dizocilpine-maleate and Hyperesthesia

Our previous study has reported that electroacupuncture (EA) at low frequency of 2 Hz had greater and more prolonged analgesic effects on mechanical allodynia and thermal hyperalgesia than that EA at high frequency of 100 Hz in rats with neuropathic pain. However, how EA at different frequencies produces distinct analgesic effects on neuropathic pain is unclear. Neuronal plastic changes in spinal cord might contribute to the development and maintenance of neuropathic pain. In the present study, we investigated changes of spinal synaptic plasticity in the development of neuropathic pain and its modulation by EA in rats with neuropathic pain. Field potentials of spinal dorsal horn neurons were recorded extracellularly in sham-operated rats and in rats with spinal nerve ligation (SNL). We found for the first time that the threshold for inducing long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn was significantly lower in SNL rats than that in sham-operated rats. The threshold for evoking the C-fiber-evoked field potentials was also significantly lower, and the amplitude of the field potentials was higher in SNL rats as compared with those in the control rats. EA at low frequency of 2 Hz applied on acupoints ST 36 and SP 6, which was effective in treatment of neuropathic pain, induced long-term depression (LTD) of the C-fiber-evoked potentials in SNL rats. This effect could be blocked by N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 and by opioid receptor antagonist naloxone. In contrast, EA at high frequency of 100 Hz, which was not effective in treatment of neuropathic pain, induced LTP in SNL rats but LTD in sham-operated rats. Unlike the 2 Hz EA-induced LTD in SNL rats, the 100 Hz EA-induced LTD in sham-operated rats was dependent on the endogenous GABAergic and serotonergic inhibitory system. Results from our present study suggest that (1) hyperexcitability in the spinal nociceptive synaptic transmission may occur after nerve injury, which may contribute to the development of neuropathic pain; (2) EA at low or high frequency has a different effect on modulating spinal synaptic plasticities in rats with neuropathic pain. The different modulation on spinal LTD or LTP by low- or high-frequency EA may be a potential mechanism of different analgesic effects of EA on neuropathic pain. LTD of synaptic strength in the spinal dorsal horn in SNL rats may contribute to the long-lasting analgesic effects of EA at 2 Hz.

Topics: Action Potentials; Animals; Bicuculline; Dizocilpine Maleate; Drug Combinations; Electroacupuncture; Excitatory Amino Acid Antagonists; GABA Antagonists; Hyperesthesia; Ligation; Long-Term Synaptic Depression; Male; Methysergide; Naloxone; Narcotic Antagonists; Nerve Fibers, Unmyelinated; Neuralgia; Neuronal Plasticity; Pain Threshold; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Spinal Nerves; Synapses; Time Factors

The purpose of this study was to investigate the expression of c-fos in the spinal cord during the development of allodynia, induced by peripheral nerve injury. Following tight ligation of the left L5 and L6 spinal nerves of Sprague- Dawley rat, the lumbar spinal cord was postfixed following perfusion. Frontal frozen sections of 40 microm were immunostained according to the peroxidase-antiperoxidase method. The allodynic threshold was checked with 8 calibrated von Frey filaments. MK-801 (0.3 mg/kg), morphine (3 mg/kg) and saline (as a placebo) were administered subcutaneously 30 min before, and 24 and 48 hrs after surgery. The tactile threshold decreased below 3 g since 2 days after surgery in the saline and morphine groups, but delayed a little in the MK-801 group. In the superficial layer the number of Fos-like immunoreactive neurones (Fos-LI) peaked at 2 hours and decreased thereafter, and reached normal levels 24 hrs following operation, for all groups. In the deep layer they were biphasic, - peaking at 2 and 24 hrs - in the saline group, but were suppressed in the morphine and MK-801 groups until 7 days following operation. The above discrepancy between the number of Fos-LI and the allodynic threshold showed that central sensitizations are not critically involved in the development of nerve injury induced tactile allodynia.

Topics: Analgesics, Opioid; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperesthesia; Ligation; Male; Morphine; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Nerves; Wounds and Injuries

Whereas tissue injury increases spinal dynorphin expression, the functional relevance of this upregulation to persistent pain is unknown. Here, mice lacking the prodynorphin gene were studied for sensitivity to non-noxious and noxious stimuli, before and after induction of experimental neuropathic pain. Prodynorphin knock-out (KO) mice had normal responses to acute non-noxious stimuli and a mild increased sensitivity to some noxious stimuli. After spinal nerve ligation (SNL), both wild-type (WT) and KO mice demonstrated decreased thresholds to innocuous mechanical and to noxious thermal stimuli, indicating that dynorphin is not required for initiation of neuropathic pain. However, whereas neuropathic pain was sustained in WT mice, KO mice showed a return to baselines by post-SNL day 10. In WT mice, SNL upregulated lumbar dynorphin content on day 10, but not day 2, after injury. Intrathecal dynorphin antiserum reversed neuropathic pain in WT mice at post-SNL day 10 (when dynorphin was upregulated) but not on post-SNL day 2; intrathecal MK-801 reversed SNL-pain at both times. Opioid (mu, delta, and kappa) receptor density and G-protein activation were not different between WT and KO mice and were unchanged by SNL injury. The observations suggest (1) an early, dynorphin-independent phase of neuropathic pain and a later dynorphin-dependent stage, (2) that upregulated spinal dynorphin is pronociceptive and required for the maintenance of persistent neuropathic pain, and (3) that processes required for the initiation and the maintenance of the neuropathic pain state are distinct. Identification of mechanisms that maintain neuropathic pain appears important for strategies to treat neuropathic pain.

