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A H Dickenson

Publications and source records attributed to A H Dickenson.

At least 55 records · Page 3Linked to original sources
PubMed1998

Effects of systemic carbamazepine and gabapentin on spinal neuronal responses in spinal nerve ligated rats.

There are few pharmacological studies of central neuronal measures in animal models of neuropathic pain. In the present study we have compared the effects of two anticonvulsants, carbamazepine and gabapentin, on spinal neuronal responses of nerve injured rats (selective ligation of spinal nerves L5 and L6, SNL) and sham-operated rats. The development and maintenance of cooling and mechanical allodynia of the lesioned hindlimb of SNL rats was followed with behavioural indices. The contralateral hindlimb of SNL rats and the ipsilateral hindlimb of sham-operated rats did not develop allodynia. Electrophysiological studies of SNL rats were then performed at two post-operative (PO) time points (PO days 7-10 and PO days 14-17). Spinal neurones of SNL rats, but not sham-operated rats, exhibited spontaneous activity at both PO days 7-10 and 14-17 (1 +/- 0.4 and 3 +/- 1 Hz, respectively). Paradoxically, the magnitude of electrical (C-fibre) and natural (mechanical and thermal) evoked neuronal responses of SNL rats at PO days 14-17 were smaller than the evoked neuronal responses of SNL rats at PO days 7-10 and sham-operated rats. The electrical evoked A-fibre responses of neurones were comparable for the three groups of rats. Both subcutaneous carbamazepine (0.5-22.5 mg/kg) and gabapentin (10-100 mg/kg) significantly reduced the spontaneous activity of spinal neurones of SNL rats at both PO time points. Carbamazepine had inhibitory effects on electrical C- and A-fibre and mechanical punctate (9 and 50 g) evoked neuronal responses of SNL rats which were significantly different to the lack of effect of carbamazepine on these measures in sham-operated rats. Gabapentin had comparable effects as carbamazepine on the electrical C-and A-fibre and mechanical punctate (9 and 50 g) evoked neuronal responses of SNL rats. In contrast to carbamazepine, gabapentin also reduced evoked neuronal responses of sham-operated rats and there was no difference between the effects of gabapentin in SNL and sham-operated rats. Robust behavioural changes in the SNL model of neuropathy are paralleled by a temporal increase in spontaneous activity and a paradoxical decrease in evoked spinal neuronal responses. The peripheral nerve dysfunction reveals an effect of carbamazepine which is maintained throughout the observation period, validating this experimental approach. Gabapentin, a novel treatment for neuropathic pain states, also reduced neuronal responses, but the actions of the drug were not dependent on nerve injury. Further studies at the spinal level may shed light on the physiology and pharmacology of the aberrant processes associated with neuropathic pain.

Acetates↗
PubMed1998

Dextropropoxyphene acts as a noncompetitive N-methyl-D-aspartate antagonist.

In order to elucidate whether opioid analgesics available on the Scandinavian market also act as noncompetitive N-methyl-D-aspartate (NMDA) antagonists, a series of commercially available opioids were screened for their affinity in [3H](RS)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine ([3H]MK-801) binding assays and potential inhibitory actions on responses to NMDA in the rat cortical wedge preparation. Of the screened compounds (codeine, dextropropoxyphene, etorphine, fentanyl, and morphine), only dextropropoxyphene, with an IC50 value in [3H]MK-801 binding of 5 microM, was found to be active. Further characterization of the interaction of dextropropoxyphene with the NMDA response in the rat cortical wedge preparation illustrated the noncompetitive NMDA antagonist activity of dextropropoxyphene. Analysis of the dextropropoxyphene inhibition curve of NMDA gave an IC50 value of 190 microM and a Hill slope of 0.8.

Analgesics, Opioid↗
PubMed1998

Evidence that [Phe1 psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2, a peripheral ORL-1 receptor antagonist, acts as an agonist in the rat spinal cord.

[Phe1 psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2, a pseudopeptide analogue of nociceptin is an antagonist in peripheral assays. Here, using in vivo electrophysiological recordings of dorsal horn neurones, [Phe1 psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2 appears to have agonist activity after spinal administration. The noxious evoked activity of the neurones was inhibited by [Phe1 psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2, which was as potent as nociceptin itself.

