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Órgano Oficial del Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz

2009, Number 2

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Salud Mental 2009; 32 (2)

Systemic amantadine diminishes inflammatory and neuropathic nociception in the rat

Coffeen U, López-Ávila A, Pellicer F

Language: English
References: 36
Page: 139-144
PDF size: 129.74 Kb.


ABSTRACT

The role of dopamine as a possible central inhibitory mediator of pain processes has been demonstrated. The administration of L-Dopa diminishes pain perception in humans as well as the response to nociceptive stimuli in animals. Also, the intracerebral microinjection of dopamine in inflammatory and neuropathic pain models (formalin test and deafferentation, respectively) reduces nociceptive response. In this sense, the selective activation of dopamine D2 receptors and the blockade of D1 in the insular cortex and spinal cord diminish nociception. Furthermore, the microinjection of dopamine or amantadine (dopamine releaser) in the anterior cingulate cortex (ACC) also reduces chronic nociception.
The efficacy of amantadine has been tested in the treatment of neuropathic pain, even when given as a single dose. There is evidence of the role of amantadine as a releaser of dopamine (DA) calcium channel (N type) dependent in the striatum as well as a low affinity non-competitive antagonist of blockade/non-blockade kinetics of the NMDA receptor. This compound has also been described as a DA agonist and an inhibitor of its reuptake. With this background, we decided to test if the effects of systemically given amantadine related to acute nociception, hyperalgesia and neuropathic nociception can be reverted by a dopaminergic blockade (using haloperidol) within the ACC.
The experiments were conducted in agreement with the Ethics Committee of the International Association for the Study of Pain and the approval of the Projects Commission of the Instituto Nacional de Psiquiatría Ramón de la Fuente (INPRF).
Male Wistar rats (250-300 g) were housed in the INPRF. During the observation period, the animals were maintained in transparent acrylic individual cages with light-dark cycles of 12 × 12 h, with feeding and hydration ad libitum.
For all surgical procedures, rats were anaesthetised with halothane 2% mixed with O2 98%.
In order to test the dopaminergic effect of amantadine within the ACC in nociception, we used the hyperalgesia model as well as a neuropathic nociception model induced by denervation. In the model of hyperalgesia, carrageenan was injected in the plantar region (50 µl at 1%), followed by a thermonociception test in which paw withdrawal latency was measured. In the neuropathic nociception model, the right sciatic nerve was denervated and chronic nociception was measured as autotomy behaviour.
Moreover, in another series of experiments, haloperidol (3 mg/200 nl) was microinjected into the ACC before the induction of hyperalgesia and neuropathic nociception. Amantadine was then injected (90 mg/kg i.p.) and the behavioural development was observed in both models.
Systemic amantadine was able to reduce both neuropathic nociception and hyperalgesia. Also, the results show, on the one hand, that haloperidol significantly decreases the antinociceptive effect of amantadine measured as paw withdrawal latency. On the other hand, amantadine can reduce nociception when administered systemically and, according to what has been published previously, when administered directly into the ACC.
Our results show that amantadine is effective in diminishing hyperalgesia and nociception induced by deafferentation. This suggests that amantadine can be a therapeutic alternative for the treatment and prevention of neuropathic pain such as phantom limb pain or pain due to deafferentation, among others.


REFERENCES

  1. Saade NE, Atweh SF, Bahuth NB, Jabbur SJ. Augmentation of nociceptive reflexes and chronic deafferentation pain by chemical lesions of either dopaminergic terminals or midbrain dopaminergic neurons. Brain Res 1997;751:1-12.

  2. Magnusson JE, Fisher K. The involvement of dopamine in nociception: the role of D1 and D2 receptors in the dorsolateral striatum. Brain Res 2000;855:260-6.

  3. Wood PB. Mesolimbic dopaminergic mechanisms and pain control. Pain 2006;120:230-4.

  4. Ertas M, Sagduyu A, Arac N, Uludag B, Ertekin C. Use of levodopa to relieve pain from painful symmetrical diabetic polyneuropathy. Pain 1998;75:257-9.

  5. Paalzow GH. L-dopa induces opposing effects on pain in intact rats: (-)- sulpiride, SCH 23390 or alpha-methyl-DL-p-tyrosine methylester hydrochloride reveals profound hyperalgesia in large antinociceptive doses. J Pharmacol Exp Ther 1992;263:470-9.

  6. Franklin KB. Analgesia and the neural substrate of reward. Neurosci Biobehav Rev 1989;13:149-54.

  7. Lyerly MA, Rossitch E Jr., Ovelmen-Levitt J, Nashold BS Jr. The deafferentation syndrome in the rat: effects of intraventricular apomorphine. Exp Neurol 1988;100:188-202.

  8. Morgan MJ, Franklin KB. Dopamine receptor subtypes and formalin test analgesia. Pharmacol Biochem Behav 1991;40: 317-22.

