A F Sullivan

Publications (34)96.52 Total impact

• Article: Differential modulation of alpha 2-adrenergic and opioid spinal antinociception by cholecystokinin and cholecystokinin antagonists in the rat dorsal horn: an electrophysiological study.

  A F Sullivan, K Hewett, A H Dickenson
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  ABSTRACT: Cholecystokinin (CCK) has been shown to reduce the spinal antinociceptive effects of opioid agonists such as morphine. The present study examined the effect of CCK and CCKB antagonists on the spinal antinociception mediated by the selective alpha 2-adrenergic agonist dexmedetomidine. Extracellular recordings of noxious-evoked C fibre responses of dorsal horn convergent neurones were made in the halothane-anaesthetized rat. Alone, intrathecal dexmedetomidine (5 micrograms) profoundly inhibited C fibre-evoked responses (92 +/- 7%). In the presence of 1 microgram intrathecal CCK the antinociceptive effect of dexmedetomidine was reduced to 27 +/- 11%. Inhibitions of C fibre-evoked responses mediated by submaximal doses (0.5 and 2.5 micrograms) dexmedetomidine were not altered by CCKB antagonists L365,260 (0.2 mg/kg subcutaneous) or PD135158 (10 micrograms intrathecal). Both CCKB antagonists did increase the inhibition of C fibre-evoked responses by the mu opioid agonists DAGOL and morphine. The results suggest CCK is able to inhibit spinal antinociception mediated via the activation of alpha 2-adrenergic receptors in addition to its well-documented interaction with spinal opioid analgesia. However the antagonist studies indicate an endogenous CCK control of spinal mu opioid mediated antinociception which does not extend to alpha 2-adrenergic antinociception.
  Brain Research 11/1994; 662(1-2):141-7. · 2.73 Impact Factor
• Article: Cross-tolerance between mu opioid and alpha-2 adrenergic receptors, but not between mu and delta opioid receptors in the spinal cord of the rat.

  E A Kalso, A F Sullivan, H J McQuay, A H Dickenson, B P Roques
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  ABSTRACT: Intrathecal administration of morphine, Tyr-D-Ser(otbu)-Gly-Phe-Leu-Thr or dexmedetomidine for 5 to 10 days rendered rats tolerant to the test drug as measured by both behavioral and electrophysiological tests. Tolerance to the alpha-2 adrenergic agonist dexmedetomidine required a longer induction time and was not as pronounced as the tolerance to the opioid agonists, probably because lower doses of dexmedetomidine relative to the ED50 dose were used to avoid sedation. In the behavioral studies we used the tail-flick test and in the electrophysiological studies recordings were made from dorsal horn nociceptive neurons under halothane anesthesia. After completion of the behavioral testing the same animals were then used in the electrophysiological study. Cross-tolerance developed clearly between the mu opioid agonist morphine and the alpha-2 adrenergic agonist dexmedetomidine, whereas no cross-tolerance was seen between the delta opioid agonist Tyr-D-Ser(otbu)-Gly-Phe-Leu-Thr and either morphine or dexmedetomidine. This is further evidence to support the assumption that in the dorsal horn the mu opioid and the alpha-2 adrenergic receptor are linked functionally, whereas the delta opioid receptor operates independently. These results have also important clinical implications indicating the potential of delta opioid agonists to restore analgesia in a morphine-tolerant patient.
  Journal of Pharmacology and Experimental Therapeutics 06/1993; 265(2):551-8. · 3.83 Impact Factor
• Article: Alterations in neuronal excitability and the potency of spinal mu, delta and kappa opioids after carrageenan-induced inflammation.

