Comparison of the effects of calmidazolium, morphine and bupivacaine on N-methyl-d-aspartate- and septide-induced nociceptive behaviour

Abstract

We have recently shown that spinal calmodulin inhibitors (W-7 and calmidazolium) dose-dependently inhibit the nociceptive reaction (biting, scratching, licking, BSL) evoked by intrathecal N-methyl-d-aspartate (NMDA) and septide, an agonist of the neurokinin (NK) NK₁ receptor. To compare this effect with that induced by standard analgesics, we now report a study of the effects of calmidazolium (14–420 nmol), bupivacaine (29–582 nmol) and morphine (26–260 nmol) when coadministered intrathecally with either NMDA (4 µg) or septide (0.5 µg). Calmidazolium had the highest potency for inhibiting septide-induced nociceptive behaviour, acting over a dose range of 34–130 nmol (dose eliciting a half-maximal response, ED₅₀, 67 nmol) lower than that of bupivacaine [ED₅₀ 234 (115–475) nmol]. Only the highest dose of morphine (260 nmol) inhibited septide-evoked BSL [ED₅₀=133 (69–255) nmol]. Higher doses of morphine could not be tested due to the appearance of an excitatory aversive reaction. Both calmidazolium [ED₅₀=232 (138–388) nmol] and bupivacaine [ED₅₀=123 (59–256) nmol] dose-dependently reduced NMDA-induced BSL reaching an almost maximal inhibition at the highest doses assayed (420 and 291 nmol, respectively). In contrast, morphine had less effect on NMDA-induced behaviour, inducing only a partial reduction of BSL even with the highest dose assayed (260 nmol). Overall, it can be concluded that the calmodulin inhibitor calmidazolium inhibits septide- and NMDA-evoked nociceptive behaviour with a potency and efficacy at least as high as those of morphine and bupivacaine.