Analgesics↗
PubMed1998

Spinal effects of bicuculline: modulation of an allodynia-like state by an A1-receptor agonist, morphine, and an NMDA-receptor antagonist.

Single-unit recordings were made in the intact anesthetized rat of the responses of dorsal horn neurons to C-, Adelta-, and Abeta-fiber stimulation. The postdischarge and windup responses of the same cells along with responses to innocuous stimuli, prod and brush, also were measured. The effects of (-)-bicuculline-methobromide (0.5, 5, 50, and 250 microg) were observed on these neuronal responses. The C- and Adelta-fiber-evoked responses were facilitated significantly in a dose-dependent manner. The input was facilitated, but as the final overall response was not increased by the same factor, windup appeared to be reduced. However, postdischarge, resulting from the increase in the excitability produced by windup, tended to be facilitated. After doses of >/=5 microg bicuculline, stimulation at suprathreshold Abeta-fiber-evoked activity caused enhanced firing, mainly at later latencies corresponding to Adelta-fiber-evoked activity in normal animals. Few cells responded consistently to brush and so no significant change was observed. Responses evoked by innocuous pressure (prod) always were observed in cells that concurrently responded to electrical stimulation with a C-fiber response. This tactile response was facilitated significantly by bicuculline. The effects of N6-cyclopentyladenosine (N6-CPA), an adenosine A1-receptor agonist, was observed after pretreatment with 50 microg bicuculline, as were the effects of morphine and 7-chlorokynurenate (7-CK). N6-CPA inhibited prod, C- and Adelta-fiber-evoked responses as well as the initial and overall final response to the train of C-fiber strength stimuli. Inhibitions were reversed with 8(p-sulphophenyl) theophylline. Morphine, the mu-receptor agonist, also inhibited the postbicuculline responses to prod, C-, and Adelta-fiber responses and initial and final responses to a train of stimuli. Inhibitory effects of morphine were reversed partly by naloxone. 7-CK, an antagonist at the glycine site on the N-methyl-D-aspartate-receptor complex, inhibited the responses to C- and Adelta-fiber-evoked activity as well as prod. The postdischarges were inhibited by this drug. Again both the initial and overall responses of the cell were inhibited. To conclude, bicuculline caused an increase in the responses of deep dorsal horn cells to prod, Adelta-fiber-evoked activity, increased C-fiber input onto these cells along with the appearance of responses at latencies normally associated with Adelta fibers, but evoked by suprathreshold Abeta-fiber stimulation. These alterations may be responsible for some aspects of the clinical phenomenon of allodynia and hyperalgesia. These altered and enhanced responses were modulated by the three separate classes of drugs, the order of effectiveness being 7-CK, N6-CPA, and then morphine.

Adenosine↗
PubMed1997

BU-224 produces spinal antinociception as an agonist at imidazoline I2 receptors.

In this electrophysiological study, the effect of BU-224 (2-(4,5-dihydroimidazol-2yl)-quinoline hydrochloride)), a novel high affinity imidazoline I2 receptor ligand, was tested on the responses of nociceptive neurones in the spinal dorsal horn. When applied spinally, akin to an intrathecal application (i.t.), BU-224 (5-250 microg) reduced the nociceptive responses of dorsal horn neurones, producing a dose-dependent inhibition of C-fibre evoked responses, postdischarge and wind-up of the cells. A complete block of the antinociceptive effects was produced when idazoxan (100 microg), with both alpha2-adrenoceptor and imidazoline I2 receptor antagonist actions, was administered i.t. 10 min prior to the maximal dose of BU-224 tested. The nonselective alpha2-adrenoceptor antagonist, yohimbine (150 microg) only partially attenuated the inhibitory effects of BU-224 when administered i.t. 10 min prior. The highly selective alpha2-adrenoceptor antagonist, atipamezole (100 microg) produced no greater reversal than yohimbine under the same conditions. Although BU-224 has been reported to possess high affinity for imidazoline I2 receptors, a minor action at spinal alpha2-adrenoceptor receptors cannot be discounted. These results demonstrate that BU-224 is an agonist and that imidazoline I2 receptors, present in the dorsal horn, might play a role in spinal nociception, although further studies are needed to fully elucidate their functional roles.