  L C Stanfa, A F Sullivan, A H Dickenson
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  ABSTRACT: These electrophysiological results show that the development of inflammation following peripheral injection of carrageenan into the paw is accompanied by alterations in the magnitude of the C-fibre evoked response of multireceptive dorsal horn neurones. The evoked response of the dorsal horn cells was found to either increase or decrease in the 3 h following the carrageenan injection, and the direction of this change was related to the degree of wind-up exhibited by the cell. Regardless of whether a cell was facilitated or inhibited by carrageenan, mu, delta and kappa opioids applied topically onto the spinal cord (equivalent to an intrathecal injection) exhibited increased antinociceptive potency. This increased effectiveness was especially marked for the mu opioid, morphine, which showed a 30-fold increase in potency. Interestingly the facilitations seen with the lowest doses of the mu and kappa opioids in this model in normal animals were absent after carrageenan. In addition, a very low dose of spinal naloxone caused a small but significant reduction in the C-fibre evoked responses. These results demonstrate that following peripheral inflammation, functional changes develop in both spinal transmission and modulatory systems. Alterations in the antinociceptive potency of opioid agonists occurs, with the mu agonist, morphine, showing the greatest change.
  Pain 10/1992; 50(3):345-54. · 5.78 Impact Factor
• Article: Evidence for the involvement of the mu but not delta opioid receptor subtype in the synergistic interaction between opioid and alpha 2 adrenergic antinociception in the rat spinal cord.

  A F Sullivan, E A Kalso, H J McQuay, A H Dickenson
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  ABSTRACT: The interaction between the spinal antinociceptive effects of selective mu or delta opioid agonists morphine and DSTBULET (Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr), respectively, and the selective alpha 2 adrenergic agonist dexmedetomidine was examined on convergent dorsal horn neuronal responses in the intact anaesthetized rat. The coadministration of intrathecal morphine (0.5 microgram, 2.5 micrograms) and dexmedetomidine (0.5 microgram) produced a greater than additive inhibition of C fibre-evoked responses. Inhibitions were reversed by either the opioid antagonist naloxone or the alpha 2 adrenergic antagonist atipamezole. The coadministration of intrathecal DSTBULET (1 microgram, 2.5 micrograms) and dexmedetomidine did not result in a supra-additive inhibition of C fibre-evoked responses. The results suggest that mu rather than delta opioid receptors are involved in the synergism of spinal opioid and alpha 2 adrenergic antinociception.
  Neuroscience Letters 06/1992; 139(1):65-8. · 2.11 Impact Factor
• Article: Spinal antinociception by Tyr-D-Ser(otbu)-Gly-Phe-Leu-Thr, a selective delta-opioid receptor agonist.

  E A Kalso, A F Sullivan, H J McQuay, A H Dickenson
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  ABSTRACT: The spinal antinociceptive potency of the delta-opioid receptor agonist, Tyr-D-Ser(otbu)-Gly-Phe-Leu-Thr (DSTBULET), was studied in rats. The tail flick test was used as nociceptive stimulus and the rotarod test was used to detect any motor or sedative effects. A dose-response curve was also made for the mu-opioid receptor agonist, morphine. The ED50 for DSTBULET was 0.3 micrograms (0.4 nmol) and a near 100% maximum effect was achieved with 5 micrograms (7.5 nmol). No motor or sedative effects were detected. Antinociception by DSTBULET was antagonized by s.c. naltrindole (1 mg/kg), a selective delta-opioid receptor antagonist, and naloxone (1 mg/kg), a non-selective opioid receptor antagonist. The ED50 for morphine was 0.5 micrograms (1.0 nmol) and the antinociceptive effects were not antagonized by naltrindole (1 mg/kg). The results evidence further the important role of the delta-opioid receptor in spinal nociceptive processing.
  European Journal of Pharmacology 06/1992; 216(1):97-101. · 2.52 Impact Factor
• Article: The antinociceptive actions of dexmedetomidine on dorsal horn neuronal responses in the anaesthetized rat.

