Ketamine blocks enhancement of spinal long-term potentiation in chronic opioid treated rats.

BACKGROUND: Long-term opioid treatment is associated with the development of hyperalgesia. In a rat model we wanted to study if chronic opioid treatment changed the induction and maintenance of spinal long-term potentiation (LTP), a form of hyperexcitability in the spinal cord. We also wanted to investigate if the clinically available NMDA receptor antagonist ketamine inhibited the effect of chronic opioid treatment on LTP. METHODS: The animals were randomized into four groups (saline, morphine 20 mg/kg/day, ketamine 20 mg/kg/day, morphine 20 mg/kg/day and ketamine 20 mg/kg/day). Drugs were given as continuous subcutaneous infusions by means of osmotic minipumps. After 7 days of treatment and during ongoing treatment single unit extracellular recordings were made from the lumbar deep dorsal horn under urethane anesthesia. Single electrical stimuli were applied to the sciatic nerve, and the C-fiber evoked responses of WDR neurons were recorded before and during 3 h following low frequency (3 Hz) electrical conditioning stimulation. RESULTS: The potentiation of C-fiber evoked responses by conditioning stimulation was significantly increased in the morphine-treated group compared to the saline group, while there was no significant difference between the saline, the ketamine and the morphine/ketamine groups. The potentiated responses in the morphine/ketamine group were significantly reduced compared to the morphine group (P=0.01). CONCLUSION: Our results indicate that animals treated with long-term opioid show amplification of stimulus-induced central sensitisation compared to opioid naïve animals. Ketamine inhibited the morphine-induced enhancement of LTP, supporting the role of ketamine in prevention of opioid induced hyperalgesia.

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.

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.

Expression of long-term potentiation in single wide dynamic range neurons in the rat is sensitive to blockade of glutamate receptors.

Plasticity in pain control systems may play an important role in clinical pain and some mechanisms of plasticity may be similar to those involved in learning. In this study we investigate the importance of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors for the maintenance of long-term potentiation (LTP) in wide dynamic range (WDR) neurons. Doses of 6-nitro-7-sulphomoylbenzoylquinoxaline-2,3-dione disodium (NBQX) and D-Q-amino-5-phosphonopentanoic acid (D-AP5) equipotent in reducing C-fiber mediated responses in controls, reduced the established LTP by about 50 and 80%, respectively. The drug effect lasted less than 1 h in controls. After induction of LTP, NBQX caused a reversible reduction of the potentiation. D-AP5, however, caused a stronger attenuation of the LTP, outlasting the effect of the drug in controls. We suggest that both pre-emptive analgesia preventing LTP induction and an early reduction of the excitation of neurons is important for the inhibition of LTP and central sensitization. Thus, it is possible that an early antinociceptive treatment preventing an excessive excitation of neurons in the dorsal horn may be of importance in preventing longlasting and pathological pain states.

Recording of long-term potentiation in single dorsal horn neurons in vivo in the rat.

We have published several reports on long-term potentiation (LTP) in single spinal wide dynamic range (WDR) neurons (responding to both innocuous and noxious stimuli) in urethane-anaesthetised rats. The protocol presented here, with single unit recordings of dorsal horn neurons before and after a nociceptive conditioning stimulation, may be useful in many electrophysiological studies of plastic changes in the spinal cord, such as LTP. We invite others to use this protocol for the study of spinal plasticity. Findings using this technique may be relevant for the understanding of changes in nociceptive transmission, induction of central sensitisation and maybe even in mechanisms of pathological pain and chronic pain states. We describe modified and alternative protocols for the study of LTP mechanisms under different conditions in intact and in spinalised animals, and after natural noxious stimuli. We present a novel method minimising peripheral influence of afferent input induced by antidromic neurogenic inflammation or inflammatory changes following a natural noxious stimulation. This is made possible by dissection of the sciatic nerve at two separate locations and local anaesthetic block distal to the stimulation site.

The COMT rs4680 Met allele contributes to long-lasting low back pain, sciatica and disability after lumbar disc herniation.

BACKGROUND: The COMT enzyme metabolizes catecholamines and thus modulates adrenergic, noradrenergic and dopaminergic signaling. A functional polymorphism in the gene encoding this enzyme, i.e. the COMT Val158Met SNP that reduces enzyme activity, has previously been linked to pain sensitivity. METHODS: We examined if the COMT Val158Met SNP could contribute to discogenic subacute low back pain and sciatica by comparing the frequency of the Val158Met genotypes of degenerative disc disease patients with healthy controls. Moreover, we examined if this SNP could predict the clinical outcome, i.e. the progression of pain and disability. RESULTS: The present data demonstrated that there were no differences in COMT genotype frequencies between the newly diagnosed patients and controls. Analysis of pain and disability in the patients over time revealed, however, a significant or border-line significant increase in McGill sensory score and Oswestry Disability Index (ODI) score for individuals with COMT Met/Met genotype. Furthermore, significant associations between the COMT Met-allele and VAS activity score, McGill sensory score and ODI score were observed in the patients 6 months after inclusion. DISCUSSION: Although the Val158Met SNP was not a risk factor for disc herniation, patients with Met/Met had more pain and slower recovery than those with Val/Met, which in turn also had more pain and slower recovery than those with Val/Val suggesting the SNP contributes to the progression of the symptoms of disc herniation. CONCLUSION: We conclude that the functional COMT Val158Met SNP contributes to long lasting low back pain, sciatica and disability after lumbar disc herniation.

[Future pain treatment]. / Fremtidig smertebehandling.

BACKGROUND: The recent rapid progress in pain research is due in large part to advances in genetics and cell and molecular biology. We now know that chronic pain (hypersensitivity due to inflammation or nerve injury) and acute nociceptive pain are different and must be treated accordingly. We will continue to reveal sophisticated mechanisms underlying different kinds of pain that can be targeted to inhibit nociceptive transmission and produce analgesia. METHODS: This review is based upon literature collected through the authors' own reading and through PubMed searches. New hopes for future pain treatments are discussed. Further, the impact of genetic factors on pain sensitivity and pain modulation are discussed, and conceivable therapeutic approaches based on genetic techniques are mentioned. RESULT: At the level of the peripheral nerve, many novel targets have recently been identified: the tetrodotoxin-resistant sodium channel, the vanilloid receptor and different calcium channels are very interesting. In the spinal cord, different approaches can be used: to either block excitatory input or to increase inhibitory control or to do both at the same time. The mechanisms for hypersensitivity are being identified and offer multiple possible targets for novel analgesics. INTERPRETATION: Many interesting targets for analgetics has emerged during that last few years, lending great hope for new and better (i.e. with less side effects) analgesic drugs in the future.

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.