Adrenergic alpha-Antagonists↗
PubMed1997

Inflammation reveals inhibition of noxious responses of rat spinal neurones by carbamazepine.

The effect of subcutaneously administered carbamazepine, a sodium channel blocker, on the electrically evoked C-fibre (noxious) vs A beta-fibre (innocuous) responses of dorsal horn neurones in non-inflamed and inflamed rats (3 h after plantar injection of carrageenan) was studied. Carbamazepine (0.5-5 mg/kg) significantly reduced the noxious evoked responses of the neurones under inflammatory, but not non-inflamed, conditions. The innocuous evoked responses of the neurones were not sensitive to carbamazepine under any conditions and administration of the vehicle alone did not influence any evoked response of these neurones. We propose that there are changes in the type, or proportion of, sodium channels underlying the transmission of noxious messages following peripheral inflammation which become sensitive to carbamazepine.

Analysis of Variance↗
PubMed1997

Gabapentin, ineffective in normal rats, markedly reduces C-fibre evoked responses after inflammation.

Gabapentin (Neurontin) is a novel anticonvulsant with an as yet unknown mechanism of action. This electrophysiological study investigated the potential antinociceptive actions of systemically administered gabapentin in normal animals and after inflammation induced by the injection of carrageenan. Gabapentin facilitated the noxious evoked responses of dorsal horn neurones recorded in normal animals. In complete contrast, gabapentin strongly and dose-dependently inhibited the C-fibre evoked response and post-discharge, but not the A beta-fibre evoked response, of neurones recorded in animals 3 h after the injection of carrageenan. This unique and selective profile of gabapentin may provide a novel treatment for clinical inflammatory pain states.

Acetates↗
PubMed1997

Blockade of spinal N- and P-type, but not L-type, calcium channels inhibits the excitability of rat dorsal horn neurones produced by subcutaneous formalin inflammation.

The effects of the intrathecal (i.t.) administration of different voltage-sensitive calcium channel (VSCC) blockers were studied in the formalin model of inflammation. The responses of convergent dorsal horn neurones after the subcutaneous injection of formalin (5% formaldehyde, 50 microliters volume) were recorded extracellularly in rats under halothane anaesthesia. Administration of the L-type calcium channel blocker verapamil, 5 and 50 micrograms, before formalin injection had no effect on either the first or second phase of the formalin response. Pre-treatment with the N-type calcium channel blocker omega-Conotoxin-GVIA, 0.1 and 0.4 microgram, reduced both phases of the formalin response. The low dose of omega-Conotoxin-GVIA significantly inhibited the first phase response whereas the high dose significantly reduced the second phase. Pre-treatment with the P-type calcium channel blocker omega-Agatoxin-IVA, 0.125 and 0.5 microgram, did not cause a significant inhibition of the first phase whereas a marked dose-related reduction in the second phase of formalin response was found with the high dose producing 95% inhibition. These results demonstrate that spinal N- and P-type, but not L-type, VSCCs are involved in the inflammation-evoked hyperexcitability of dorsal horn neurones after peripheral formalin injection. Since selective antagonists for each type of VSCC had differential effects on the formalin response, it is suggested that each type of VSCC could be preferentially regulating or coupled to the release of certain neurotransmitters in the enhanced nociceptive transmission at the spinal level following formalin inflammation.

Animals↗
PubMed1997

Distinct electrophysiological effects of two spinally administered membrane stabilising drugs, bupivacaine and lamotrigine.