  A F Sullivan, E A Kalso, H J McQuay, A H Dickenson
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  ABSTRACT: The actions of the selective alpha 2-adrenoceptor agonist dexmedetomidine were examined on the nociceptive C and innocuous A beta fibre-evoked responses of dorsal horn neurones to transcutaneous electrical stimulation in the intact anaesthetized rat. C fibre-evoked responses were dose dependently reduced by intrathecal dexmedetomidine--to a maximum 86 +/- 6% inhibition by 10 micrograms of the agonist. The ED50 for inhibition of C fibre responses was estimated to be 2.5 micrograms. A beta-evoked responses were inhibited to a lesser degree--a maximum 54 +/- 8% inhibition after 10 micrograms dexmedetomidine. The antinociceptive effects of dexmedetomidine were reversed by the alpha 2-adrenoceptor antagonist atipamezole and the opioid antagonist naloxone. The results are discussed with reference to adrenergic and opioid mechanisms in the spinal cord.
  European Journal of Pharmacology 05/1992; 215(1):127-33. · 2.52 Impact Factor
• Article: Dextromethorphan and levorphanol on dorsal horn nociceptive neurones in the rat.

  A H Dickenson, A F Sullivan, L C Stanfa, H J McQuay
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  ABSTRACT: Intrathecal administration of dextromethorphan and levorphanol and intravenous injection of dextromethorphan were tested on the electrophysiological response of deep multireceptive dorsal horn neurones to peripheral stimuli. Both blockade of C-fibre input to the cells and wind-up, the increase in C-fibre firing with repeated stimulus, were recorded. Intrathecal injection of levorphanol (0.25-100 micrograms) had a typical opioid effect, blocking the C-fibre input. Its affect on wind-up was dose-dependent, paralleled precisely the blocking effect on the C-fibre input and both effects were reversed by naloxone. Unlike levorphanol and other opiates, intrathecal administration of dextromethorphan (50-500 micrograms) blocked the C-fibre input and A beta response in parallel and was not reversed by naloxone. Wind-up was reduced by a maximum of 56% at the largest dose tested. Intravenous injection of dextromethorphan (5 mg/kg) also produced a reduction in wind-up but not in the C-fibre response.
  Neuropharmacology 01/1992; 30(12A):1303-8. · 4.81 Impact Factor
• Article: FLFQPQRF-amide modulates alpha 2-adrenergic antinociception in the rat dorsal horn in vivo.

  A F Sullivan, E A Kalso, H J McQuay, A H Dickenson
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  ABSTRACT: The interaction between FLFQPQRFamide and alpha 2-adrenergic spinal antinociception was examined in an electrophysiological study in the intact anaesthetised rat. The inhibition of C fibre-evoked neuronal responses by the selective alpha 2-adrenergic agonist dexmedetomidine was significantly reduced by intrathecal FLFQPQRFamide pretreatment. The results suggest a modulatory role of FLFQPQRFamide in spinal alpha 2-adrenergic antinociception.
  Brain Research 11/1991; 562(2):327-8. · 2.73 Impact Factor
• Article: NMDA receptors and central hyperalgesic states.

  A H Dickenson, A F Sullivan
  Pain 10/1991; 46(3):344-6. · 5.78 Impact Factor
• Article: Electrophysiologic studies on the spinal antinociceptive action of kappa opioid agonists in the adult and 21-day-old rat.

