Opioid receptors: electrophysiological and neurophysiological approaches.
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Central Nervous System↗
Biomedical subjects
A H Dickenson
Publications and source records attributed to A H Dickenson.
Time-related roles of excitatory amino acid receptors during persistent noxiously evoked responses of rat dorsal horn neurones.
The responses of convergent dorsal horn neurones to peripheral injection of formalin (5% formaldehyde, 50 microliters volume) were recorded extracellularly in the halothane anaesthetized rat. The control response of dorsal horn neurones to formalin was biphasic, with a first phase from 0-10 min and the second inflammatory phase from 10-60 min. Pre-administered intrathecal CNQX (5, 50 and 500 micrograms), 5 min before formalin injection, significantly reduced both the first phase (40 +/- 22, 52 +/- 20 and 40 +/- 28% inhibition, respectively, P < 0.05) and the second phase of the formalin response (40 +/- 20% inhibition, P < 0.05, 93 +/- 4% inhibition, P < 0.0001 and 65 +/- 17% inhibition, P < 0.05, respectively). Post-administered CNQX, administered 5 min after the peripheral injection of formalin, was less efficacious, as compared to pre-administered CNQX, at reducing the second phase of the formalin response. The lowest dose of post-administered CNQX (5 micrograms) facilitated the second phase of the response (47 +/- 19% facilitation, P < 0.05), and the higher dose (50 micrograms) produced smaller inhibitions of the response (42 +/- 10% inhibition, P < 0.05) than those observed with pre-administration of the same dose. However, the highest dose of CNQX (500 micrograms) studied produced similar inhibitions of the second phase of the formalin response, irrespective of the timing of administration. Intrathecal administration of 7-chlorokynurenate (7CK, 0.25-2.5 micrograms), a functional antagonist at the glycine site of the NMDA receptor, did not alter the first phase of the formalin response. The second phase of the formalin response was significantly inhibited, and to a similar extent, by both pre- and post-administration of 2.5 micrograms of 7CK (67 +/- 10% and 56 +/- 7% inhibition respectively, P < 0.05 for both). Overall, our results clearly demonstrate differential time-related roles of different transmitter systems in the induction and maintenance of inflammatory evoked persistent pain responses, and such events may become increasingly relevant to the control of pain in the clinic.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Electrophysiological study on spinal antinociceptive interactions between adenosine and morphine in the dorsal horn of the rat.
The effects of intrathecal N6-cyclopentyladenosine (N6-CPA), an A1-receptor agonist, and morphine, a mu opioid-receptor agonist were studied on the electrically evoked responses of deep dorsal horn neurones in the rat. Both caused inhibitions, when applied alone, of the C-fibre evoked response and post-discharges. Enhanced inhibitory effects were observed when N6-CPA (5 micrograms) was given with morphine (1 microgram). Increasing the dose of morphine (5 micrograms) with the same dose of N6-CPA occluded the expected inhibitions. By contrast, the A delta-fibre evoked response, inhibited by morphine alone, was significantly facilitated by the combination. Parallel activation of purinergic and opioid inhibitory systems within the dorsal horn as well as complex interactions between them are likely.
Adenosine↗
Spinal cord pharmacology of pain.
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Humans↗
The roles of spinal adenosine receptors in the control of acute and more persistent nociceptive responses of dorsal horn neurones in the anaesthetized rat.
