Metabotropic glutamate receptor subtype 5 (mGlu5) and nociceptive function. I. Selective blockade of mGlu5 receptors in models of acute, persistent and chronic pain.
The excitatory neurotransmitter, glutamate, is particularly important in the transmission of pain information in the nervous system through the activation of ionotropic and metabotropic glutamate receptors. A potent, subtype-selective antagonist of the metabotropic glutamate-5 (mGlu5) receptor, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has now been discovered that has effective anti-hyperalgesic effects in models of inflammatory pain. MPEP did not affect rotarod locomotor performance, or normal responses to noxious mechanical or thermal stimulation in naïve rats. However, in models of inflammatory pain, systemic administration of MPEP produced effective reversal of mechanical hyperalgesia without affecting inflammatory oedema. In contrast to the non-steroidal anti-inflammatory drugs, indomethacin and diclofenac, the maximal anti-hyperalgesic effects of orally administered MPEP were observed without acute erosion of the gastric mucosa. In contrast to its effects in models of inflammatory pain, MPEP did not produce significant reversal of mechanical hyperalgesia in a rat model of neuropathic pain.
Walker
K
K
Nervous System Research, Novartis Pharma AG, CH-4002, Basle, Switzerland. kath.walker@pharma.novartis.com
Bowes
M
M
Panesar
M
M
Davis
A
A
Gentry
C
C
Kesingland
A
A
Gasparini
F
F
Spooren
W
W
Stoehr
N
N
Pagano
A
A
Flor
P J
PJ
Vranesic
I
I
Lingenhoehl
K
K
Johnson
E C
EC
Varney
M
M
Urban
L
L
Kuhn
R
R
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D002908:Chronic Disease; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000188:drug therapy* / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine