formalin or capsaicin (Birch et al, 1992;Nagahisa et al, 1992;Rupniak et al, 1995;Santos and Calixto, 1997). However, this effect is not specific to the antagonists action on the NK1 receptor since similar levels of attenuation occur with the less active enantiomers (Nagahisa et al, 1992;Rupniak et al, 1995;Smith et al, 1994).…”

Transmission pathways and mediators as the basis for clinical pharmacology of pain

“…This is demonstrated by a multitude of animal studies from the past that focus on the role of NK receptors in pain transmission [167 - 169]. However, when the results of animal studies were applied to a human model, action at neurokinin receptors was not found to be more effective than established pain treatments (ibuprofen and pregabalin) [170, 171].…”