n-n--dibenzhydrylethane-1-2-diamine-dihydrochloride and Inflammation

This study set out to characterize the contribution of group III metabotropic glutamate receptor 7 activation to nociceptive behaviour and mechanical hypersensitivity in a novel formalin test in sheep. The mGlu receptor 7 allosteric agonist, N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082; 2-20 mM), the nonselective group III mGlu receptor agonist L-(+)-2-amino-4-phosphonobutyric acid (0.2-20 mM) and drug vehicle were injected intrathecally into naive subjects (n=7 per group), or 5 min preformalin (3%; 0.2 ml)/saline injection (intradermal), into the lower forelimb of adult female sheep (n=5-7 per group). Forelimb withdrawal thresholds to noxious mechanical stimulation and pain behaviours (time spent nonweight bearing or flinching) were assessed for up to 180 min. Formalin induced a characteristic biphasic pain-behaviour response and mechanical hyperalgesia between 1-5 and 30-120 min postinjection. Treatment with AMN082, but not L-(+)-2-amino-4-phosphonobutyric acid significantly inhibited both early and late phase formalin-induced hyperalgesia and pain behaviours. AMN082 also induced a rapid but short lasting analgesia in naive subjects. These data suggest that enhancing endogenous metabotropic glutamate receptor 7 activity in spinal cord, using the novel allosteric modulator, AMN082, blocks pain and hyperalgesia, and may be of therapeutic benefit for the treatment of inflammatory pain.

Topics: Aminobutyrates; Animals; Behavior, Animal; Benzhydryl Compounds; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Formaldehyde; Hyperalgesia; Inflammation; Injections, Spinal; Pain; Receptors, Metabotropic Glutamate; Sheep

This study characterized the contribution of metabotropic glutamate receptor 7 (mGlu7 receptor) activation to the development of inflammatory hyperalgesia and allodynia, using a novel, systemically active mGlu7 receptor allosteric agonist, N, N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082). The effects of AMN082 (0.1, 1 or 5 mg/kg, intraperitoneally; 5 or 50 nmol, intrathecally) or diclofenac (5 mg/kg, intraperitoneally) administered 30 min preprocedure or 3 h postprocedure on hindpaw withdrawal latency (in seconds) to thermal stimulation, and response threshold (in grams) to mechanical stimulation, were measured in adult rats (n = 6-8 per group) before and up to 24 h after intradermal injection of carrageenan into the hindpaw or hindpaw incision. Precarrageenan injection of 1 and 5 mg/kg AMN082, but not diclofenac inhibited thermal hyperalgesia, whereas postcarrageenan, both AMN082 and diclofenac attenuated thermal hyperalgesia and allodynia. In the paw incision model, presurgical and postsurgical administration of 1 and 5 mg/kg AMN082 inhibited thermal hyperalgesia, but not allodynia, whereas diclofenac was effective in attenuating both thermal hyperalgesia and allodynia but only when administered postsurgically. Intrathecal injection of AMN082 postcarrageenan and postsurgery also significantly attenuated thermal hyperalgesia. Enhancing endogenous mGlu7 receptor activity inhibits postinjury stimulus-evoked hypersensitivity and may be of therapeutic benefit for the treatment of inflammatory and incision-induced pain.

Topics: Allosteric Regulation; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzhydryl Compounds; Carrageenan; Diclofenac; Disease Models, Animal; Hyperalgesia; Inflammation; Injections, Intradermal; Injections, Spinal; Male; Pain; Pain, Postoperative; Phosphoserine; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate

In this study, the effect of (S)-3,4-dicarboxyphenylglycine (DCPG), a selective mGlu8 receptor agonist, has been investigated in inflammatory and neuropathic pain models in order to elucidate the role of mGlu8 receptor in modulating pain perception. Inflammatory pain was induced by the peripheral injection of formalin or carrageenan in awake mice. Systemic administration of (S)-3,4-DCPG, performed 15 min before formalin, decreased both early and delayed nociceptive responses of the formalin test. When this treatment was carried out 15 min after the peripheral injection of formalin it still reduced the late hyperalgesic phase. Similarly, systemic (S)-3,4-DCPG reduced carrageenan-induced thermal hyperalgesia and mechanical allodynia when administered 15 min before carrageenan, but no effect on pain behaviour was observed when (S)-3,4-DCPG was given after the development of carrageenan-induced inflammatory pain. When microinjected into the lateral PAG (RS)-alpha-methylserine-O-phoshate (MSOP), a group III receptor antagonist, antagonised the analgesic effect induced by systemic administration of (S)-3,4-DCPG in both of the inflammatory pain models. Intra-lateral PAG (S)-3,4-DCPG reduced pain behaviour when administered 10 min before formalin or carrageenan; both the effects were blocked by intra-lateral PAG MSOP. (S)-3,4-DCPG was ineffective in alleviating thermal hyperalgesia and mechanical allodynia 7 days after the chronic constriction injury of the sciatic nerve, whereas it proved effective 3 days after surgery. Taken together these results suggest that stimulation of mGlu8 receptors relieve formalin and carrageenan-induced hyperalgesia in inflammatory pain, whereas it would seem less effective in established inflammatory or neuropathic pain.

Topics: Analysis of Variance; Animals; Benzhydryl Compounds; Benzoates; Carrageenan; Dinucleoside Phosphates; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Excitatory Amino Acid Antagonists; Formaldehyde; Glycine; Hyperalgesia; Inflammation; Male; Mice; Pain; Pain Measurement; Pain Threshold; Phosphoserine; Reaction Time; Receptors, Metabotropic Glutamate