g(m1)-ganglioside and Pain

In a rat model of morphine tolerance, we examined the hypotheses that thermal hyperalgesia to radiant heat develops in association with the development of morphine tolerance and that both the development and expression of thermal hyperalgesia in morphine-tolerant rats are mediated by central NMDA and non-NMDA receptors and subsequent protein kinase C (PKC) activation. Tolerance to the analgesic effect of morphine was developed in rats utilizing an intrathecal repeated treatment regimen. The development of morphine tolerance and thermal hyperalgesia was examined by employing the tail-flick test and paw-withdrawal test, respectively. Intrathecal MK 801 (an NMDA receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; a non-NMDA receptor antagonist), or GM1 ganglioside (an intracellular PKC inhibitor) treatment was given to examine the effects of these agents on the development and expression of thermal hyperalgesia in morphine-tolerant rats. Tolerance to the analgesic effect of morphine was reliably developed in rats following once daily intrathecal (onto the lumbosacral spinal cord) injection of 10 micrograms of morphine sulfate for 8 consecutive days as demonstrated by the decreased analgesia following morphine administration on day 8 as compared to that on day 1. In association with the development of morphine tolerance, thermal hyperalgesia to radiant heat developed in these same rats. Paw-withdrawal latencies were reliably decreased in morphine-tolerant rats as compared to nontolerant (saline) controls when tested on day 8 before the last morphine treatment and on day 10 (i.e., 48 hr after the last morphine treatment). The coincident development of morphine tolerance and thermal hyperalgesia was potently prevented by intrathecal coadministration of morphine with MK 801 (10 nmol) or GM1 (160 nmol), and partially by CNQX (80 nmol). MK 801 (5, 10 nmol, not 2.5 nmol) and CNQX (80, 160 nmol, not 40 nmol), but not GM1 (160 nmol), also reliably reversed thermal hyperalgesia in rats rendered tolerant to morphine when tested 30 min after each drug treatment on day 10 (48 hr after the last morphine treatment). The data indicate that thermal hyperalgesia develops in association with the development of morphine tolerance and that the coactivation of central NMDA and non-NMDA receptors is crucial for both the development and expression of thermal hyperalgesia in morphine-tolerant rats. Furthermore, intracellular PKC activation plays a critical role in the

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dizocilpine Maleate; Drug Tolerance; Excitatory Amino Acid Antagonists; G(M1) Ganglioside; Hot Temperature; Hyperalgesia; Injections, Spinal; Male; Morphine; Pain; Protein Kinase C; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate

The effect of the ganglioside GM1 on autotomy, a nociceptive behavioral marker for neuropathic pain, and substance P depletion was determined in a rat model of peripheral mononeuropathy, sciatic cryoneurolysis (SCN). SCN is produced by the application of a cryoprobe to the common sciatic nerve using a freeze-thaw-freeze cycle. Due to structural sparing of the nerve, regenerative processes are not precluded. After this peripheral nerve insult, behavioral and neurochemical changes occur that support the use of SCN as a neuropathic pain model. These changes include: autotomy with coincident transient weight loss and paling of eye color suggestive of increased sympathetic activity, spontaneous nociceptive behaviors, touch-evoked allodynia, prolonged mechanical allodynia, ipsilateral decrease of immunoreactive substance P, and increases in spinal cord dynorphin expression. Incidence and severity of autotomy were assessed after the intraperitoneal administration of GM1 (1, 10, and 20 mg/kg) or saline injected daily for 2 days before SCN, the day of surgery, and for 14 days after surgery. In a subset of two rats from each treatment group, transcardiac perfusion was performed and spinal cords were processed for substance P immunoreactivity. GM1 at 10 and 20 mg/kg doses significantly attenuated autotomy as compared with saline-treated rats (P = 0.007 and 0.0001, respectively). However, GM1, at the doses studied, failed to alter the spinal substance P depletion 21 days after SCN. These results indicate that the ganglioside GM1 may have a role in the clinical management of neuropathic pain after peripheral nerve injury.

Topics: Animals; Behavior, Animal; Disease Models, Animal; G(M1) Ganglioside; Male; Pain; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Self Mutilation; Spinal Cord; Substance P

The effect of AGF 44, an ester derivative of ganglioside GM1, on formalin-induced nociceptive behavior was examined in normal and streptozotocin-diabetic rats. AGF 44 (30 mg/kg/day i.p. for 7 days) produced a significant reduction of the second phase (20-40 min) and a lesser degree of suppression of the first phase (1-2 min) of the formalin test in both control and diabetic rats. Diabetic rats showed an increased response during the quiescent period (5-16 min) which was ameliorated by treatment with AGF 44 (30 mg/kg i.p.) for the last 7 days of a 5 week period of diabetes. These results indicate that AGF 44 can diminish responses to a prolonged nociceptive stimulus in both normal and diabetic rats and reduces the exaggerated nociceptive behavior of diabetic rats.

