Although HA has an H1-mediated pronociceptive (i.e. pain-enhancing) effect on afferent fibres (and possibly in the spinal cord), HA is able to activate antinociceptive (pain-relieving)
responses in the brain stem through an action on both H1 and H2 receptors (Glick and Crane 1978; Thoburn et al. 1994). Inhibitors of brain HA metabolism also have analgesic activity (Malmberg-Aiello et al. 1997). Based on these findings, one would expect a HA-releasing drug like thioperamide to induce analgesia, but it does not (Li et al. 1996). H1 antagonists block HA analgesia, but these drugs also have their own analgesic properties, depending on the test and the species. It is not clear to what extent these effects represent actions at peripheral versus CNS H1 receptors (Ghelardini et al. 1998; Mobarakeh et al. 2000; Rumore and Schlichting 1986; Olsen et al. 2002). It does seem clear, however, that brain H2 receptor activation is an important component of both opioid and stress-induced non-opioid pain-relieving responses (Barke and Hough 1994; Hough and Nalwalk 1992; Hough et al. 1990; Gogas and Hough 1989). The findings that H2 agonists do not penetrate the blood-brain barrier and that some of these drugs produce brain damage (Swaab et al. 1992) has limited development of new analgesics based on the H2 receptor.
In doses larger than those needed to block HA receptors, several (but not all) H2 and H3 antagonists induce powerful morphine-like pain relief when injected directly into the brain (Hough et al. 1997, 2000). The prototype analgesic discovered in these studies, named improgan, is derived from the H2 antagonist cimetidine. In contrast with cimetidine, however, improgan lacks activity at over 50 receptors, including all known HA and opioid receptors (Hough et al. 2000; Hough 2001). Impentamine, a congener of HA, also induces improgan-like analgesia, suggesting the possibility that these drugs act at an unknown HA receptor, but this has not been established (Hough et al. 1999).
Was this article helpful?