A selective blockade of the relay of messages by C-fibres into the spinal cord is a logical approach to the reduction of nociceptive transmission. Here we compared the effect of two distinctly different sodium channel blockers, the local anaesthetic bupivacaine and the novel anti-epileptic lamotrigine, on the responses of dorsal horn neurones following noxious and innocuous stimulation. Dorsal horn neuronal responses following acute repetitive C-fibre electrical stimulation (three times the C-fibre threshold at 0.5 Hz) were recorded in intact halothane anaesthetised rats. Wind up, an enhanced C-fibre evoked response of dorsal horn neurones, and an associated post discharge were observed following repetitive stimulation. The effects of spinally administered bupivacaine and lamotrigine on the dorsal horn neuronal responses were investigated. Spinal bupivacaine (25-1000 microg/50 microl) dose dependently reduced the C-fibre evoked responses (r2 = 0.5, P < 0.0003), wind up (r2 = 0.4, P < 0.002) and the post discharge (r2 = 0.34, P < 0.005) of these neurones. The effects of bupivacaine were long lasting, up to 120 min post-administration. The Abeta-fibre evoked responses were not dose-dependently reduced by bupivacaine. Spinal lamotrigine (50-1000 microg/50 microl) did not significantly reduce the C- or Abeta-fibre evoked responses. In contrast there was a tendency for wind up and post discharge to be facilitated by lamotrigine. Although both bupivacaine and lamotrigine are sodium channel blockers, the effects of the two drugs on the C-fibre and Abeta-fibre evoked responses were completely different. Bupivacaine reduced C-fibre evoked responses whereas lamotrigine had a tendency to facilitate responses. The profile of sodium channel blockers would appear highly diverse and the status of lamotrigine as a potential analgesic remains unclear.

Anesthetics, Local↗
PubMed1997

The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord.

1. The aim of this review is to consider the relative roles of inhibitory and excitatory amino acid receptor-mediated events in the processes leading to pain transmission in the spinal cord. 2. Emphasis will be on the roles of the inhibitory and excitatory amino acids, GABA and glutamate, and how the relative balance between activity in these systems appears to determine the level of pain transmission. 3. The N-methyl-D-aspartate (NMDA) receptor for glutamate has been implicated in the generation and maintenance of central (spinal) states of hypersensitivity. It has been shown that activation of this receptor underlies wind-up, whereby the level of transmission of noxious messages is potentiated. Antagonists at this receptor-channel complex prevent or block enhanced (hyperalgesic) pain states induced by tissue damage, inflammation, nerve damage and ischemia. 4. Information concerning amplification systems in the spinal cord, such as the NMDA receptor, is a step toward understanding why and how a painful response is not always matched to the stimulus. Such events have parallels with other plastic events such as long-term potentiation (LTP) in the hippocampus. 5. However, the roles of inhibitory transmitter systems can also change insofar as opioid, adenosine and GABA transmission in the spinal cord can vary in different pain states. 6. Changes in GABA systems have been well-documented and discussion will center on whether this has clinical implications. 7. In addition to behavioral and electrophysiological approaches to the pharmacology of pain the current status of the use of markers of early onset genes such as c-fos, as monitors of activity, will be discussed. 8. Hyperalgesia would appear to be balanced by inhibitions during inflammatory conditions but not in neuropathic states, pains due to nerve damage. In the latter case, events reminiscent of LTP may predominate, whereas they are held in check by inhibitions under conditions of inflammation.

Animals↗
PubMed1997

Plasticity: implications for opioid and other pharmacological interventions in specific pain states.

The spinal mechanisms of action of opioids under normal conditions are reasonably well understood. The spinal effects of opioids can be enhanced or reduced depending on pathology and activity in other segmental and nonsegmental pathways. This plasticity will be considered in relation to the control of different pain states using opioids. The complex and contradictory findings on the supraspinal actions of opioids are explicable in terms of heterogeneous descending pathways to different spinal targets using multiple transmitters and receptors--therefore opioids can both increase and decrease activity in descending pathways. These pathways could exhibit considerable plasticity. There is increasing evidence that delta opioid receptor agonists have the potential to replace morphine as major analgesics with reduced side-effect profiles. The concept of preemptive analgesia, based on preventing the induction of some of the negative plastic influences on opioid controls and the detrimental effects of pain, is sound, but experimental verification in the clinical setting is difficult. For example, a delayed compensatory upregulation of inhibitory systems, particularly in inflammation, may counter persistent painful inputs. Combination therapy with opioids may be beneficial in many pain states where either negative influences are blocked or inhibitory controls are enhanced. Finally, developmental aspects of these systems are discussed in connection with the treatment of pain in young children, where inhibitory systems in the spinal cord are immature.

