Fundytus, et al. (2001): Knockdown of spinal metabotropic glutamate receptor 1 (mGluR1) alleviates pain and restores opioid efficacy after nerve injury in rats

[Wise Young]

British Journal of Pharmacology 132:354-367 (2001)
© Nature Publishing Group 2001

Knockdown of spinal metabotropic glutamate receptor 1 (mGluR1) alleviates pain and restores opioid efficacy after nerve injury in rats
Marian E. Fundytus*,1,2,3, Kiran Yashpal3, Jean-Guy Chabot4, Michael G. Osborne3, Celeste D. Lefebvre3, Andy Dray2, James L. Henry1,5 and Terence J. Coderre3,6

1 Department of Physiology, McGill University, Montreal, Quebec, Canada
2 ASTRA Research Centre Montreal, Montreal, Quebec, Canada
3 Pain Mechanisms Laboratory, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
4 Douglas Hospital Research Centre, Montreal, Montreal, Quebec, Canada
5 Department of Psychiatry, McGill University, Montreal, Quebec, Canada
6 Département de médecine, Université de Montréal, Montreal, Quebec, Canada

*Correspondence: Marian E. Fundytus, Department of Oncology, Division of Palliative Care, McGill University, Ross 6.10, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1; E-mail: marian.fundytus@muhc.mcgill.ca


1. Nerve injury often produces long-lasting spontaneous pain, hyperalgesia and allodynia that are refractory to treatment, being only partially relieved by clinical analgesics, and often insensitive to morphine. With the aim of assessing its therapeutic potential, we examined the effect of antisense oligonucleotide knockdown of spinal metabotropic glutamate receptor 1 (mGluR1) in neuropathic rats.

2. We chronically infused rats intrathecally with either vehicle, or 50 µg day-1 antisense or missense oligonucleotides beginning either 3 days prior to or 5 days after nerve injury. Cold, heat and mechanical sensitivity was assessed prior to any treatment and again every few days after nerve injury.

3. Here we show that knockdown of mGluR1 significantly reduces cold hyperalgesia, heat hyperalgesia and mechanical allodynia in the ipsilateral (injured) hindpaw of neuropathic rats.

4. Moreover, we show that morphine analgesia is reduced in neuropathic rats, but not in sham-operated rats, and that knockdown of mGluR1 restores the analgesic efficacy of morphine.

5. We also show that neuropathic rats are more sensitive to the excitatory effects of intrathecally injected N-methyl-D-aspartate (NMDA), and have elevated protein kinase C (PKC) activity in the spinal cord dorsal horn, two effects that are reversed by knockdown of mGluR1.

6. These results suggest that activity at mGluR1 contributes to neuropathic pain through interactions with spinal NMDA receptors and PKC, and that knockdown of mGluR1 may be a useful therapy for neuropathic pain in humans, both to alleviate pain directly, and as an adjunct to opioid analgesic treatment.

British Journal of Pharmacology (2001) 132, 354 - 367


Keywords: Knockdown; antisense oligonucleotide; metabotropic glutamate receptor; neuropathy; hyperalgesia; allodynia; pain; opioid analgesia; NMDA sensitivity; nerve injury


Abbreviations: ACSF, artificial cerebrospinal fluid; AS, antisense; AUC, area under the curve; DHPG, dihydroxyphenylglycine; LSD, least significant difference; mGluR, metabotropic glutamate receptor; MS, missense; NMDA, N-methyl-D-aspartate; PAG, periaqueductal gray; PDBu, phorbol-12,13-dibutyrate; PI, phosphatidylinositol; PKC, protein kinase C; PO, phosphodiester bonded; PS, phosphorothioate modified; (S)-4CPG, (S)-4-carboxyphenylglycine; SNB, spontaneous nociceptive behaviour