  A F Sullivan, A H Dickenson
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  ABSTRACT: The spinal antinociceptive actions of the selective kappa opioid receptor agonists U50488H and U69593 were investigated in anesthetized adult rats and 21-day-old rat pups. Single unit extracellular recordings were made of dorsal horn neurons responding to both innocuous and noxious peripheral stimuli. Mixed effects on neuronal responses were seen after intrathecal administration of lower doses of the kappa agonists but with higher doses selective inhibitions of C fiber-evoked responses were produced by either U50488H or U69593 in both the adult (ED50 420 and 250 micrograms, respectively) and pup (ED50 63 and 13 micrograms, respectively). In the adult intrathecal U50488H similarly inhibited the more prolonged nociceptive response evoked by s.c. formalin. Intravenous U50488H (4 mg/kg) also produced a rapid and selective inhibition of nociceptive responses in the adult rat. Intrathecal administration of the nonselective opiate antagonist naloxone reduced the inhibitions mediated by U50488H and U69593 in the pup and the adult. However, intrathecal norbinaltorphimine, a selective kappa antagonist, only prevented the action of the kappa agonists in the pup and not in the adult. Kappa receptors are reported to be sparse in the adult rat spinal cord so developmental changes in this receptor may be responsible for the differential action of norbinaltorphimine in the rat pup and adult.
  Journal of Pharmacology and Experimental Therapeutics 04/1991; 256(3):1119-25. · 3.83 Impact Factor
• Article: Antinociception produced by capsaicin: spinal or peripheral mechanism?

  A Dickenson, N Ashwood, A F Sullivan, I James, A Dray
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  ABSTRACT: We have studied the effects of capsaicin, administered at concentrations found to be antinociceptive in behavioural tests, on nociceptive responses evoked both in spinal dorsal horn neurons in vivo and in spinal ventral roots in vitro. In halothane anesthetized rats, C-fibre evoked input produced by transcutaneous electrical stimulation in the peripheral receptive field was recorded from single wide dynamic range neurons located in superficial and deep dorsal horn of the lumbar spinal cord. This input was reduced by systemic administration of capsaicin at an antinociceptive dose (20 mumol/kg s.c.). Intradermal injections of capsaicin localized to the peripheral receptive field produced a transient increase in C-fibre evoked activity followed by a prolonged period of localized insensitivity to C-fibre stimulation. Spinal i.t. administered capsaicin also produced a rapid but reversible attenuation of peripherally evoked C-fibre input. In a neonatal rat spinal cord-tail preparation maintained in vitro, superfusion of the spinal cord with capsaicin (100-500 nM) produced a transient depolarization which was followed by an attenuation of responses to peripheral noxious heat and to spinal administration of substance P. Similar activity was produced by a prolonged superfusion of the spinal cord with substance P (50-200 nM). An HPLC method was used to estimate the concentration of capsaicin in a number of tissues following s.c. administration at an antinociceptive dose. In addition capsaicin concentrations were determined in the spinal cord following an i.t. administration.(ABSTRACT TRUNCATED AT 250 WORDS)
  European Journal of Pharmacology 11/1990; 187(2):225-33. · 2.52 Impact Factor
• Article: Intrathecal etorphine, fentanyl and buprenorphine on spinal nociceptive neurones in the rat.

  A H Dickenson, A F Sullivan, H J McQuay
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  ABSTRACT: Single unit recordings were made in the lumbar dorsal horn in the intact anaesthetized rat from convergent, multireceptive neurones. Activity was evoked by A beta and C fibre transcutaneous electrical stimulation of hind paw receptive fields. Three opioids, fentanyl, etorphine and buprenorphine were applied either intrathecally or intravenously and their effects on neuronal responses were examined. Intrathecal fentanyl and etorphine produced clear selective naloxone-reversible inhibitions of C fibre-evoked responses (ED50 = 24 micrograms and 0.6 micrograms respectively). Fentanyl, a mu opioid receptor agonist, was more potent at a given dose when given systemically, but etorphine, a non-selective opioid agonist, was similarly potent by both routes. In contrast to fentanyl and etorphine, intrathecal buprenorphine produced facilitations of C fibre-evoked responses at a low dose (15 micrograms), but inhibited both C and A beta fibre-evoked responses equally at a higher dose (125 micrograms). Inhibitions were found to be irreversible by naloxone. No inhibition of either C or A beta responses occurred following intravenous buprenorphine (10-1070 micrograms). The results are discussed in the light of the relationships between lipophilicity, opioid receptor selectivity and potency for spinally applied opioids.
  Pain 09/1990; 42(2):227-34. · 5.78 Impact Factor
• Article: Differential interactions of cholecystokinin and FLFQPQRF-NH2 with mu and delta opioid antinociception in the rat spinal cord.

