Knockdown of spinal metabotropic glutamate receptor 1 (mGluR(1)) alleviates pain and restores opioid efficacy after nerve injury in rats.
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 (mGluR(1)) in neuropathic rats. 2. We chronically infused rats intrathecally with either vehicle, or 50 microg 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 mGluR(1) 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 mGluR(1) 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 mGluR(1). 6. These results suggest that activity at mGluR(1) contributes to neuropathic pain through interactions with spinal NMDA receptors and PKC, and that knockdown of mGluR(1) may be a useful therapy for neuropathic pain in humans, both to alleviate pain directly, and as an adjunct to opioid analgesic treatment.
Fundytus
M E
ME
Department of Physiology, McGill University, Montreal, Quebec, Canada. marian.fundytus@muhc.mcgill.ca
Yashpal
K
K
Chabot
J G
JG
Osborne
M G
MG
Lefebvre
C D
CD
Dray
A
A
Henry
J L
JL
Coderre
T J
TJ
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010146:Pain / Q000235:genetics / Q000503:physiopathology*; D010147:Pain Measurement; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*; D012584:Sciatic Nerve / Q000293:injuries*; D014110:Touch
D000701:Analgesics, Opioid; D016376:Oligonucleotides, Antisense; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D015240:Phorbol 12,13-Dibutyrate; D008734:Methoxyhydroxyphenylglycol; D016202:N-Methylaspartate; D009020:Morphine; C010117:3,4-dihydroxyphenylglycol