The effects of sham and full spinalization on the systemic potency of μ‐ and κ‐opioids on spinal nociceptive reflexes in rats

Abstract

1 Flexor withdrawal reflexes to noxious mechanical pinch stimuli were recorded as single motor unit activity in a-chloralose anaesthetized rats, by means of tungsten bipolar electrodes inserted percutaneously into hindlimb flexor muscles. The relative spinal and supraspinal contributions to y-and K-opioid agonists in inhibiting these spinal reflexes, together with possible potency changes elicited by surgical trauma, were examined by comparing their relative potencies in spinally unoperated, sham spinalized and spinalized rats. 2 The noxious stimuli, which were of comparable intensity in the three groups, elicited similar mean firing rates of the motor units in all groups. This indicates that the excitability levels in the reflex pathway were not greatly affected by either sham or actual spinalization. 3 The ,-agonists morphine and fentanyl, and the K-agonist U-50,488H, inhibited the reflexes in a dosedependent manner, when administered intravenously in a log2 cumulative dose regime. 4 The surgery of sham spinalization had little effect on the potency of morphine and fentanyl, whereas it doubled the potency of U-50,488. 5 Spinalization did not affect the potency of morphine. In contrast it decreased the potency of fentanyl 2-4 fold and that of U-50,488 approximately 6 fold. 6 The effects of all agonists were antagonized by naloxone. Dose-dependence studies indicating that antagonism of U-50,488H required about 5 times the dose of naloxone that antagonized morphine. 7 The data suggest that surgical trauma to the spinal column and/or dura mater triggers supraspinal mechanisms that significantly enhance the potency of K-but not P-agonists.8 It is concluded that most of the effects of systemic morphine on spinal reflexes are mediated, under all three conditions tested, by direct effects in the spinal cord. In contrast, the inhibition of reflexes by U-50,488H is mediated at both spinal and supraspinal levels, the latter being enhanced in the presence of surgical trauma. The differences between morphine and fentanyl remain unexplained.

Enhancement of fentanyl antinociception by subeffective doses of nitroparacetamol (NCX-701) in acute nociception and in carrageenan-induced monoarthritis

“…However, it is possible to infer that the action does not take place as a result of a direct action on the opioid receptor, since no reversal was observed with the opioid-receptor antagonist naloxone at a dose capable of reverse antinociceptive actions of mu and kappa opioid receptors in similar experiments (Herrero and Headley, 1991). This is supported by previous studies in which a potentiation of morphine antinociception by the NSAID metamizol was not reversed by naloxone (Taylor et al, 1998).…”

“…Experiments were performed on 250 to 330 g male Wistar rats following the technique described previously in detail (Herrero and Headley, 1991;Solano and Herrero, 1997;Romero-Sandoval et al, 2003). Briefly, rats were initially anaesthetized with halothane (5% in oxygen for induction and 2% for maintenance).…”

Reversal by naloxone of the spinal antinociceptive actions of a systemically‐administered NSAID

“…Two aspects of the results obtained in these experiments indicate that the NSAID flunixin does not act as an opioid agonist. Firstly, in rats with normal paws it had little activity under conditions in which p-opioid (as here) and K-opioid agonists are effective (Herrero & Headley, 1991). Secondly, the small effects it had were not reversed by a dose of naloxone high enough to block actions mediated at both p-and K-opioid receptors (see Herrero & Headley, 1991) but not a2-adrenoceptors (as shown here).…”

“…Details of methods have been described previously (Hartell & Headley, 1991;Herrero & Headley, 1991 1 Hz,16 stimuli, during which frequencydependent facilitation ('wind-up') occurred; Mendell, 1966).…”

Kappa opioids and the modulation of pain

“…Visceral nociceptor afferents are colocalized with sommatocutaneous afferents in the dorsal root ganglion and in the dorsal horn, and this often contributes to somatic referred pain accompanying visceral nociception . KOP agonists have been found to be antinociceptive in both cutaneous and in mechanical visceral nociceptive models (Burton and Gebhart 1998;Herrero and Headley 1991). In experimental models of visceral pain they have been shown to be effective analgesics (reviewed in (Rivière 2004)).…”