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Calcitonin gene-related peptide receptor antagonists: beyond migraine pain--a possible analgesic strategy for osteoarthritis?

Bullock CM, Kelly S - Curr Pain Headache Rep (2013)

Bottom Line: Given the recent development of small molecule CGRP receptor antagonists with clinical efficacy against migraine pain, the interrogation of the role of CGRP in OA pain mechanisms is extremely timely.In this article, we provide the background to the importance of CGRP in pain mechanisms and review the emerging clinical and preclinical evidence implicating a role for CGRP in OA pain.We suggest that the CGRP receptor antagonists developed for migraine pain warrant further investigation in OA.

View Article: PubMed Central - PubMed

Affiliation: Arthritis Research UK Pain Centre, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Leicestershire, LE12 5RD, UK, stxcb1@nottingham.ac.uk.

ABSTRACT
Osteoarthritis (OA) pain is poorly understood and managed, as current analgesics have only limited efficacy and unwanted side effect profiles. A broader understanding of the pathological mechanisms driving OA joint pain is vital for the development of improved analgesics. Both clinical and preclinical data suggest an association between joint levels of the sensory neuropeptide calcitonin gene-related peptide (CGRP) and pain during OA. Whether a direct causative link exists remains an important unanswered question. Given the recent development of small molecule CGRP receptor antagonists with clinical efficacy against migraine pain, the interrogation of the role of CGRP in OA pain mechanisms is extremely timely. In this article, we provide the background to the importance of CGRP in pain mechanisms and review the emerging clinical and preclinical evidence implicating a role for CGRP in OA pain. We suggest that the CGRP receptor antagonists developed for migraine pain warrant further investigation in OA.

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Related in: MedlinePlus

CGRP receptor composition. The CGRP receptor is a hetero-trimeric protein comprised of the GPCR calcitonin receptor-like receptor (CLR), coupled to a receptor activity modifying protein (RAMP). There are three RAMP isoforms that govern receptor pharmacology; RAMP1 containing receptors are CGRP-binding, whilst RAMP2/3 containing receptors are adrenomedullin-binding .The intracellular receptor component protein (RCP) facilitates secondary messenger signaling. Different tissues/cells can express multiple RAMP isoforms, resulting in a complex pharmacological profile
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Fig1: CGRP receptor composition. The CGRP receptor is a hetero-trimeric protein comprised of the GPCR calcitonin receptor-like receptor (CLR), coupled to a receptor activity modifying protein (RAMP). There are three RAMP isoforms that govern receptor pharmacology; RAMP1 containing receptors are CGRP-binding, whilst RAMP2/3 containing receptors are adrenomedullin-binding .The intracellular receptor component protein (RCP) facilitates secondary messenger signaling. Different tissues/cells can express multiple RAMP isoforms, resulting in a complex pharmacological profile

Mentions: Until relatively recently, there was believed to be two CGRP receptor subtypes in existence, differing in their sensitivity to the classical CGRP receptor antagonist CGRP8-37 [25]. However, following the discovery of the molecular identity of the composition of the CGRP receptor, it is now widely held that only one CGRP receptor exists (Fig. 1). The CGRP receptor was identified following the discovery that when expressed in HEK293 cells, the orphan Family B GPCR, calcitonin receptor-like receptor (CLR), showed high affinity binding sites for CGRP and was pharmacologically responsive to CGRP administration [26]. Shortly after, it was discovered that to fully function, CLR required a single transmembrane protein called receptor activity modifying protein 1 (RAMP1), to aid the transport of CLR to the cell surface [27] (Fig. 1). To date, three isoforms of RAMPs have been identified, with CLR and RAMP2/3 complexes forming adrenomedullin receptors [28]. Thus, the formation of multiple calcitonin receptors is possible, raising the intriguing possibility that under certain conditions (i.e. disease), there may be a dynamic regulation of RAMP isoform expression governing tissue pharmacology.Fig. 1


Calcitonin gene-related peptide receptor antagonists: beyond migraine pain--a possible analgesic strategy for osteoarthritis?

