6-methyl-2-(phenylethynyl)pyridine and Constriction--Pathologic

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.

Topics: Acetic Acid; Animals; Carrageenan; Central Nervous System; Constriction, Pathologic; Edema; Formaldehyde; Hyperalgesia; Male; Mice; Mice, Inbred ICR; Motor Activity; Pain; Pain Measurement; Pain, Postoperative; Psychomotor Performance; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Spinal Nerves; Thiazoles; Vincristine

Activation of spinal cord dorsal horn ionotropic glutamate receptors leads to pain-related behaviors. However, the role of spinal metabotropic glutamate receptors (mGlu), particularly the mGlu5 receptor subtype, in nociception has not been well characterized. A recently described subtype selective and potent mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP) was used to evaluate the role of the mGlu5 receptor in cold sensitivity. Intrathecal (i.t.) injection of group I (mGlu1 and mGlu5 receptors) mGlu receptor-selective agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) increased the hind paw frequency and duration of lifting of rats placed on a cold (4 degrees C) surface, a behavior similarly observed in rats with a chronic constriction injury (CCI) of the sciatic nerve. In contrast, rats i.t. injected with DHPG did not display increased lifting when placed on a room temperature surface. I.t. injection of MPEP before i.t. injection of DHPG blocked DHPG-evoked cold hypersensitivity, suggesting that activation of spinal mGlu5 receptors induces this behavioral response. In contrast, i.t. injection of MPEP after i.t. injection of DHPG had no effect. In addition, i.t. injection of MPEP did not affect cold hypersensitivity in rats with a CCI. These data suggest that acute activation of spinal cord mGlu5 receptors results in increased sensitivity to cold, but ongoing cold hypersensitivity does not involve activation of the mGlu5 receptor.

Topics: Animals; Behavior, Animal; Cold Temperature; Constriction, Pathologic; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Injections, Spinal; Male; Methoxyhydroxyphenylglycol; Pain; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Sciatic Nerve; Spinal Cord

The present series of experiments were designed to examine the contribution of metabotropic glutamate receptor subtype 5 (mGluR5) to neuropathic pain by determining the effects of the selective mGluR5 antagonist MPEP (2-methyl-6-(phenylethynyl)-pyridine) on neuropathy-induced cold hypersensitivity. Unilateral chronic constriction injury (CCI) to the sciatic nerve in rats produced an increase in the number of hind paw withdrawals from a cold surface (4 +/- 2 degrees C) which was dose-dependently inhibited by systemic (i.p.) injection of MPEP (ID(50) = 11.3 mg/kg). In vivo brain mGluR5 receptor occupancy following systemic (i.p.) MPEP revealed that >90% occupancy is required for behavioral efficacy. Intracerebroventricular (i.c.v.) injection of MPEP dose-dependently inhibited CCI-induced cold hypersensitivity (ID(50) = 123.5 nmol), while microinjection of MPEP directly into the rostral ventromedial medulla (RVM) potently inhibited this hypersensitivity (ID(50) = 1.3 pmol). A role for mGluR5 in the RVM was further supported by the observation that intra-RVM injection of the mGluR5 agonist CHPG (10 nmol; 2-chloro-5-hydroxyphenylglycine) produced cold hypersensitivity in naïve rats that was blocked by pretreatment with intra-RVM MPEP (3 nmol). Intrathecal (500 nmol; i.t.) or intraplantar (300 nmol; i.pl.) injection of MPEP was ineffective in reversing CCI-induced cold hypersensitivity. These results demonstrate that mGluR5 contributes to cold hypersensitivity following peripheral neuropathy exclusively at supraspinal sites in the CNS. Additionally, mGluR5 in the RVM significantly contributes to the maintenance of cold hypersensitivity, likely via activation of descending nociceptive facilitatory systems.

Topics: Animals; Cold Temperature; Constriction, Pathologic; Excitatory Amino Acid Antagonists; Injections, Intraventricular; Injections, Spinal; Male; Medulla Oblongata; Microinjections; Pain; Peripheral Nervous System Diseases; Pyridines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Sciatic Nerve