Ion Channels and Osteoarthritic Pain: Potential for Novel Analgesics

Abstract

Osteoarthritis (OA) is a debilitating chronic condition widely prevalent in ageing populations. Because the pathology of the disease includes cartilage erosion and joint remodelling, OA patients experience a great deal of pain. Despite numerous studies, details of OA are frequently inseparable from other types of chronic pain, and its causes are unknown. In most circumstances in OA, the cartilage lacks afferent innervation, although other joint tissues contain nociceptive neurones. In addition to physical joint damage, there is a strong element of joint inflammation. Genetic studies have identified several associations between ion channels and OA pain, including NaV1.7, P2X7, and TRPV1, but several other channels have also been implicated. Many ion channels involved with OA pain are common to those seen in inflammatory pain. This review considers causes of OA pain and discusses three possible pain-reducing strategies involving ion channel modulation: chondroprotection, innate afferent nerve inhibition, and inhibition of inflammatory hyperalgesia. Future targets for OA pain analgesia could involve a number of ion channels.

P2X7, a critical regulator and potential target for bone and joint diseases

“…The pain control and anti-inflammtory are crucial for the treatment of osteoarthritis (Pelletier, Fernandes, Jovanovic, Reboul, & Martel-Pelletier, 2001a). Studies revealed that P2X7 receptor is closely related to the occurence of pain and inflammtory response (Staunton, Lewis, & Barrett-Jolley, 2013).…”

Blocking of the P2X7 receptor inhibits the activation of the MMP-13 and NF-κB pathways in the cartilage tissue of rats with osteoarthritis

“…As is well known, the purinergic membrane receptor superfamily may be divided into the P1 and P2 receptor families. The P2 family, which can be further divided into the P2X and P2Y subtypes, is closely related to OA-induced pain (11,12). Importantly, a previous study reported that P2 receptor signaling is altered in OA, and that it is associated with an elevated ATP level (12).…”

Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain

“…This clinical target of Na v 1.7 in osteoarthritis pain is supported by the reported knockout studies and additional literature. 9,19,20 The chiral bicycle 48 was also prepared starting with 39 and using commercially available α-methylbenzyl analog 43 in the presence of catalytic TFA to give an approximate 1:1 mixture of isomers 44 and 45 which was separated via silica gel chromatography (Scheme 7). The resulting single enantiomer 45 next underwent Boc-removal in the presence of excess TFA and the resulting lactam was coupled with indazole bromide 21 using CuI-Buchwald conditions to give 46.…”