Topics: Animals; Behavior, Animal; Diabetes Mellitus, Experimental; Escape Reaction; Female; Formaldehyde; G(M1) Ganglioside; Male; Nociceptors; Pain; Rats; Rats, Sprague-Dawley

In a rat model of painful peripheral mononeuropathy, this study examined the effects of post-injury treatment with a monosialoganglioside, GM1, on abnormal nociceptive behaviors and spinal cord neural activity resulting from loose ligation of the rat common sciatic nerve (chronic constrictive injury, CCI). Thermal hyperalgesia and spontaneous pain behaviors of CCI rats were assessed by measuring foot-withdrawal latencies to radiant heat and by rating spontaneous hind paw guarding positions, respectively. Neural activity within different regions of the spinal cord was inferred in both CCI and sham-operated rats by employing the [14C]-2-deoxyglucose (2-DG) autoradiographic technique to measure spinal cord glucose metabolism. Intraperitoneal (i.p.) GM1 treatment (10 mg/kg) initiated 1 h or 24 h after injury and once daily for the first 9 post-injury days reduced thermal hyperalgesia of the hind paw ipsilateral to nerve ligation and lowered spontaneous pain behavior rating scores in CCI rats. Sciatic nerve ligation reliably increased basal 2-DG metabolic activity of CCI rats in all four sampled regions (laminae I-IV, V-VI, VII, VIII-IX) of spinal cord lumbar segments (L2-L5) both ipsilateral and contralateral to nerve ligation 10 days after injury. Consistent with the drug's effects on spontaneous pain behaviors, 10 daily GM1 treatments (10 mg/kg, i.p.) initiated 1 h after nerve ligation reduced spinal cord 2-DG metabolic activity in laminae V-VI and VII ipsilateral to nerve ligation and in all four sampled regions contralateral to nerve ligation. This attenuation of the increased spinal cord glucose utilization that occurs in the absence of overt peripheral stimulation may reflect an influence of GM1 on increased neural activity contributing to spontaneous pain. Since gangliosides are thought to protect neurons from excitotoxic effects of excitatory amino acids, these results suggest that ganglioside treatment may result in attenuation of excitatory neurotoxicity that may occur following peripheral nerve injury. Thus, ganglioside treatment could provide a new approach to the clinical management of neuropathic pain syndromes following peripheral nerve injury.

Topics: Animals; Behavior, Animal; Female; G(M1) Ganglioside; Glucose; Pain; Pain Measurement; Peripheral Nervous System Diseases; Rats; Rats, Inbred Strains; Sciatic Nerve; Spinal Cord

Our previous experiments demonstrated that systemic treatment with GM1 ganglioside reduces nociceptive behaviors and spinal cord metabolic activity in a rat model of painful peripheral mononeuropathy produced by experimental sciatic nerve ligation (chronic constrictive injury, CCI). In the present study, we examined the effects of intrathecal (i.t.) GM1 treatment on thermal hyperalgesia and spontaneous pain behaviors resulting from nerve ligation in order to determine the locus of GM1 action. In addition, a local anesthetic agent, bupivacaine, given alone or combined with i.t. GM1, was applied to the injured sciatic nerve to determine if peripheral nerve anesthesia would influence post-injury nociceptive behaviors. Thermal hyperalgesia to radiant heat decreased in a dose-dependent manner when GM1 (10-80 nmol, i.t.) was administered once daily onto the lumbar segments of the spinal cord beginning 1 h after experimental nerve injury and continued for the first 9 days after nerve ligation. Moreover, this GM1 (80 nmol) treatment regimen reliably lowered spontaneous pain behavior rating scores in CCI rats suggesting the possible attenuation of spontaneous pain. The central site of i.t. GM1 action is located at the caudal (probably lumbar) spinal cord, since i.t. injection of 20 nmol GM1 onto the cervical spinal cord did not produce any protective effect. A single perinerve injection of a local anesthetic agent, bupivacaine (0.5%, 0.6 ml), on the 3rd day after nerve ligation reduced thermal hyperalgesia for at least 24 h following injection, a duration longer than that of the local anesthetic action of bupivacaine. Neither a single bupivacaine injection nor four daily i.t.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anesthesia, Local; Animals; Behavior, Animal; Bupivacaine; G(M1) Ganglioside; Injections, Spinal; Male; Pain; Pain Measurement; Peripheral Nervous System Diseases; Rats; Rats, Inbred Strains; Sciatic Nerve

Neuropathic pain following nerve injury is thought to involve central nervous system Ca(2+)-mediated neuronal plastic changes. This study provides evidence that induction and/or maintenance of post-injury neuropathic pain behaviors in the rat is associated with increases in membrane-bound protein kinase C (PKC), a Ca(2+)-dependent process known to mediate central nervous system neuronal plasticity. In addition, spinal cord administration of GM1 ganglioside, an intracellular inhibitor of PKC translocation/activation, reverses both increased levels of membrane-bound PKC and pain-related behaviors. Thus, persistent post-injury neuropathic pain may be mediated by the initiation of excitatory neuropathological processes resulting from an increase in membrane-bound PKC.

Topics: Animals; Behavior, Animal; G(M1) Ganglioside; Pain; Peripheral Nerve Injuries; Phorbol 12,13-Dibutyrate; Protein Kinase C; Rats; Spinal Cord