Neuropathic pain: nerves bursting with excitement ...
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Animals↗
Biomedical subjects
A H Dickenson
Publications and source records attributed to A H Dickenson.
Different increase in C-fibre evoked responses after nociceptive conditioning stimulation in sham-operated and neuropathic rats.
Mechanisms of neuropathic pain are not clear. Recently we showed long-term potentiation (LTP) of wide dynamic range (WDR) neurones after electrical conditioning stimulation of the sciatic nerve in normal rats. In this study we investigated the effects of the same conditioning on both the evoked responses of WDR cells and on vital signs in neuropathic rats. Nerve injury was produced by tight ligation of the L5 and L6 spinal nerves and a control group received sham surgery. The electrical conditioning gave a significantly smaller LTP in neuropathic rats as compared to controls. Despite giving a smaller LTP in neuropathic rats, the rise in mean arterial blood pressure and heart rate induced by the conditioning was exactly the same as in the control group. The threshold for activating C-fibres was significantly lower and the baseline tended to be higher in neuropathic rats. Thus, it is suggested that the nerve injury itself is likely to induce an LTP-like state in the neurones studied. Further studies using the LTP-inducing model can provide new information on the mechanisms of neuropathic pain.
Animals↗
Enlargement of the receptive field size to low intensity mechanical stimulation in the rat spinal nerve ligation model of neuropathy.
One characteristic of plasticity after peripheral tissue or nerve damage is receptive field reorganization, and enlargement of receptive field size has been suggested to occur in certain models of neuropathic pain. The aim of the present study was to explore whether enlargement of neuronal receptive fields could contribute to the mechanical allodynia found on the ipsilateral paw in the spinal nerve ligation model of neuropathy. After ligation of L(5)-L(6) spinal nerves, all rats developed behavioral signs of mechanical allodynia, while the sham-operated control group displayed no such changes. The characteristics of the evoked responses of the neurones recorded in the dorsal horn of the rats were similar between the spinal nerve ligation, the sham operated control group, and the nonoperated control group, except for spontaneous activity, which was significantly increased in the spinal nerve ligation group. The mean size of the receptive field on the ipsilateral hindpaw, mapped using low-intensity stimulation with 9-g von Frey hair, was significantly increased in the spinal nerve ligation group, as compared to the sham-operated group. No significant difference was seen with 15- or 75-g von Frey hairs. The distribution of the receptive fields over the plantar surface of the paw was similar between the study groups. The enlargement of receptive field for non-noxious touch could be an indication of central sensitization in this model.
Animals↗
Comment on: Svendsen et al; some problems with wind-up and its calculation, PAIN 83 (1999) 109-111.
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Humans↗
Effects of spinally administered P2X receptor agonists and antagonists on the responses of dorsal horn neurones recorded in normal, carrageenan-inflamed and neuropathic rats.
1. The function and role of P2X receptors in the spinal transmission of nociception was investigated using the selective P2X receptor agonists, alpha,beta-methylene ATP (alpha,beta-me ATP) and beta, gamma-methylene-L-ATP (beta,gamma-me-L-ATP) and the P2X receptor antagonists pyridoxal-phosphate-6-azophenyl-2',4'-disulphonate (PPADS) and suramin. 2. Intrathecal administration of 5 and 50 microg of beta,gamma-me-L-ATP produced a significant facilitation of the C-fibre evoked response and a tendency towards increased excitability of the post-discharge, but not Abeta-fibre evoked response of dorsal horn neurones recorded in normal animals. Administration of similar doses of alpha,beta-me ATP did not produce an overall change in the response of the neuronal population. 3. Peripheral administration of 20 microg of these agonists into the paw of the rat evoked firing in the dorsal horn neurones. 4. Intrathecal administration of the antagonists, suramin (50 and 500 microg) and PPADS (5, 50 and 500 microg), to normal animals and to animals with a model of neuropathy induced by spinal nerve ligation did not alter the evoked neuronal responses. In contrast, intrathecal administration of 500 microg of suramin to animals 3 h after the induction of carrageenan inflammation produced a significant inhibition of the C-fibre evoked response of the neurones. Similar inhibitions were also seen following high doses of intrathecal PPADS, although this did not reach significance. 5. These results suggest that spinal P2X receptors may play a role in the modulation of spinal nociceptive transmission following the development of inflammation, but that these receptors play at most a minor role in spinal nociceptive processing in normal and neuropathic animals.