Topics: Animals; Chronic Disease; Disease Models, Animal; Dizocilpine Maleate; Dynorphins; Excitatory Amino Acid Antagonists; Hyperesthesia; Immune Sera; Injections, Spinal; Ligation; Lumbosacral Region; Male; Mice; Mice, Knockout; Neuralgia; Pain Measurement; Pain Threshold; Physical Stimulation; Reaction Time; Receptors, Opioid; Spinal Cord; Spinal Nerves

Antagonists of NMDA glutamate receptors have been shown to alleviate neuropathic pain in rats and humans. However, NMDA antagonists can cause significant side effects ranging from behavioral disturbances to injury of neurons in the posterior cingulate/retrosplenial (PC/RS) cortex. We have found that alpha-2 adrenergic agonists prevent the PC/RS neurotoxic side effects of NMDA antagonists. In the present study of adult female rats subjected to sciatic nerve ligation (Bennett neuropathic pain model) and tested for paw withdrawal latency (PWL) following a thermal stimulus, we evaluated the ability of the NMDA antagonist, MK-801, to alleviate neuropathic pain either by itself or when administered together with the alpha-2 adrenergic agonist, clonidine. We found that MK-801, at a dose (0.05 mg/kg s.c.) that is known to cause mild hyperactivity but is subthreshold for producing PC/RS neurotoxic changes, relieved the neuropathic pain state associated with sciatic nerve ligation. However, the relief at this dose was very transient, and no neuropathic pain-relieving effect was observed at a lower dose (0. 025 mg/kg s.c.) of MK-801. Clonidine, at a dose (0.05 mg/kg s.c.) that prevents the cerebrocortical neurotoxic effects of MK-801, decreased sensitivity to the thermal stimulus equally under all conditions (ligated, sham ligated, unoperated), but did not specifically relieve neuropathic pain in the ligated limb. Combining this dose of clonidine with an ineffective dose (0.025 mg/kg s.c.) of MK-801 provided specific, complete and long lasting (up to 4 h) relief from neuropathic pain. Rats receiving this drug combination did not display hyperactivity or any other behavioral disturbance typically associated with MK-801 treatment, nor show neurotoxic changes in cerebrocortical neurons. In separate experiments on normal unoperated rats, we found that clonidine (0.05 mg/kg s.c.) counteracted the hyperactivity induced by MK-801 (0.05 mg/kg s.c.) and returned activity levels to a normal range. These findings signify that clonidine, which does not specifically relieve neuropathic pain, can potentiate the neuropathic pain-relieving action of MK-801, while also protecting against neurotoxicity and hyperactivity side effects of MK-801. The potentiation is of a sufficient magnitude that it permits cutting the MK-801 dose requirement in half, thereby achieving prolonged neuropathic pain relief while doubling the margin of safety against any type of side effect that might be med

Topics: Adrenergic alpha-Agonists; Analysis of Variance; Animals; Clonidine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Female; Hindlimb; Hyperesthesia; Hyperkinesis; Neuralgia; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Sciatic Nerve

It is known that peripheral nerve injury induces time-dependent changes in dorsal horn function. The current study investigated the time dependency of the effects of intrathecal morphine and MK-801, an N-methyl-D-aspartate antagonist, on the thermal hyperesthesia evoked by unilateral constriction injury to the sciatic nerve in the rat.. In rats with a unilateral constriction injury to the sciatic nerve, paw withdrawal latency against thermal stimulation for the injured paw was typically 3 s less than that for the uninjured paw during the first 5 weeks after the injury. Drugs were administered intrathecally 1 or 5 weeks after the nerve injury.. Intrathecal morphine increased the paw withdrawal latencies of both the injured paw and the uninjured paw in an equally dose dependent manner in the 1-week study. In the 5-week study, morphine increased the paw withdrawal latency of the uninjured paw in a dose-dependent manner, but not that of the injured paw. Intrathecal MK-801 increased the paw withdrawal latency of the injured paw to the level of the uninjured paw in a dose-dependent manner in both the 1- and 5-week studies.. These data indicate that (1) an N-methyl-D-aspartate receptor-mediated spinal facilitation may be the common mechanism maintaining the thermal hyperesthesia evoked by the constriction injury, and (2) the effects of intrathecal morphine on this thermal hyperesthesia are time-dependent.