  D S Magnuson, A F Sullivan, G Simonnet, B P Roques, A H Dickenson
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  ABSTRACT: An in vivo preparation of the rat spinal cord was used to investigate the electrophysiological actions of two non-opioid peptides, cholecystokinin (CCK8) and FLFQPQRF-NH2 (FMRFamide-like peptide) applied intrathecally. These compounds were examined alone and as a pretreatment before DAGO, a mu opioid agonist, and DSTBULET, a delta opioid agonist, both which selectively reduce C-fibre evoked dorsal horn neurone activity elicited by transcutaneous electrical stimulation. Given alone, CCK8 (1 microgram) elicited a modest enhancement of C-fibre induced activity which returned to control levels after 20 min, while FLFQPQRF-NH2 (10 micrograms) had no significant effect on C-fibre evoked firing. As a pretreatment, however, both peptides selectively prevented the inhibition of C-fibre evoked activity normally resulting from intrathecal DAGO, while having no effect on that resulting from DSTBULET. Further, CCK8 enhanced the facilitation of C-fibre evoked firing normally observed with low doses of DAGO. These data indicate that the anti-opioid roles suggested for CCK8 and FLFQPQRF-NH2 may be specific for neural elements utilizing the mu opioid receptor.
  Neuropeptides 09/1990; 16(4):213-8. · 1.55 Impact Factor
• Article: Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat.

  J E Haley, A F Sullivan, A H Dickenson
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  ABSTRACT: Subcutaneous injection of formalin into the hindpaw peripheral receptive field of deep dorsal horn multireceptive (convergent) nociceptive neurones was used to produce a prolonged (1 h) activation of the cells. This chemical noxious stimulus produced a first peak of firing which lasted 10 min followed by a second peak of prolonged activity which was monitored for 50 min. gamma-D-glutamylglycine (DGG), a non-selective N-methyl-D-aspartate (NMDA) and quisqualate/kainate (non-NMDA) receptor antagonist was applied intrathecally both as a pretreatment and after the formalin. A complete abolition of both peaks of the formalin response was produced by DGG pretreatment (1000 micrograms) (n = 4). This dose produced profound inhibition of the acute C-fibre evoked responses of the same cells. However, no inhibitions were produced when the antagonist was applied once the formalin response had developed (n = 4). The selective NMDA receptor antagonist 5-amino-phosphonovaleric acid (AP5) was administered intrathecally (250 and 500 micrograms) as a 40 min pretreatment and caused a small inhibition of the first peak but a marked dose-related reduction in the second prolonged phase (n =7). AP5 did not influence the C-fibre inputs onto the cells. The non-competitive NMDA receptor channel blockers, ketamine and MK801, were administered i.v. during the second phase of firing. Ketamine (1-8 mg/kg) caused a short-lasting but marked and dose-related inhibition of the neuronal responses to formalin (n = 11). MK801 (0.5-1 mg/kg) resulted in a prolonged inhibition of cell firing during the second phase of the response (n = 11).(ABSTRACT TRUNCATED AT 250 WORDS)
  Brain Research 07/1990; 518(1-2):218-26. · 2.73 Impact Factor
• Article: Differential effects of excitatory amino acid antagonists on dorsal horn nociceptive neurones in the rat.