1. We describe here the effects of intrathecal selective adenosine receptor agonists on acute and more persistent evoked responses of dorsal horn nociceptive neurones recorded in intact rats anaesthetized with halothane. 2. The effects of the A1 receptor agonist, N6-cyclopentyladenosine and the non-selective agonist 2-chloroadenosine as well as the A2a receptor agonist, 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride were gauged on the C-, A delta-, A beta-fibre, post-discharge and wind-up responses produced by peripheral tanscutaneous stimulation. The antagonists, theophylline and 8(p-sulphophenyl) theophylline were also tested alone and to reverse the agonist effects. 3. Subcutaneous formalin (5%) was used to produce a more prolonged nociceptive response initiated by peripheral inflammation. 4. Both N6-cyclopentyladenosine and 2-chloroadenosine produced inhibitions of the C-fibre evoked responses, wind-up and post-discharge of the neurones with no significant effects on the A beta responses. By contrast, the A delta evoked responses were facilitated over the same time course and dose-range as the inhibitions. N6-cyclopentyladenosine was more potent and effective than 2-chloroadenosine. In marked contrast to these agonists, the A2a agonist produced only weak non-specific inhibitions. Theophylline and 8(p-sulphophenyl) theophylline alone had no effect on the acute responses but prevented or reversed inhibitory effects of N6-cyclopentyladenosine. 5. The formalin response was markedly inhibited by spinal N6-cyclopentyladenosine with both the acute first phase and more prolonged second phase being dose-dependently inhibited. N6-cyclopentyladenosine was considerably more potent on the formalin response than on the other neuronal measures. 6 The results suggest a role of adenosine Al receptors in the modulation of both acute and inflammatory nociception in the spinal cord.
Anesthesia↗
Central acute pain mechanisms.
This account will consider the events occurring in the spinal cord that give rise to acute pain. The transmission and control of acute pain is not immutable but subject to plasticity so that the dividing line between acute and chronic pain is difficult to draw. Very brief acute pain is transmitted in a simple way and rarely produces difficulties in treatment. The situation within the spinal cord changes if the stimulus continues. After only seconds of C-fibre stimulation, additional peptides are released from C fibres, and spinal N-methyl-D-aspartate (NMDA) receptor activation and nitric oxide production occur. Soon after, genes are induced in central neurones, and increases and decreases in diverse pharmacological systems involved in pain transmission and modulation occur over periods of only a few hours. This rapid plasticity has important implications for the pharmacological treatment of acute because both the level of pain transmission and pain modulation will be altering over time.
Acute Disease↗
Differential modulation of alpha 2-adrenergic and opioid spinal antinociception by cholecystokinin and cholecystokinin antagonists in the rat dorsal horn: an electrophysiological study.
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.
Analgesics↗
Bi-directional effects of intrathecal NMDA and substance P on rat dorsal horn neuronal responses.
Intrathecal NMDA (5 ng) facilitated wind-up but not C-fibre evoked responses, whereas 50 ng facilitated C-fibre and A delta-fibre evoked responses but not wind-up of convergent dorsal horn neurones in the halothane anaesthetized rat. Higher doses of NMDA and SP (10-500 ng) were without effect. Co-administered SP (10 ng) with NMDA (5 ng) facilitated A delta-fibre evoked responses and wind-up. Excitatory amino acid and peptide interactions are discussed.
Animals↗
Enhanced responses of rat dorsal horn neurons after UV irradiation of the hindpaw; roles of the NMDA receptor.
Recordings were made from nociceptive dorsal horn neurones in the anaesthetized rat 3 and 5 days after ultraviolet (UV) irradiation of the hindpaw. The electrically evoked A beta-fibre-evoked responses from the paw were enhanced and their thresholds were lowered. Spontaneous neuronal activity was increased but the C-fibre-evoked responses were unaltered. These enhanced responses, suggestive of allodynia, were reduced by N-methyl-D-aspartate receptor (NMDA) antagonism.
Action Potentials↗
Enhanced alpha-2 adrenergic controls and spinal morphine potency in inflammation.
The antinociceptive potency of spinal morphine is enhanced in rats after carrageenan-induced inflammation. This electrophysiological study examines whether changes in alpha-2 adrenergic systems are responsible. Dorsal horn nociceptive neurones were recorded under halothane anaesthesia in normal animals and animals with carrageenan inflammation. There was a mild increase in potency of the selective alpha-2 adrenoceptor agonist dexmedetomidine following carrageenan (ED50 = 1 microgram). Intrathecal idazoxan (100 micrograms), an alpha-2 antagonist, produced a significant facilitation of the C-fibre evoked response in carrageenan-treated but not normal animals. However since neither idazoxan (100 micrograms) or atipamezole (50 micrograms, another antagonist) influenced the potency of spinal morphine, the increased alpha-2 adrenergic activity in inflammation does not contribute to the enhanced potency of spinal morphine.