Topics: Animals; Constriction, Pathologic; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hot Temperature; Hyperesthesia; Injections, Spinal; Male; Morphine; Naloxone; Rats; Rats, Sprague-Dawley; Reflex; Sciatic Nerve; Time Factors

Usually, a barrage of impulses ("injury discharge") is evoked following sensory nerve damage. It has been suggested that injury discharge may produce the hyperexcitatory state in the spinal cord, and this hyperexcitability may cause neurogenic pain. In the present study, the authors examined the role of injury discharge in developing the hyperesthetic state following nerve constriction injury.. A model of thermal hyperesthesia caused by a constriction injury created by making four loose ligations around the rat sciatic nerve was examined. To block the injury discharge, 0.5% bupivacaine was applied to the sciatic nerve before constriction injury. To block the hyperexcitatory state, (+)-MK-801, an N-methyl-D-aspartate antagonist, was administered intrathecally 15 min before the nerve lesion.. Blocking injury discharge significantly delayed the development of hyperesthesia. Bupivacaine had no effect on the development of hyperesthesia when bupivacaine was applied to the sciatic nerve 15 min after the nerve constriction injury. Systemic bupivacaine had no effect on the development of thermal hyperesthesia. Intrathecal (+)-MK-801 also delayed the development of hyperesthesia when (+)-MK-801 was administered intrathecally 15 min before the nerve injury. When (+)-MK-801 was administered 15 min after the nerve injury, (+)-MK-801 had no effect on the development of hyperesthesia.. These results suggest that injury discharge may induce facilitation of spinal dorsal horn neurons, and this spinal facilitation may play an important role in developing thermal hyperesthesia following sciatic nerve constriction injury.

Topics: Animals; Constriction, Pathologic; Dizocilpine Maleate; Hot Temperature; Hyperesthesia; Injections, Spinal; Nerve Fibers; Rats; Sciatic Nerve

The spinal mechanisms underlying the hyperesthetic state during inflammation are little understood. To gain a better understanding of these mechanisms, this study evaluated the effects of intrathecal morphine; MK-801, an N-methyl-D aspartic (NMDA) antagonist; and CP-96,345, an NK1 antagonist, on the hyperesthesia observed after carageenan injection of the rat paw.. In rats injected with 2 mg carageenan, the paw withdrawal latency (PWL) for the injected paw was typically 5-6 s less than that for the untreated paw, at 2 h after the carageenan injection. Drugs were administered 2 h after the carageenan injection. The magnitude of hyperesthesia was evaluated with the difference score (DS), which was calculated by subtracting the PWL of the untreated paw from the PWL of the injected paw.. Intrathecal morphine increased PWLs of both the injected and the untreated paws equally in a dose-dependent manner, but intrathecal morphine did not affect the level of DS. Intrathecal MK-801 increased PWLs of the injected paw to the level of the untreated paw in a dose-dependent manner and increased the DS levels. Intrathecal CP-96,345 had no effect on PWLs of either the injected or the untreated paw. Coadministration of MK-801 with morphine reduced the DS for each dose of morphine.. These data indicate that (1) an NMDA receptor, but not an NK1 receptor, plays an important role in maintaining the hyperesthesia after carageenan injection; and (2) NMDA antagonism has a simple additive interaction with morphine in the carageenan model of inflammatory hyperesthesia.

Topics: Animals; Biphenyl Compounds; Carrageenan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Hyperesthesia; Injections, Spinal; Male; Morphine; N-Methylaspartate; Neurokinin B; Rats; Rats, Sprague-Dawley

This study evaluated the effects of intrathecally coadministered morphine and the N-methyl-D-aspartate (NMDA) antagonist (+)5-methyl-10,11-dihydro-5H- dibenzocyclohepten-5,10-imine maleate (MK-801) on the thermally evoked hindpaw withdrawal latency (PWL) in rats with one paw (ipsilteral) rendered hyperesthetic by the unilateral application of loose ligatures to the sciatic nerve (delta PWL (+/- S.D.) = PWLhyperesthetic paw - PWLnormal paw = -3.1 +/- 1.2 s). Intrathecal morphine produced a dose-dependent (0.1-10 micrograms; P less than 0.0001) elevation in the thermal response latency of both the contralateral (normal) and ipsilateral (hyperesthetic) paw. delta PWL did not vary with morphine, indicating that the dose-response curves were parallel but shifted to the right for the hyperesthetic paw. For the normal paw, MK-801 (10 micrograms) was without effect upon the response latency; whereas, the response latency of the hyperesthetic paw was elevated to the same as the normal paw, i.e. the hyperesthesia was selectively abolished (delta PWL (+/- S.D.) = -0.067 +/- 2.73). Co-administration of MK-801 with morphine did not alter the effects of morphine in the normal paw, but reduced the delta PWL for each dose of morphine. These results suggest that NMDA antagonism (1) does not alter the thermal sensitivity in the normal paw, (2) selectively abolishes the hypersensitivity of the hypersthetic paw and (3) has a simple additive interaction with the antinociceptive effects of morphine in the hyperesthetic paw.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Drug Interactions; Hot Temperature; Hyperesthesia; Injections, Spinal; Male; Morphine; N-Methylaspartate; Pain; Peripheral Nervous System Diseases; Rats; Rats, Inbred Strains; Sciatic Nerve; Spinal Cord; Time Factors