title: The effects of sham and full spinalization on the systemic potency of mu- and kappa-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 alpha-chloralose anaesthetized rats, by means of tungsten bipolar electrodes inserted percutaneously into hindlimb flexor muscles. The relative spinal and supraspinal contributions to mu- and kappa-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 mu-agonists morphine and fentanyl, and the kappa-agonist U-50,488H, inhibited the reflexes in a dose-dependent 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 kappa- but not mu-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.
authors.affiliation: Department of Physiology, School of Medical Sciences, University of Bristol.
authors.forename: J F
authors.initials: JF
authors.lastname: Herrero
authors.forename: P M
authors.initials: PM
authors.lastname: Headley
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D003655:Decerebrate State / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009270:Naloxone / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000503:physiopathology; D010812:Physical Stimulation; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D012018:Reflex / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects*
chemical_list: D000700:Analgesics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D005283:Fentanyl