Bullock CM, Kelly S - Curr Pain Headache Rep (2013)

CGRP receptor composition. The CGRP receptor is a hetero-trimeric protein comprised of the GPCR calcitonin receptor-like receptor (CLR), coupled to a receptor activity modifying protein (RAMP). There are three RAMP isoforms that govern receptor pharmacology; RAMP1 containing receptors are CGRP-binding, whilst RAMP2/3 containing receptors are adrenomedullin-binding .The intracellular receptor component protein (RCP) facilitates secondary messenger signaling. Different tissues/cells can express multiple RAMP isoforms, resulting in a complex pharmacological profile
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824306&req=5

Fig1: CGRP receptor composition. The CGRP receptor is a hetero-trimeric protein comprised of the GPCR calcitonin receptor-like receptor (CLR), coupled to a receptor activity modifying protein (RAMP). There are three RAMP isoforms that govern receptor pharmacology; RAMP1 containing receptors are CGRP-binding, whilst RAMP2/3 containing receptors are adrenomedullin-binding .The intracellular receptor component protein (RCP) facilitates secondary messenger signaling. Different tissues/cells can express multiple RAMP isoforms, resulting in a complex pharmacological profile
Mentions: Until relatively recently, there was believed to be two CGRP receptor subtypes in existence, differing in their sensitivity to the classical CGRP receptor antagonist CGRP8-37 [25]. However, following the discovery of the molecular identity of the composition of the CGRP receptor, it is now widely held that only one CGRP receptor exists (Fig. 1). The CGRP receptor was identified following the discovery that when expressed in HEK293 cells, the orphan Family B GPCR, calcitonin receptor-like receptor (CLR), showed high affinity binding sites for CGRP and was pharmacologically responsive to CGRP administration [26]. Shortly after, it was discovered that to fully function, CLR required a single transmembrane protein called receptor activity modifying protein 1 (RAMP1), to aid the transport of CLR to the cell surface [27] (Fig. 1). To date, three isoforms of RAMPs have been identified, with CLR and RAMP2/3 complexes forming adrenomedullin receptors [28]. Thus, the formation of multiple calcitonin receptors is possible, raising the intriguing possibility that under certain conditions (i.e. disease), there may be a dynamic regulation of RAMP isoform expression governing tissue pharmacology.Fig. 1

Bottom Line: Given the recent development of small molecule CGRP receptor antagonists with clinical efficacy against migraine pain, the interrogation of the role of CGRP in OA pain mechanisms is extremely timely.In this article, we provide the background to the importance of CGRP in pain mechanisms and review the emerging clinical and preclinical evidence implicating a role for CGRP in OA pain.We suggest that the CGRP receptor antagonists developed for migraine pain warrant further investigation in OA.

View Article: PubMed Central - PubMed

Affiliation: Arthritis Research UK Pain Centre, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Leicestershire, LE12 5RD, UK, stxcb1@nottingham.ac.uk.

ABSTRACT
Osteoarthritis (OA) pain is poorly understood and managed, as current analgesics have only limited efficacy and unwanted side effect profiles. A broader understanding of the pathological mechanisms driving OA joint pain is vital for the development of improved analgesics. Both clinical and preclinical data suggest an association between joint levels of the sensory neuropeptide calcitonin gene-related peptide (CGRP) and pain during OA. Whether a direct causative link exists remains an important unanswered question. Given the recent development of small molecule CGRP receptor antagonists with clinical efficacy against migraine pain, the interrogation of the role of CGRP in OA pain mechanisms is extremely timely. In this article, we provide the background to the importance of CGRP in pain mechanisms and review the emerging clinical and preclinical evidence implicating a role for CGRP in OA pain. We suggest that the CGRP receptor antagonists developed for migraine pain warrant further investigation in OA.

Show MeSH
Related in: MedlinePlus