Humans↗
PubMed1997

Distinct inhibitory effects of spinal endomorphin-1 and endomorphin-2 on evoked dorsal horn neuronal responses in the rat.

Intrathecal endomorphin-1 and endomorphin-2 (0.25-50 micrograms) dose-relatedly reduced all components of electrical evoked C-fibre responses of spinal neurones. These effects were partially reversed by naloxone. Endomorphin-1, but not endomorphin-2, dose-relatedly reduced the A beta-fibre evoked responses. Peak inhibitory effects of endomorphin-1 and -2 were at 15-20 min post-administration. Thus spinal endomorphin-2 had selective effects on noxious responses, whereas endomorphin-1 was non-selective.

Analgesics, Opioid↗
PubMed1997

NMDA receptor antagonists: interactions with opioids.

The N-methyl-D-aspartate (NMDA) receptor for glutamate has been implicated in the generation and maintenance of central (spinal) states of hypersensitivity. Thus antagonists at this receptor-channel complex have the potential not to totally abolish pain, but to prevent or block hyperalgesic states induced by tissue damage, inflammation, nerve damage and ischaemia. Information on amplification systems in the spinal cord such as the NMDA receptor is a step towards understanding why and how a painful stimulus is not always related to the response. There are now sufficient controlled clinical studies with agents such as ketamine to believe that, in humans, NMDA mediated events are critical in pathological and/or prolonged pain states. Consequently, use of antagonists may aid the treatment of difficult clinical pains when given alone or in combination with opioids. The combinations of opioids and NMDA antagonists may be especially helpful since some NMDA mediated events can be difficult to control with opioids alone (eg. neuropathic pain states). In addition, the ability of opioids to act presynaptically on C-fibre terminals to reduce transmitter release produces synergistic inhibitions with postsynaptically acting NMDA receptor antagonists. Consequently, low dose combinations may be possible with low side-effect liability. Finally, NMDA receptor activation would appear to be responsible for the generation of nitric oxide and prostanoids which further enhance pain transmission whereas adenosine release acts to control these NMDA mediated events. Thus, further targets for the indirect control of NMDA induced activity are possible.

Analgesics, Opioid↗
PubMed1996

Amplification of spinal nociceptive transmission depends on the generation of nitric oxide in normal and carrageenan rats.

It has been proposed that nitric oxide (NO) is involved in the spinal transmission of nociceptive information, particularly following the development of peripheral inflammation. In this electrophysiological study the ability of the nitric oxide synthase inhibitor 7-nitro indazole (7-NI), which does not block endothelial nitric oxide in vivo, to inhibit the electrically evoked responses of dorsal horn neurones recorded in both normal animals and in animals 3 h after the injection of carrageenan into the ipsilateral hind paw, was investigated. In both normal and carrageenan inflamed animals, 7-NI (1-100 micrograms), administered intrathecally, strongly inhibited the NMDA receptor mediated wind-up and post-discharge of the neurones, having relatively little effect on the acute C- or A beta-fibre evoked activity of the neurones. This inhibitory action of 7-NI on the noxious evoked responses of the neurones was completely blocked by the prior intrathecal administration of 500 micrograms of L-arginine. Inflammation did not alter the effects of 7-NI since there was no difference in the dose-response curve between the normal and carrageenan animals. In normal animals, stimuli of sufficient duration/intensity to enable the activation of NMDA receptors to occur, shown in this study by the occurrence of wind-up, also lead to the generation of nitric oxide, which then participates in nociceptive transmission. These effects appear to be independent of the vascular effects of NO. Inflammation-induced changes could facilitate activation of spinal NMDA receptors, such that nitric oxide is now generated by stimuli previously sub-threshold for this event. Previous studies, reporting a unique role of NO in nociceptive transmission following the development of peripheral inflammation, may have resulted from inadequate stimuli in the normal animal.

