Novel agonist of α₄β₂* neuronal nicotinic receptor with antinociceptive efficacy in rodent models of acute and chronic pain

Abstract

ObjectiveTo demonstrate the antinociceptive and antihypersensitivity mechanisms of Cris-104 (1-{2-[5-(4-fluorophenyl)–1H-pyrazol-4-yl]ethyl}piperidine), a novel selective α4β2* nicotinic acetylcholine receptor (nAChR) agonist, in rodent acute/inflammatory and chronic pain models.Materials and methodsHot-plate and formalin tests in mice were used to examine Cris-104-induced antinociceptive effects on thermal/inflammatory pain. Cris-104 effects on hypersensitivity, norepinephrine (NE) release in the spinal dorsal horn, and neuronal activity in the locus coeruleus (LC) were examined in rats with lumbar spinal nerve ligation using behavioral, microdialysis, and extracellular recording methods. Cris-104 effects on spontaneous locomotion were examined in an open-field test.ResultsCris-104 induced dose-dependent antinociception effects in hot-plate and formalin tests, and these effects were blocked by the general nAChR antagonist mecamylamine, the selective α4β2* nAChR antagonist dihydro-beta-erythroidine, and the α2-adrenoceptor antagonist yohimbine, but not by the α1-adrenoceptor antagonist prazosin. Systemic and spinally perfused Cris-104 increased NE concentrations in microdialysates from the spinal cord in both normal and SNL rats. Systemic Cris-104 increased neuronal activity in the LC of normal rats. Mecamylamine blocked the effects of Cris-104 on spinal NE release and LC neuronal activity. Systemic Cris-104 did not affect locomotor activity significantly.ConclusionThe α4β2 neuronal nAChR agonist, Cris-104, was effective for treatment of pain via descending noradrenergic inhibition of pain signaling.

Development of pyrazole derivatives in the management of inflammation

“…Some pyrazole derivatives ( 44–45 ; 73 ; 74 ; 103–107 ; 109 ; 110 ) modulate both first (neurogenic) and second (inflammatory) phases of formalin test [39,68,74,76,78,83] while certain derivatives ( 22 ; 38–40 ; 68 ; 77 ) only decreased the pain reaction at the inflammatory phase [31,44,45,61]. Compounds 43–45 and 109 [68,76] reduced pain response to intraplantar injection of acidified saline, capsaicin, or glutamate that supports the involvement of ASIC‐1α channel, TRPV‐1 receptor, and glutamatergic pathways, respectively.…”

“…The central analgesic effect, as well as spinal [61,64,74,75] or supraspinal mechanisms [33,76,79,83] of pyrazole derivatives, has been explored using tail‐flick ( 22 ; 97 ; 100 ; 103–108 ) and/or hot plate ( 68–72 ; 81 ; 109 ; 110 ) tests. An increase in latency to thermal stimulus response suggests antinociceptive property, as demonstrated for LQFM008 ( 73 ) in both tests [78].…”

“…An increase in latency to thermal stimulus response suggests antinociceptive property, as demonstrated for LQFM008 ( 73 ) in both tests [78]. The involvement of the central mechanism has also been assessed through spinal nerve injury, in which pyrazole‐sulfonamide ( 101 ; 102 ) derivatives [69], compound MR309 ( 78 ), and Cris‐104 ( 110 ) [67,83] prevented mechanical and cold allodynia. The fused‐benzenesulfonamide derivative attenuated thermal hyperalgesia and mechanical allodynia in streptozotocin‐induced diabetic neuropathic pain [70].…”

Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

“…Additional efforts have directed attention to other nAchR subunit combinations. Recently, epibatine analogs with high affinity for a4b2 nAChRs were evaluated in chronic pain models (Debom et al, 2014;Li et al, 2018;Sudo et al, 2018). The analogs C-9515 and C-163 dose-dependently reduced the formalin and the CCI-induced hyperalgesia (Li et al, 2018).…”

“…Further chemical modifications originated the compound Cris-104, a selective a4b2 ligand with an improved ADME profile (Debom et al, 2014). Cris-104 exerted analgesic effects in diverse chronic pain models, such as diabetes-induced neuropathy, spared nerve ligation (SNL), and formalin test (Debom et al, 2014;Sudo et al, 2018). Open field performances showed that the analgesic doses of Cris-104 does not produce significant alterations on the locomotor activity (Debom et al, 2014;Sudo et al, 2018).…”