  9. Sotres-Bayon F, Torres-Lopez E, Lopez-Avila A, Del Angel R, Pellicer F. Lesion and electrical stimulation of the ventral tegmental area modify persistent nociceptive behavior in the rat. Brain Res 2001;898:342-9.

  10. Gao X, Zhang Y, Wu G. Effects of dopaminergic agents on carrageenan hyperalgesia after intrathecal administration to rats. Eur J Pharmacol 2001;418:73-7.

  11. Coffeen U, Lopez-Avila A, Ortega-Legaspi JM, Del Angel R, Lopez- Munoz FJ et al. Dopamine receptors in the anterior insular cortex modulate long-term nociception in the rat. Eur J Pain 2008;12:535-43.

  12. Lopez-Avila A, Coffeen U, Ortega-Legaspi JM, Del Angel R, Pellicer F. Dopamine and NMDA systems modulate long-term nociception in the rat anterior cingulate cortex. Pain 2004; 111:136-43.

  13. Pud D, Eisenberg E, Spitzer A, Adler R, Fried G et al. The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: a double blind, randomized, placebo controlled trial. Pain 1998;75:349-54.

  14. Eisenberg E, Pud D. Can patients with chronic neuropathic pain be cured by acute administration of the NMDA receptor antagonist amantadine? Pain 1998;74:337-9.

  15. Takahashi T, Yamashita H, Zhang YX, Nakamura S. Inhibitory effect of MK-801 on amantadine-induced dopamine release in the rat striatum. Brain Res Bull 1996;41:363-7.

  16. Kornhuber J, Quack G, Danysz W, Jellinger K, Danielczyk W et al. Therapeutic brain concentration of the NMDA receptor antagonist amantadine. Neuropharmacol 1995;34:713-21.

  17. Kornhuber J, Bormann J, Hubers M, Rusche K, Riederer P. Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor- gated ion channel: a human postmortem brain study. Eur J Pharmacol 1991;206:297-300.

  18. Karobath M, Leitich H. Antipsychotic drugs and dopamine-stimulated adenylate cyclase prepared from corpus striatum of rat brain. Proc Nat Acad Sci 1974;71:2915-8.

  19. Vernier VG, Harmon JB, Stump JM, Lynes TE, Marvel JP et al. The toxicologic and pharmacologic properties of amantadine hydrochloride. Toxicol Appl Pharmacol 1969;15: 642-65.

  20. Fletcher EA, Redfern PH. The effect of amantadine on the uptake of dopamine and noradrenaline by rat brain homogenates. J Pharm Pharmacol 1970;22:957-9.

  21. Heikkila RE, Cohen G. Evaluation of amantadine as a releasing agent or uptake blocker for H 3 -dopamine in rat brain slices. Eur J Pharmacol 1972;20:156-60.

  22. Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983;16:109-10.

  23. Lopez-Avila A, Sotres-Bayon F, Del Angel R, Pellicer F. Time span between nociceptive stimulus and denervation modifies autotomy behavior in the rat. Analgesia 1999;4:475-78.

  24. Wall PD, Scadding JW, Tomkiewicz MM. The production and prevention of experimental anesthesia dolorosa. Pain 1979;6:175-82.

  25. Albe-Fessard D, Giamberardino MA, Rampin O. Comparison of different animal models of chronic pain. In: S. L (ed.). Ad Pain Res Ther. New York: Raven Press; 1990; p. 11-27.

  26. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988;32:77-88.

  27. Lopez-Avila A, Rodriguez-Manzo G, Coffeen U, Del Angel R, Pellicer F. Self-injury behaviour induced by intraplantar carrageenan infiltration: a model of tonic nociception. Brain Res Prot 2004;13:37-44.

  28. Johansen JP, Fields HL, Manning BH. The affective component of pain in rodents: direct evidence for a contribution of the anterior cingulate cortex. Proc Nat Acad Sci 2001;98:8077-82.

  29. Pellicer F, Torres-López E, Sotres-Bayón F, López-Avila A, Coffeen U et al. The affective and cognitive dimension of nociception in an animal model: The role of the anterior cingulate cortex. In: Lucas A (ed.). Prog Pain Res; 2006.

  30. Treede RD, Kenshalo DR, Gracely RH, Jones AK. The cortical representation of pain. Pain 1999;79:105-11.

  31. Treede RD. Assessment of pain as an emotion in animals and in humans[comment]. Exp Neurol 2006;197:1-3.

  32. Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000;288:1769-72.

  33. Zhuo M. Neuronal mechanism for neuropathic pain. Molecular Pain 2007;3:14.

  34. Willis WD, Coggeshall RE. Sensory mechanisms of the spinal cord. Plenum Press; 1991.

  35. Basbaum AI. Effects of central lesions on disorders produced by multiple dorsal rhizotomy in rats. Exp Neurol 1974;42:490-501.

  36. Coderre TJ, Melzack R. Procedures which increase acute pain sensitivity also increase autotomy. Exp Neurol 1986;92: 713-22.




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