Adenosine Triphosphate↗
Neuronal inhibitory effects of methadone are predominantly opioid receptor mediated in the rat spinal cord in vivo.
This study aims to assess whether the antinociceptive actions of methadone are mediated solely through opioid mechanisms, or whether its reported affinity for NMDA receptors has physiological relevance in vivo. Methadone is a mu-opioid receptor agonist reported to relieve pain unresponsive to other opioids. It is a racemic mixture comprising d- and l-optical isomers; the d-isomer has a lower affinity for opioid receptors, and both also exhibit NMDA receptor binding, likely to indicate antagonist activity. d -Methadone is antinociceptive in behavioural studies via non-opioid mechanisms, which could include functional NMDA receptor-blocking activity. Here we investigate the ability of d - and dl -methadone to inhibit noxious and innocuous electrically-evoked responses of dorsal horn neurones in the anaesthetized rat. Racemic methadone (5, 25, 50, 250 microg) applied spinally, dose-relatedly inhibited the C-fibre evoked response, input and wind-up of the neurones, with a profile resembling that of morphine. d-Methadone (5, 25, 50, 250, 500 microg) was also inhibitory, although less potent by a factor of between 13 and 48 depending on the neuronal measure; its profile of inhibition resembled that of the racemic mixture rather than an NMDA receptor antagonist. Both compounds had minimal effects on Abeta-fibre-evoked activity. The inhibitory effects of both d - and dl -methadone on noxious-evoked activity were naloxone reversible. The naloxone reversibility of d -methadone inhibitions is best interpreted as indicative of a purely opioid mechanism of action. However, the ability of naloxone to reverse the effects of d -methadone may also reflect a degree of synergy between weak NMDA antagonist and opioid agonist activity.
Analgesics, Opioid↗
Effect of spinal morphine after long-term potentiation of wide dynamic range neurones in the rat.
BACKGROUND: Studies have shown that long-term increase in the excitability of single wide dynamic range neurones in the spinal dorsal horn of rats may be induced after tetanic stimulation to the sciatic nerve. This sensory event is possibly an in vivo counterpart of long-term potentiation, described in the brain. This study investigated whether this phenomenon occurs in the halothane-anesthetized rat and whether the antinociceptive effects of spinally administered morphine are altered when tested on the enhanced activity. METHODS: Single unit extracellular recordings were made in three different groups of halothane-anesthetized rats (n = 6 in each group). In group 1, the evoked neuronal responses of wide dynamic range neurones by a single electrical stimulus to the peripheral nerve were recorded every 4 min, for 1 h before (baseline) and for 3 h after brief high-frequency conditioning stimulation of the sciatic nerve. In group 2, morphine was applied onto the spinal cord after long-term potentiation had been established. Increasing concentrations of morphine were added until the C fiber-evoked responses were abolished; this was followed by naloxone reversal. In group 3, the same protocol as in group 2 was used except a waiting period substituted for the electrical conditioning. RESULTS: The C fiber-evoked responses were significantly increased (P < 0.001) after conditioning compared with baseline and those in control animals. Further, significantly higher concentrations of morphine (P = 0.008) were needed to abolish the C fiber-evoked responses in tetanized animals than in control animals. Naloxone reversed the effects of morphine to the predrug potentiated baseline in group 2, showing that opioids do not block the maintenance of spinal long-term potentiation. CONCLUSIONS: Long-term potentiation of C fiber-evoked responses also can be induced in halothane-anesthetized rats, and morphine seems to have less potency during such conditions. These data suggest that long-term potentiation-like mechanisms may underlie some forms of hyperalgesia associated with a reduced effect of morphine.
Analgesics, Opioid↗
The race to control pain: more participants, more targets.