Adrenergic alpha-2 Receptor Antagonists↗
Characterization of a potent agonist for NPFF receptors: binding study on rat spinal cord membranes.
Specific receptors for the octapeptide FLFQPQRFamide (NPFF), a mammalian FMRFamide-like neuropeptide with anti-opiate properties have been identified in rat central nervous system. However, exploration of the biological role of this peptide requires a peptidase-resistant agonist. In this study, the stability and binding characteristics of [125I]DYLMeFQPQRFamide, a radioiodinated analogue of NPFF, on rat spinal cord tissue were determined and compared with those of [125I]YLFQPQRFamide, the reference ligand which previously permitted to characterize NPFF binding sites. In a binding assay, [125I]DYLMeFQPQRFamide remained intact in the presence of membranes without peptidase inhibitors, whereas [125I]YLFQPQRFamide was completely hydrolysed. The specific binding was time-dependent, dose-dependent, saturable and reversible. [125I]DYLMeFQPQRFamide shared the same binding characteristics as [125I]YLFQPQRFamide (Kd = 0.07 nM; Bmax = 14.7 fmol/mg protein). Binding was not affected by various spinal cord opioids or peptides. Autoradiographic studies indicated that binding sites were mainly located in the most external layers of dorsal horn where high densities of NPFF binding sites have previously been described. [125I]YLFQPQRFamide and [125I]DYLMeFQPQRFamide binding sites were both GTP-regulated. These findings indicate that DYLMeFQPQRFamide should be of value in studies on NPFF-mediated actions in vivo.
Amino Acid Sequence↗
Electrophysiologic analysis of preemptive effects of spinal opioids on N-methyl-D-aspartate receptor-mediated events.
BACKGROUND: Spinal N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms may contribute to reduced opioid sensitivity in conditions of pain. The effectiveness of spinal opioids in inhibiting NMDA-mediated nociceptive events was assessed with two models. In addition, opioid dose-response curves with preemptive administration were compared with early and late postadministrations. METHODS: Dorsal horn nociceptive neuronal responses were recorded in the intact halothane anesthetized rat to acute repetitive C-fiber electrical stimulation (0.1 and 0.5 Hz) and to the peripheral injection of 5% formalin. At 0.5 Hz but not at 0.1 Hz, there was an enhanced C-fiber evoked response of dorsal horn neurons elicited by repetitive C-fiber stimulation (wind-up), which is mediated by the NMDA receptor. Formalin produced a biphasic response; the late protracted inflammatory phase was NMDA receptor-mediated. RESULTS: With 0.5-Hz stimulation a large degree of wind-up was elicited; it was less sensitive to 5 micrograms morphine compared with the effect of the same dose on the residual wind-up elicited at 0.1 Hz. Preadministration and early postadministration of morphine were equieffective at inhibiting the second-phase formalin response. In contrast, administration of the fast-acting mu opioid, D-Ala-Gly-MePHe-Gly-ol, given late postadministration (during the second phase) was less effective than preadministration. Increasing the dose of D-Ala-Gly-MePHe-Gly-ol produced complete inhibitions. CONCLUSIONS: NMDA receptor-mediated neuronal responses, such as wind-up and the established second phase of the formalin response, are poorly responsive to opioids. Dose increases and preemptive opioids effectively inhibit these NMDA receptor-mediated events.
Analgesics↗
Neurophysiology of opioid poorly responsive pain.
This review has covered the five potential causes for opioid poorly responsive pain, namely (a) a loss of opioid receptors on the spinal terminals of C-fibres as a result of peripheral nerve damage, (b) an accumulation of morphine-3-glucuronide, (c) changes in the non-opioid peptides, F8Fa or CCK, either spinally or supraspinally, (d) actions of the opioid peptide dynorphin and (e) spinally generated hypersensitive states via activation of the NMDA receptor. The loss of opioid receptors is likely to be important where peripheral nerve pathology or compression occurs, but the evidence suggests that increasing the dose will overcome the reduced opioid response. Morphine-3-glucuronide is unlikely to be a factor, nor is dynorphin, but the endogenous peptides CCK and F8Fa may be important. Finally, there is an association between the NMDA receptor and hyperalgesia/allodynia and reduced opioid sensitivity. Dextrorphan and ketamine reduce NMDA mediated events and so are available to test this hypothesis.
