Distinct physiological role of amidino-TAPA-sensitive and DAMGO-insensitive μ-opioid receptor splice variants in the mouse spinal cord.

Abstract The physiological role of the distinct splice variants for cloned mouse μ-opioid receptor (mMOR-1), mMOR-1J, mMOR-1K and mMOR-1L, which are sensitive to N α -amidino-Tyr- d -Arg-Phe-β-Ala (amidino-TAPA) and insensitive to [ d -Ala 2 , N -MePhe 4 ,Gly-ol 5 ]enkephalin (DAMGO), was described in the mouse spinal cord. The antinociception induced by intrathecally (i.t.) injected amidino-TAPA was attenuated by i.t. pretreatment with antisera against the endogenous opioid peptides dynorphin A, dynorphin B, α-neo-endorphin, or [Leu 5 ]enkephalin in naive mice. However, in mice whose spinal mMOR-1J had been knocked-down using the antisense oligodeoxynucleotide (ODN) for exon-12 of mMOR-1 gene, the inhibiting effect of antiserum against dynorphin A on amidino-TAPA-induced antinociception was eliminated. In contrast, the inhibiting effect of antisera against dynorphin B or α-neo-endorphin on amidino-TAPA-induced antinociception was eliminated in mice whose spinal mMOR-1K had been knocked-down using the antisense ODN for exon-13 of mMOR-1 gene. Moreover, the inhibiting effect of antisera against dynorphin A or [Leu 5 ]enkephalin on amidino-TAPA-induced antinociception was eliminated in mice whose spinal mMOR-1L had been knocked-down using the antisense ODN for exon-14 of mMOR-1 gene. The present results suggest that the distinct antinociceptive profile of amidino-TAPA, that is the release of endogenous κ- and δ-opioid peptides in spinal cord, is mediated through the activation of mMOR-1J, mMOR-1K or mMOR-1L, which contain the sequence encoded by exon-12, exon-13 or exon-14 of mMOR-1 gene, respectively.