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Acetates↗
The effectiveness of spinal and systemic morphine on rat dorsal horn neuronal responses in the spinal nerve ligation model of neuropathic pain.
The treatment of pain arising from nerve injury can be difficult and the opioid sensitivity of neuropathic pain remains debatable. Clinical and animal studies report a wide range in the effectiveness of morphine, ranging from inadequate to potent analgesia. In this electrophysiological study we compare the effectiveness of spinal versus systemic administration of morphine on the natural and electrically evoked responses of spinal neurones of rats with a selective spinal nerve (L5/6) ligation. Recordings were made 1 week and/or 2 weeks after ligation. We have also compared the effects of morphine, by the two routes, on normal and sham operated animals. In spinal nerve ligated rats, morphine (0.1-5 microg) administered via the intrathecal route produced greater dose-dependent inhibitions of the neuronal responses compared with those produced by the systemic route (1-6 mg/kg). The dose response curves for intrathecal morphine on the C-fibre evoked and noxious natural stimuli evoked neuronal responses (mechanical and thermal) of spinal nerve ligated rats were to the left of those of sham operated and normal rats, suggesting an enhanced potency of intrathecal morphine after nerve injury. This was clearest for the lower doses of the opioid. The effects of spinal morphine on the responses to low intensity stimuli were similar in all groups of rats. In contrast to the spinal route, systemic morphine was less effective in inhibiting the evoked neuronal responses of spinal nerve ligated rats. This was especially clear for the C-fibre evoked and noxious natural stimuli evoked responses (mechanical and thermal) of spine nerve ligated rats. Our results suggest that the effectiveness of morphine may be partly related to the timing of the treatment relative to the duration of the neuropathy, the route of administration and also the neuropathic symptom. Spinal opioids may be a useful approach to pain control in neuropathic pain states where systemic routes produce inadequate analgesia.
Analgesics, Opioid↗
The role of non-N-methyl-D-aspartate ionotropic glutamate receptors in the spinal transmission of nociception in normal animals and animals with carrageenan inflammation.
The role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate receptors in spinal nociceptive transmission in both normal animals and animals with carrageenan inflammation was investigated using the AMPA/kainate receptor antagonist 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (NBQX) and the selective GluR5 kainate receptor antagonist LY382884 [3S,4aR,6S,8aR-6-(4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8, 8a-deca-hydroisoquinoline-3-carboxylic acid]. In normal animals, spinal administration of 100 microg of LY382884 produced a significant inhibition of both the C-fibre-evoked response and post-discharge of dorsal horn neurons, with the wind-up of the neurons being reduced by both 50 and 100 microg of LY382884. The spinal actions of LY382884 were enhanced following 3 h of carrageenan inflammation, such that doses of 20 microg and above were able to produce significant inhibitions of the noxious-evoked response of the neurons. Spinal administration of NBQX in normal animals (5-50 microg) inhibited the C-fibre-evoked response of the dorsal horn neurons, but only 50 microg of NBQX was able to inhibit the wind-up and post-discharge of the neurons. Following 3 h of carrageenan inflammation, the ability of NBQX to inhibit the wind-up and post-discharge of the neurons was markedly enhanced. These data suggest that both AMPA and kainate GluR5 receptors play an enhanced role in spinal nociceptive processing following the development of peripheral inflammation, as antagonists at both receptors are more effective against nociceptive responses, including wind-up under these inflammatory conditions.
Animals↗
The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.
Many damage-sensing neurons express tetrodotoxin (TTX)-resistant voltage-gated sodium channels. Here we examined the role of the sensory-neuron-specific (SNS) TTX-resistant sodium channel alpha subunit in nociception and pain by constructing sns-null mutant mice. These mice expressed only TTX-sensitive sodium currents on step depolarizations from normal resting potentials, showing that all slow TTX-resistant currents are encoded by the sns gene. Null mutants were viable, fertile and apparently normal, although lowered thresholds of electrical activation of C-fibers and increased current densities of TTX-sensitive channels demonstrated compensatory upregulation of TTX-sensitive currents in sensory neurons. Behavioral studies demonstrated a pronounced analgesia to noxious mechanical stimuli, small deficits in noxious thermoreception and delayed development of inflammatory hyperalgesia. These data show that SNS is involved in pain pathways and suggest that blockade of SNS expression or function may produce analgesia without side effects.