Analgesics, Opioid↗
The effect of intrathecal administration of RP67580, a potent neurokinin 1 antagonist on nociceptive transmission in the rat spinal cord.
The effect of intrathecal application of the selective neurokinin 1 (NK1) receptor antagonist RP67580 and its enantiomer RP68651 was studied on the responses of dorsal horn nociceptive neurones to formalin in the rat. The first and second phases of the formalin response were inhibited by RP67580 in a dose-related manner (1-10 micrograms), whereas RP68651 (5 micrograms) facilitated the second phase of the response. The same doses of RP67580 had minimal effects on the acute C-fibre responses. The NK1 receptor appears to play a role in prolonged nociceptive transmission in the spinal cord.
Animals↗
Cholecystokinin as a factor in the enhanced potency of spinal morphine following carrageenin inflammation.
1. Cholecystokinin (CCK) has been shown to diminish opioid analgesia. Here we investigate whether changes in the physiological levels of spinal CCK are responsible for the enhanced potency of spinal morphine in animals following carrageenin inflammation, as compared with normal animals. 2. Single dorsal horn nociceptive neurones were recorded in intact halothane-anaesthetized rats in the presence and absence of carrageenin-induced inflammation and comparisons were made between the two groups of animals. Inflammation was induced by the injection of 100 microliters of 2% lambda-carrageenin into the hind paw. 3. The inhibitory effect of intrathecal morphine on the C-fibre-evoked responses of the neurones was enhanced in the carrageenin-treated animals such that the effects of 0.25 microgram and 10 micrograms of morphine in normal animals were comparable to those of 0.01 microgram and 2.5 micrograms in the carrageenin animals. The effect of 0.2 mg kg-1 of the CCKB antagonist, L-365,260, on the antinociceptive potency of intrathecal morphine was examined in both groups of animals. In normal animals, L-365,260 produced a significant enhancement in the effect of morphine indicating a tonic CCK modulation in these animals, but it had no effect on the inhibitions produced by either dose of morphine in the carrageenin animals. 4. The inhibition of the C-fibre-evoked response produced by intrathecal morphine in the presence of 1 microgram of CCK was examined in both groups of animals. CCK attenuated the effects of morphine only in animals with carrageenin inflammation, having no effect on the action of morphine in normal animals. 5. The effects of both CCK and L-365,260 were therefore dependent on the inflammatory state of the animal, with each drug being active in opposite situations.6. We propose that in normal animals, morphine may produce a maximal stimulation of the release of CCK such that exogenous CCK is unable to reduce further the analgesic effects under these conditions.However, the differential effects of the agonist and antagonist in the normal and inflamed rats points to a role of CCK in the enhanced opiate actions. This enhancement of the potency of spinal morphine in inflammation is best explained by a reduction in spinal CCK release by morphine in this state.
Animals↗
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.
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.
Adrenergic alpha-Agonists↗
The spinal and peripheral roles of bradykinin and prostaglandins in nociceptive processing in the rat.
The effect of peripheral and intrathecal administration of the bradykinin B2 receptor antagonist HOE140 and the non-steroidal anti-inflammatory drug indomethacin were studied on the response of dorsal horn nociceptive neurones to formalin in the anaesthetized rat. Peripheral pretreatment with HOE140 reduced both phases of the formalin response whereas subcutaneous administration of indomethacin (5 mg/kg) reduced only the second phase. Pre-treatment with intrathecal HOE140 resulted in a dose-dependent reduction of the second phase whereas a high dose (500 micrograms) intrathecal indomethacin reduced both phases of the response. Bradykinin plays a role in peripheral nociception during the first and second phase of the response whereas the prostaglandins are only involved during the second phase. The converse is true centrally, the prostaglandins appear to be involved in both phases of the formalin response whereas bradykinin only plays a central role during the second phase of the response.
Animals↗
Spinal antinociception by Tyr-D-Ser(otbu)-Gly-Phe-Leu-Thr, a selective delta-opioid receptor agonist.
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.
Amino Acid Sequence↗