Assessing the role of metabotropic glutamate receptor 5 in multiple nociceptive modalities.
Preclinical data, performed in a limited number of pain models, suggest that functional blockade of metabotropic glutamate (mGlu) receptors may be beneficial for pain management. In the present study, effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective mGlu5 receptor antagonist, were examined in a wide variety of rodent nociceptive and hypersensitivity models in order to fully characterize the potential analgesic profile of mGlu5 receptor blockade. Effects of 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), as potent and selective as MPEP at mGlu5/mGlu1 receptors but more selective than MPEP at N-methyl-aspartate (NMDA) receptors, were also evaluated in selected nociceptive and side effect models. MPEP (3-30 mg/kg, i.p.) produced a dose-dependent reversal of thermal and mechanical hyperalgesia following complete Freund's adjuvant (CFA)-induced inflammatory hypersensitivity. Additionally, MPEP (3-30 mg/kg, i.p.) decreased thermal hyperalgesia observed in carrageenan-induced inflammatory hypersensitivity without affecting paw edema, abolished acetic acid-induced writhing activity in mice, and was shown to reduce mechanical allodynia and thermal hyperalgesia observed in a model of post-operative hypersensitivity and formalin-induced spontaneous pain. Furthermore, at 30 mg/kg, i.p., MPEP significantly attenuated mechanical allodynia observed in three neuropathic pain models, i.e. spinal nerve ligation, sciatic nerve constriction and vincristine-induced neuropathic pain. MTEP (3-30 mg/kg, i.p.) also potently reduced CFA-induced thermal hyperalgesia. However, at 100 mg/kg, i.p., MPEP and MTEP produced central nerve system (CNS) side effects as measured by rotarod performance and exploratory locomotor activity. These results suggest a role for mGlu5 receptors in multiple nociceptive modalities, though CNS side effects may be a limiting factor in developing mGlu5 receptor analgesic compounds.
Zhu
Chang Z
CZ
Neuroscience Research, Global Pharmaceutical Research and Development, Dept. 4N5, Bldg. AP9A, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500, USA. Chang.Z.Zhu@abbott.com
Wilson
Sonya G
SG
Mikusa
Joseph P
JP
Wismer
Carol T
CT
Gauvin
Donna M
DM
Lynch
James J
JJ
Wade
Carrie L
CL
Decker
Michael W
MW
Honore
Prisca
P
D019342:Acetic Acid; D000818:Animals; D002351:Carrageenan; D002490:Central Nervous System / Q000502:physiology; D003251:Constriction, Pathologic / Q000473:pathology; D004487:Edema / Q000139:chemically induced; D005557:Formaldehyde; D006930:Hyperalgesia / Q000139:chemically induced; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology* / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D010149:Postoperative Pain / Q000473:pathology; D011597:Psychomotor Performance / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000502:physiology; D013127:Spinal Nerves / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1; D005557:Formaldehyde; D014750:Vincristine; C121465:6-methyl-2-(phenylethynyl)pyridine; D002351:Carrageenan; D019342:Acetic Acid