Afferent Pathways↗
Electrophysiological studies on the postnatal development of the spinal antinociceptive effects of the delta opioid receptor agonist DPDPE in the rat.
1. The antinociceptive effects of the delta opioid receptor selective agonist, DPDPE [(D-Pen2,D-Pen5)-enkephalin] was studied in rats aged postnatal day (P) 14, P21, P28 and P56. 2. Antinociceptive effects of DPDPE were measured as percentage inhibition of the C-fibre evoked response and post-discharge of dorsal horn neurones evoked by peripheral electrical stimulation. DPDPE was administered by topical application, akin to intrathecal injection. 3. DPDPE (0.1-100 microg) produced dose-related inhibitions at all ages; these inhibitions were reversed by 5 microg of the opioid antagonist naloxone. 4. The dose-response curves for C-fibre evoked response and post-discharge of the neurones were not different in rats aged P14 and P21. DPDPE was significantly more potent at P14 and P21 compared with its inhibitory effects on these responses at P28 and P56. 5. DPDPE produced minor inhibitions of the A-fibre evoked response of the neurones at P14, P21, P28 and P56, suggesting that the inhibitory effects of DPDPE are mediated via presynaptic receptors on the terminals of C-fibre afferents. 6. Since spinal delta opioid receptor density changes little over this period, the increased antinociceptive potency of DPDPE in the rat pups compared with the adult is likely to be due to post-receptor events, or in developmental changes in the actions of other transmitter/receptor systems within the spinal cord.
Afferent Pathways↗
Pain relief.
This meeting contained a considerable body of data on both basic science and clinical studies dedicated to the alleviation of pain. Presentations covered a number of exciting areas, where both novel disclosed compounds and clinical data were covered. From these we have selected excitability blockers acting on sodium and calcium channels, progress in drugs acting at glutamate receptors, cannabinoid receptors, capsaicin analogs, novel opioids acting at receptors other than the mu receptor for morphine, substance P antagonists and cyclooxygenase (COX)-2 inhibitors as being of particular interest.
Journal Article↗
Postnatal development of multiple opioid receptors in the spinal cord and development of spinal morphine analgesia.
The postnatal ontogeny of mu, delta and kappa opioid receptor binding sites in the spinal cord of rat pups at various postnatal days was determined using in vitro autoradiographical methods. The functional effect of spinal morphine was also assessed using in vivo electrophysiological methods in rats at P14, P21 and adults (P56). Both mu and kappa opioid receptor binding-sites are present from P0 and spread relatively diffusely throughout the spinal cord. Overall binding peaks at P7 and subsequently decreases to adult levels with the mu opioid receptor binding sites regressing to become denser in the superficial dorsal horn. delta Opioid receptor binding was first seen at P7, and no distinction between superficial and deeper laminae was seen. In the adult, the relative proportions of the opiate receptors in the superficial dorsal horn are 63%, 22% and 15%, for mu, delta and kappa receptor binding sites, respectively. C-fibre evoked dorsal horn neuronal responses recorded from anaesthetized rat pups were highly sensitive to spinal morphine at P21, (EC50 0.005 microgram), compared to the adult (EC50 0.9 microgram). However, the EC50 (0.2 microgram) at P14 was greater than at P21 despite the fact that mu receptor binding was greater at P14. Opioid receptor binding is developmentally regulated and undergoes substantial postnatal reorganization. However, the number of mu receptor binding sites appears not to be the only determinant of functional sensitivity to spinal morphine. Other factors, such as coupling of the receptors are likely to be important.
Analgesics↗
Inflammation alters the effects of mGlu receptor agonists on spinal nociceptive neurones.
Several types of metabotropic glutamate receptor are known to be located in the spinal cord. This study examined the effects of the metabotropic glutamate receptor agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD), (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) and (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3S)-ACPD) on the electrically evoked responses of dorsal horn neurones recorded in normal animals and in animals 3 h after the induction of carrageenan inflammation. The group I and II agonist (1S,3R)-ACPD produced facilitations of the noxious evoked neuronal responses in normal animals, but inhibited these responses following carrageenan inflammation. The group II agonist (1S,3S)-ACPD also produced inhibitions in the carrageenan animals, in contrast to the mixed effects seen in normal animals. The group I agonist (S)-3,5-DHPG produced mixed effects (inhibitions and facilitations) in both normal and carrageenan animals. This in vivo study shows that the effects of metabotropic glutamate receptor agonists are more complex than in vitro studies have suggested to date.
Animals↗
Alpha2-adrenoceptor antagonists enhance responses of dorsal horn neurones to formalin induced inflammation.
Intrathecally applied alpha2-adrenoceptor antagonists atipamezole, idazoxan and yohimbine had no significant effect on any neuronal response in normal animals. In contrast, all three antagonists (100 microg) significantly increased the area under the curve of the total response to formalin, especially the second phase. Our results suggest the alpha2-adrenoceptor-mediated noradrenergic inhibitory system in the spinal cord is dormant under normal conditions, but controls both the magnitude and duration of the neuronal responses to subcutaneous injection of formalin.
Adrenergic alpha-Antagonists↗
Electrophysiological characterization of spinal neuronal response properties in anaesthetized rats after ligation of spinal nerves L5-L6.
1. Despite a number of models of nerve injury, few studies have examined how peripheral nerve injury influences spinal somatosensory processing. 2. Ligation of two (L5-L6) of the three spinal nerves that form the sciatic nerve produces a partial denervation of the hindlimb. Following ligation, rats exhibited withdrawal responses to normally innocuous punctate mechanical and cooling stimuli (acetone) applied to the lesioned hindpaw. Such mechanical and cooling allodynia was not observed in sham-operated rats. 3. A significantly greater proportion of spinal neurones of ligated rats exhibited spontaneous activity at post-operative (PO) days 7-10 (P = 0.03) and 14-17 (P = 0.0001), compared with sham controls. The frequency of the spontaneous activity was significantly higher than that of the sham controls (P = 0.03 and P = 0.02 for days 7-10 and days 14-17, respectively). 4. At the earlier PO period, significantly (P = 0.02) more neurones of spinal nerve-ligated (SNL) rats responded to brush compared with the sham controls; at the later PO period the proportion of neurones of SNL rats responsive to prod was significantly (P = 0.007) reduced compared with the sham controls. The magnitude of the evoked neuronal response of SNL rats at PO days 7-10 was comparable to that of the sham controls. The magnitudes of brush- and prod-evoked neuronal responses of SNL rats were significantly smaller (P = 0.05 and P = 0.002, respectively) than the sham controls at PO days 14-17. In addition, neuronal responses of SNL rats to mechanical punctate stimuli and the C fibre-evoked neuronal responses were significantly reduced at the later PO period, compared with sham controls. Abeta-fibre-induced wind-up was not observed under any conditions. 5. These complex changes in neuronal responses are both time and modality dependent. The plasticity of some of the neuronal and behavioural responses following nerve injury was difficult to reconcile. We suggest that an interplay between pathological peripheral and central mechanisms may account for some of the changes that could contribute to allodynia and hyperalgesia.
Acetone↗
Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors.
Development of analgesic agents for the treatment of severe pain requires the identification of compounds that are devoid of opioid receptor liabilities. A potent (inhibition constant = 37 picomolar) neuronal nicotinic acetylcholine receptor (nAChR) ligand called ABT-594 was developed that has antinociceptive properties equal in efficacy to those of morphine across a series of diverse animal models of acute thermal, persistent chemical, and neuropathic pain states. These effects were blocked by the nAChR antagonist mecamylamine. In contrast to morphine, repeated treatment with ABT-594 did not appear to elicit opioid-like withdrawal or physical dependence. Thus, ABT-594 may be an analgesic that lacks the problems associated with opioid analgesia.
Analgesics, Non-Narcotic↗