Animals↗
PubMed1996

The opioid ketobemidone has a NMDA blocking effect.

There are clinical observations that neurogenic pain can respond well to the opioid ketobemidone, in contrast to pethidine and morphine. This has led us to the hypothesis that the analgesic effect of ketobemidone in neurogenic pain may be due to both opioid as well as additional non-opioid effects. The present study was therefore made to evaluate the effects of ketobemidone. The study consists of two parts. (1) Single unit recordings were made from dorsal horn neurones in the halothane-anaesthetised rat. Neurones were activated by transcutaneous electrical stimulation of their receptive fields at C-fibre strength and their responses quantified. The wind-up of the neurones, due to N-methyl-D-aspartate (NMDA) receptor activation, leading to marked increases in C-fibre responses and an associated post-discharge was also measured. Ketobemidone, applied to the spinal cord, equivalent to an intrathecal injection, dose-dependently and selectively reduced C-fibre evoked responses. Ketobemidone was also found to block wind-up more effectively than morphine at equieffective doses, but unlike morphine in a non-naloxone-reversible manner. (2) In a binding study ketobemidone was shown to inhibit [3H]MK-801 binding with a Ki value of 26 microM. Therefore, ketobemidone appears to possess both mu opioid agonist as well as NMDA blocking effects.

Analgesics, Opioid↗
PubMed1996

Metabotropic glutamate receptor activation contributes to nociceptive reflex activity in the rat spinal cord in vitro.

The contribution of metabotropic glutamate receptor activation to the spinal segmental reflex response evoked at high-intensity electrical stimulation suggesting a role in nociception, has been examined in an in vitro preparation of neonatal rat spinal cord. Segmental reflex responses were recorded as a ventral root depolarization evoked following drug perfusion to the spinal cord or by electrical activation of high-threshold nociceptive afferent fibres. Superfusion of the selective metabotropic glutamate receptor agonist, (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD], to the spinal cord produced a dose-dependent, reversible ventral root depolarization (EC50 = 58 +/- 7 microM; n = 4), which was antagonized by the selective metabotropic glutamate receptor antagonist, (+)-alpha-methyl-4-carboxyphenylglycine (MCPG; IC50 = 243 +/- 61 microM; n = 4). MCPG, over the same concentration range (10 microM-5.0 mM) did not affect N-methyl-D-aspartate-induced ventral root depolarizations. In contrast, the specific N-methyl-D-aspartate receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) reduced N-methyl-D-aspartate-evoked ventral root depolarization but did not affect the depolarization evoked by (1S,3R)-ACPD, thus indicating the specificity of the antagonists for these aggregate responses. MCPG significantly reduced the prolonged phase of the single shock C-fibre-evoked ventral root depolarization (IC50 = 2.9 +/- 0.2 mM; n = 3-5). Low frequency high intensity stimulation of the dorsal root evoked a wind-up response, the amplitude of which was attenuated by both D-AP5 and MCPG in a dose-dependent manner. The ventral root depolarization evoked by capsaicin application (1.0 microM, 30 s) was blocked by both MCPG (IC50 = 809 +/- 35 microM; n = 4) and D-AP5 (IC50 = 143 +/- 43 microM; n = 4). These data suggest that both D-AP5 and MCPG reduced C-fibre-induced ventral root responses. In addition to N-methyl-D-aspartate receptor, metabotropic glutamate receptor activation appears to be involved in the generation of the segmental spinal reflex evoked by high-intensity stimulation in the neonatal rat spinal cord in vitro.

Animals↗
PubMed1996

Inhibitory action of nociceptin on spinal dorsal horn neurones of the rat, in vivo.

Intrathecally administered nociceptin (5, 50, 225 micrograms) dose-relatedly inhibited the C-fibre evoked wind-up and post-discharge of dorsal horn neurones, but not the baseline C-fibre evoked responses. Spinal naloxone 50 micrograms, but not 10 micrograms, reversed the effects of nociceptin. Thus the antinociceptive role of nociceptin in the spinal cord differs from that of classical opioids.

Animals↗