Differential antinociceptive effects induced by intrathecally administered endomorphin-1 and endomorphin-2 in the mouse
Introduction
Endomorphin-1 and endomorphin-2 are two recently discovered endogenous peptides which selectively activate μ-opioid receptors Zadina et al., 1997, Goldberg et al., 1998, Gong et al., 1998, Hosohata et al., 1998. Immunoreactivities to these peptides are localized in many areas of the central nervous system involved in pain processing, including the dorsal horn of the spinal cord, trigeminal nucleus, and the periaqueductal gray Martin-Schild et al., 1997, Martin-Schild et al., 1998, Martin-Schild et al., 1999, Pierce et al., 1998. In the spinal cord, endomorphin-like immunoreactivity is found in the superficial laminae of the dorsal horn, where endomorphin-2 is co-localized with substance P and calcitonin gene-related peptide. Moreover, dorsal rhizotomy or capsaicin treatment abolishes endomorphin-2-immumoreactivity in the dorsal horn Martin-Schild et al., 1998, Pierce et al., 1998. Thus, it is likely that endomorphins are present in terminals of primary sensory afferents Martin-Schild et al., 1997, Martin-Schild et al., 1998, Martin-Schild et al., 1999, Pierce et al., 1998. Some differences have been noted for the distribution of endomorphin-1 and endomorphin-2 in the brain and spinal cord. Endomorphin-1 is seen more than endomorphin-2 in the brain, whereas endomorphin-2 dominates in the spinal cord (Martin-Schild et al., 1999). Both of these peptides display high affinity and selectivity for the μ-opioid receptor in vivo and in vitro. Neither endomorphin had appreciable affinity for δ- and κ-opioid receptors (Zadina et al., 1997). Distinct pharmacological properties of endomorphins have been reported in both electrophysiological (Chapman et al., 1997) and behavioral experiments Zadina et al., 1997, Stone et al., 1997, Goldberg et al., 1998, Tseng et al., 2000. The antinoception induced by endomorphin-1 and endomorphin-2 given intrathecally (i.t.) or intracerebroventricularly (i.c.v.) is selectively blocked by pretreatment with the non-selective opioid receptor antagonist, naloxone or the μ-opioid receptor antagonist, β-funaltrexamine Stone et al., 1997, Zadina et al., 1997, Goldberg et al., 1998, indicating that they are mediated by the stimulation of μ-opioid receptors. Furthermore, pretreatment with the μ1-opioid receptor antagonist, naloxonazine, attenuates the antinociception induced by i.t. administered endomorphin-2 but not by endomorphin-1, suggesting that endomorphin-2-induced antinociception may be mediated by the stimulation of μ1-opioid receptors Sakurada et al., 1999, Sakurada et al., 2000a.
Although antinociceptive effects induced by both endomorphin-1 and endomorphin-2 are mediated by the stimulation of μ-opioid receptors, some differential antinociceptive effects induced by endomorphin-1 and endomorphin-2 have been noted. The antinociception induced by endomorphin-2, but not by endomorphin-1, is blocked by pretreatment with antiserum against dynorphin A-(1-17) and by the κ-opioid receptor antagonist nor-binaltorphimine, indicating that endomomorphin-2 appears to stimulate a different subtype of μ-opioid receptor, which subsequently induces the release of dynorphins that act on κ-opioid receptors to produce antinociception (Tseng et al., 2000). Intrathecal pretreatment with antiserum against dynorphin A-(1-17) or [Met5]enkephalin blocks the antinociception induced by supraspinally administered endomorphin-2 but not endomorphin-1, indicating that endomorphin-2 but not endomophin-1 given supraspinally releases both dynorphins and [Met5]enkephalin from the spinal cord to produce antinociception (Ohsawa et al., 2000). The present study was conducted to determine whether there are any differential actions of endomorphin-1 and endomorphin-2 administered on production of antinociception in the mouse. We found that antinociceptive effects induced by both endomorphin-1 and endomorphin-2 given i.t. are initially mediated by the stimulation of μ-opioid receptors, the endomorphin-2-induced antinociception contains an additional component, that is mediated by the release of dynorphin A-(1-17) and [Met5]enkephalin acting on κ- and δ-opioid receptors, respectively.
Section snippets
Animal
Adult male ddY mice weighing 22–25 g were housed in a light- and temperature-controlled room (light on 0900–2100 h; 24 °C) and had free access to food and water. The experiments were performed with the approval of the Committee of Animal Experiments at Tohoku Pharmaceutical University.
Drugs
Endomorphin-1 and endomorphin-2 were synthesized in our laboratory. Endomorphins were prepared by the Fmoc strategy using a Shimadzu PSSM-8 peptide synthesizer (Kyoto, Japan) in our laboratory. After cleavage the
Time course of paw-withdrawal responses to i.t.-administered endomorphin-1 and endomorphin-2
Groups of mice were injected i.t. with CSF and different doses of endomorphin-1 and endomorphin-2, and the paw-withdrawal responses were measured 1, 5, 10, 15 and 20 min after injection. The i.t.-injection of endomorphin-1 and endomorphin-2 at doses of 0.039–5.0 nmol caused a dose-dependent increase in intensity and duration of the inhibition of the paw-withdrawal response. The inhibition reached its peak rapidly 1 min after injection, rapidly declined, and returned to the preinjection levels
Discussion
Endomorphin-1 and endomorphin-2 given i.t. are about equipotent in inhibiting the tail pressure (Sakurada et al., 1999) and the paw withdrawal responses. The peak effects appeared rapidly 1 min after i.t. administration, declined rapidly, and returned to the control level in 15 min. The rapid onset of antinociception after i.t. administration of endomorphins are in agreement with those of Stone et al. who reported a rapid onset and short duration of the hot-water tail-flick inhibition induced
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