Involvement of endogenous opioid peptides in the antinociception induced by the novel dermorphin tetrapeptide analog amidino-TAPA

Lack of a rewarding effect and a locomotor-enhancing effect of the selective μ-opioid receptor agonist amidino-TAPA

“…As we reported previously, amidino-TAPA has a pharmacological profile that is distinct from the traditional μ-opioid receptor agonists, including the release of endogenous κ-opioid peptides via activation of μ-opioid receptors (Mizoguchi et al 2007). The activation of κ-opioid receptors is well known to suppress the development of psychological dependence on and the locomotor-enhancing effect of μ-opioid receptor agonists Narita et al 1993).…”

“…We previously reported that intrathecally administered amidino-TAPA causes the release of the endogenous κ-opioid peptides dynorphin A, dynorphin B, or α-neoendorphin in the spinal cord to produce the antinociception (Mizoguchi et al 2007). To elucidate the involvement of endogenous κ-opioid peptides in the antinociception induced by s.c.-administered amidino-TAPA, prodynorphin-knockout mice, which lack the precursor for the endogenous κ-opioid peptides, and wild-type C57BL/6J mice were used.…”

“…Since the rewarding effect as well as the analgesic effect of narcotic analgesics is mediated through μ-opioid receptors (Herz and Spanagel 1995), there are currently no opioid analgesics available in the clinic that have high potency and efficacy for antinociception without a rewarding effect. Amidino-TAPA is a selective μ-opioid receptor agonist that we have recently developed as a new peptidic analgesic (Ogawa et al 2002a, b;Mizoguchi et al 2007). In the present study, amidino-TAPA injected s.c. was approximately 13 times more potent than morphine in a behavioral assay for antinociception.…”

“…Because of its high affinity and selectivity for μ-opioid receptors, amidino-TAPA produces an extreme potent and long-lasting antinociception in mice (Ogawa et al 2002a, b;Mizoguchi et al 2007). Its potency for antinociception in mice is approximately 10 times and 400 times higher than that of morphine by the subcutaneous (s.c.) and intrathecal injection routes, respectively (Mizoguchi et al 2007;Ogawa et al 2002a, b;Sato et al 1999). Unlike most peptidic analgesics, which are generally ineffective by oral administration, amidino-TAPA is effective for antinociception by oral administration with a slightly higher potency than morphine (Ogawa et al 2002a, b).…”

“…Unlike most peptidic analgesics, which are generally ineffective by oral administration, amidino-TAPA is effective for antinociception by oral administration with a slightly higher potency than morphine (Ogawa et al 2002a, b). Interestingly, amidino-TAPA has an antinociceptive mechanism in the spinal cord that is distinct from the traditional μ-opioid receptor agonist [D-Ala 2 -N-Me-Phe 4 , Gly-ol 5 ]-enkephalin (DAMGO) (Mizoguchi et al 2007). Unlike DAMGO, the antinociception induced by amidino-TAPA is mediated through the release in the spinal cord of the endogenous κ-opioid peptides dynorphin A, dynorphin B, and α-neo-endorphin and the endogenous δ-opioid peptide [Leu 5 ]enkephalin, which are released by the activation of μ-opioid receptors.…”