Studies on Transgenic Animals

16 May

The background presence of B2 receptors and the inducible nature of B1 recep- tors combine to make it difficult to assess the individual role of each receptor in pain and inflammation  and hence which would make the best analgesic drug discovery target. The emergence of transgenic technology has thus been of crucial help in this research area.

The first knock-out produced (Borkowki et al. 1995) had a deletion of the entire coding region of the B2 receptor gene. These mice are fertile and visually indistinguishable from WT littermates. Bradykinin fails to produce responses in ileum, uterus and superior cervical ganglia (SCG) in these mice, all tissues which express functional  B2 receptors  in WT mice (Borkowki et al. 1995). The nociceptive response to intraplantar injection of bradykinin  was absent in the −/−  mice and there  was no hyperalgesia following paw injection  of carrageenan;  however, the nociceptive response  to formalin was preserved, as was the induction of thermal hyperalgesia following intraplantar Freund’s adjuvant (Rupniak et al. 1997b).

Electrophysiological studies in isolated SCG showed that expression of func- tional B1 receptors was stimulated by IL-1β in ganglia taken from the B2(−/−) mice (Seabrook et al. 1997), suggesting that  the remaining  nociceptive re- sponses were operated  through  B1 receptors. This was confirmed in studies on a mouse in which the B1 receptor  gene had been inactivated  (Pesquero et al. 2000). These mice are healthy, fertile and normotensive  yet have a re- duced response to inflammation  with LPS. Surprisingly, in the absence of any

inflammatory stimulus these mice are analgesic in tests of thermal and chem- ical nociception in a similar manner to mice treated with an opioid analgesic. In an isolated spinal cord preparation there was a reduction  in wind up of a nociceptive spinal reflex (Pesquero et al. 2000).

In contrast to the B2(−/−) mouse, in the B1(−/−) mouse thermal hyperalge- sia following intraplantar CFA is absent both ipsilateral and, to a lesser extent, contralateral  to the injected paw, reinforcing the idea that it is the spinal B1 receptors which are crucial to spinal cord sensitisation in the nociceptive pro-

cess (Calixto et al. 2001; Ferreira et al. 2001). Intrathecal injection of selective B1 or B2 receptor agonists failed to produce thermal hyperalgesia in the re- spective −/− mice, confirming  a functional  role at the spinal level for both receptors (Ferreira et al. 2002). Partial lesion of the sciatic nerve in B1(−/−) mice produced much less mechanical allodynia and thermal hyperalgesia than was seen in WT animals subjected to the same procedure (Ferreira et al. 2005). In response to the pronounced species-to-species differences in the pharma- cology of the B1 receptor, both rats (Hess et al. 2004) and mice (Fox et al. 2005) have been engineered to express the human B1 receptor so as to facilitate the evaluation of antagonists at the human B1 receptor as putative analgesics (see the following section).

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