  A H Dickenson, A F Sullivan
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  ABSTRACT: The effects of two excitatory amino acid receptor antagonists gamma-D-glutamylglycine (DGG) and 2-amino-5-phosphonovaleric acid (APS), applied onto the spinal cord surface, were tested on the responses of dorsal horn nociceptive neurones in the anaesthetized rat. DGG is a non-selective antagonist at both the N-methyl-D-aspartate (NMDA) and non-NMDA receptors, whereas AP5 acid is selective for the NMDA receptor. DGG dose-dependently reduced the A and C fibre-evoked responses of neurones in all laminae of the dorsal horn and also inhibited the post-discharges of intermediate and deep neurones resulting from repeated C fibre stimulation. There was little difference in the effects of the antagonist on the intermediate neuronal population compared to superficial or deep cells in the dorsal horn. AP5 has little effect on C fibre-evoked activity in superficial cells but produced slight inhibitions of the C fibre-evoked responses and clear reductions in the post-discharge of the deep neurones. This contrasts with the excitatory effects of the antagonist on both types of responses in the intermediate cells. A fibre-evoked responses were unaffected by AP5. Taking into account the results with the two antagonists it appears that both A and C fibre-evoked responses of dorsal horn nociceptive neurones are mediated by non-NMDA receptors whilst the C fibre-evoked wind-up of deep dorsal horn cells involves the NMDA receptor which also seems to mediate, in a complex manner, C fibre responses of intermediate, presumed substantia gelatinosa neurones. The results are discussed with regard to nociceptive mechanisms in the dorsal horn.
  Brain Research 02/1990; 506(1):31-9. · 2.73 Impact Factor
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  Available from: Anthony H Dickenson

  Article: Delta-opioid mediated inhibitions of acute and prolonged noxious-evoked responses in rat dorsal horn neurones.

  A F Sullivan, A H Dickenson, B P Roques
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  ABSTRACT: 1. The effects of a selective delta-opioid agonist Tyr-D-Ser(Otbu)-Gly-Phe-Leu-Thr (DSTBULET) were examined on the C- and A beta-evoked responses of convergent dorsal horn neurones in the halothane anaesthetized, intact rat. 2. Intrathecal DSTBULET produced selective dose-dependent inhibitions of electrically-evoked C fibre responses of both superficial and deep neurones. A near-complete inhibition of 83 +/- 5% followed 100 micrograms of DSTBULET and the ED50 was 9 micrograms (13.5 nmol). Inhibitions were antagonised by intrathecal naloxone and ICI 174,864 but were not antagonised by pretreatment with intrathecal beta-funaltrexamine at a dose that blocked mu-opioid effects. By contrast, DSTBULET produced excitations of electrically-evoked responses of cells recorded in a zone intermediate between the superficial and deep neurones. 3. DSTBULET (50 micrograms) was also tested on the more prolonged noxious neuronal response produced by subcutaneous formalin (5%, 50 microliters) into the receptive field. DSTBULET profoundly inhibited the response to formalin. Pretreatment with ICI 174,864 before DSTBULET antagonised the effects of the delta-agonist on the formalin response. 4. The full peptidase inhibitor kelatorphan, known to protect endogenous enkephalins, was also tested on the formalin response. The intrathecal administration of 50 micrograms kelatorphan has previously been shown to inhibit electrically-evoked C fibre resonses of dorsal horn neurones and to be antagonised by ICI 174,864. The same dose of kelatorphan inhibited the formalin response in the present study. 5. From this study it appears that the delta-opioid agonist DSTBULET can produce profound inhibitions of the responses of convergent neurones to nociceptive afferent inputs. Furthermore, activation of delta-opioid receptors either by DSTBULET, or by protection of endogenous enkephalins with kelatorphan, can inhibit a more prolonged chemically-evoked nociceptive input onto these dorsal horn neurones.
  British Journal of Pharmacology 12/1989; 98(3):1039-49. · 4.41 Impact Factor
• Article: The spinal antinociceptive actions of morphine metabolites morphine-6-glucuronide and normorphine in the rat.

  A F Sullivan, H J McQuay, D Bailey, A H Dickenson
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  ABSTRACT: The profound and prolonged effects of morphine in patients with renal dysfunction have been associated with high plasma levels of the opiate metabolites morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) rather than an increased concentration of morphine. We present here electrophysiological evidence to suggest that potent spinal antinociception can be produced by both M6G and normorphine, another metabolite of morphine. Extracellular recordings of A beta- and C-fibre-evoked responses of convergent dorsal horn neurones were made in the halothane anaesthetised rat. M6G elicited dose-dependent, naloxone-reversible inhibitions of C-fibre-evoked responses which were completely suppressed (8% of control) by 2 micrograms M6G whereas A beta-fibre-evoked responses were only reduced to 57% of controls. The ED50 for the effects of M6G on C-fibre-evoked activity was calculated to be 0.53 micrograms. Systemic administration of M6G (2 mg/kg) also profoundly reduced noxious evoked neuronal activity. Intrathecal normorphine was less potent than M6G but complete selective inhibitions of C-fibre-evoked response could be elicited by 25 micrograms and the ED50 was calculated to be 2.68 micrograms. No such inhibitions were observed following administration of M3G. A comparison with intrathecal morphine in the same preparation reveals that normorphine is equipotent with morphine whereas M6G is 13-fold more potent. These results therefore confirm that M6G and normorphine might be significant contributers to opiate analgesia after administration of morphine.
  Brain Research 04/1989; 482(2):219-24. · 2.73 Impact Factor
• Article: Intrathecal opioids, potency and lipophilicity.

  H J McQuay, A F Sullivan, K Smallman, A H Dickenson
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  ABSTRACT: To determine the relationship between potency and lipophilicity for intrathecal opioids, morphine, normorphine, pethidine and methadone were studied in an electrophysiological model in the rat. Dose-response curves were constructed for the opioid effects on C fibre evoked activity of dorsal horn nociceptive neurones following intrathecal application of each opioid, and the ED50 values were correlated with lipid solubility. A significant inverse correlation was found (P = 0.002; r = 0.998) so that the most lipid soluble drugs were the least potent. The possible mechanism of this relationship, the implications for spinal opioid use and the effect of different administration routes on the relationship between lipid solubility and potency are considered.
  Pain 02/1989; 36(1):111-5. · 5.78 Impact Factor
• Article: Electrophysiological studies on the spinal effects of dermorphin, an endogenous mu-opioid agonist.

  A F Sullivan, A H Dickenson
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  ABSTRACT: The intrathecal administration of dermorphin, an endogenous heptopeptide first discovered in amphibia, produces dose-dependent selective inhibitions of C fibre-evoked responses in rat dorsal horn nociceptive neurones (ED50 0.11 micrograms). Naloxone (10 micrograms) but not ICI 174,864 (125 micrograms) antagonised the effects of the peptide. A beta-fibre-evoked activity was relatively unaffected. Thus dermorphin can profoundly inhibit nociceptive afferent input in the spinal cord, and in this preparation is more potent (approximately 40X) than morphine.
  Brain Research 10/1988; 461(1):182-5. · 2.73 Impact Factor
• Article: Evidence that endogenous enkephalins and a delta opioid receptor agonist have a common site of action in spinal antinociception.

  A H Dickenson, A F Sullivan, B P Roques
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  ABSTRACT: A selective agonist at the delta subtype of the opioid receptor (Tyr-D-Ser(Otbu)-Gly-Phe-Leu-Thr) (DSTBULET), and kelatorphan, a mixed peptidase inhibitor which can protect endogenous enkephalins were applied together onto to the lumbar spinal cord of the intact anaesthetized rat. The combined administration of these agents produced inhibitions of the responses of dorsal horn neurones activated by peripheral stimulation which were no greater than the inhibitions with either the agonist or peptidase inhibitor alone (50-60% inhibitions). The results indicate that endogenous opioids protected by kelatorphan and delta opioid receptor agonists act on a common receptor site to produce spinal antinociception.
  European Journal of Pharmacology 05/1988; 148(3):437-9. · 2.52 Impact Factor