In Search of Analgesia: Emerging Poles of GPCRs in Pain

Table 1

GPCR Families and Their G Protein–Dependent Roles in Pro- and Antinociceptive Processing

GPCR familya Rolec Subtype(s) G protein(s)a, b Description Source
5-HT (Serotonin) +/−d 5-HT1A,B,D,E,F Gi/o Descending facilitation and inhibition; peripheral sensitization. 5-HT1 agonists are used to treat migraine. 17, 51
5-HT2A,B,C Gq/11
5-HT4,5A,6,7 Gs
Acetylcholine (muscarinic) −e M2,M5 Gi/o Antinociceptive by supraspinal and spinal mechanisms; support analgesic effects of opioid and α2AR agonists. Cholinesterase inhibition (neostigmine) produces analgesia in acute and chronic pain in humans. 52, 53
M1, M3, M5 Gq/11
Adenosine − A1 Gi/o Antinociceptive and antihyperalgesic actions in spinal cord. Systemic agonists elicit severe motor effects, but enzymatic conversion of extracellular AMP to adenosine in the spinal cord produces analgesia without motor effects, suggesting novel approach for analgesic therapeutics. 54–56
A2A,B Gs
A3 Gi/o
Adrenergic +/− α1A,B,D Gq/11 α1ARs are pronociceptive, particularly in sympathetic nervous system dysfunction. α2AR agonists have analgesic actions throughout the CNS in acute, inflammatory, and neuropathic pain. βARs are involved in the negative affective component of pain and endogenous pain sensitivity in humans. 57–60
α2A,B,C Gi/o
β1,2,3 Gs
Angiotensin +f AT1 Gq/11,Gi/o Supraspinal angiotensin is pronociceptive. Spinal administration appears ineffective. 61, 62
AT2 Gi/o
Anaphylatoxin + C3a Gi/o C3a and C5a, components of the activated complement system, mediate neuroimmune function. Blockade of the complement system reduces pain in animal models of acute, inflammatory, and neuropathic pain. 63–66
C5a Gi/o, G16
C5L2 NA
Apelin − APJ Gi/o One study, linking the apelin receptor to nociception, reports that supraspinal administration of apelin-13 produced antinociception and potentiated morphine. 67
Bile aid NAg GPBA Gs Bile acids induce visceral pain, but GPBA is not nociceptive per se; levels of GPBA are low in CNS. 68, 69
Bombesin +/− BB1–3 Gq/11 Bombesin receptors exist throughout CNS. Supraspinal bombesin receptors produce antinociception, but spinal activation results in hypersensitivity. 70, 71
Bradykinin + B1 Gi/o, Gq/11 Peripheral injection of bradykinin causes pain behavior and heat hyperalgesia. B2 is constitutively expressed in sensory neurons. B1 expression is upregulated in response to inflammation, nerve injury, and trophic factor application. 72–74
B2 Gs,Gi/0,Gq/11
Calcitonin +/− CT, AMY1–3, CGRP, AM1,2w Gs CGRP is expressed by a subset of predominantly nociceptive sensory neurons and mediates central and peripheral sensitization and neurogenic inflammation. CGRP antagonists are under exploration as antimigraine agents. Calcitonin is reportedly analgesic in humans. Amylin is expressed by small sensory neurons, implying nociception. Activation of AM receptors in the spinal cord produces heat hyperalgesia. 75–77
Cannabinoid − CB1,2 Gi/0 CB1 receptors are expressed in CNS and produce both analgesic and psychoactive effects. CB2 receptors, putatively absent in CNS, inhibit acute, inflammatory, and neuropathic pain. Clinical utility of cannabinoid agonists is under study. 18, 78, 79
Calcium-sensing NA CaS Gi/o, Gq/11 Calcium-sensing GPCRs are widespread among neurons, oligodendrocytes, and keratinocytes and respond to extracellular calcium, magnesium, polyamines, L-amino acids, ionic strength, and pH. GPRC6A was identified by genomic screening and is a promiscuous amino acid receptor. 49
GPRC6 Gq/11
Chemokine + CCR1–10, CXCR1–6, CX3CR1, XCR1 Gi/0 Chemokine receptors modulate calcium channel activity through Gi/o. Chemokines have emerged as key modulators of neuropathic and inflammatory chronic pain. Chemokines and their receptors form a link between the immune and nervous systems. 80–83
Cholecystokinin + CCK1,2 Gq/11 Activation of CCK receptors has pronociceptive and/or antiopioid activity at several levels along the neuroaxis. 17, 84
Corticotropin-releasing factor +/− CRF1,2 Gs Brain CRF receptors are critical to hypothalamic-pituitary axis responses to pain and stress. Acute activation of this system results in analgesia; chronic activation may enhance pain. Many chronic pain states are associated with HPA axis dysfunction. 85–87
Dopamine +/− D1,5 Gq/11 Dopamine receptors are widely expressed throughout the brain and contribute to descending pain modulation. Evidence exists for both antinociceptive D2 and pronociceptive D1 actions in spinal cord. 17, 88
D2–4 Gi/0
Endothelin +/− ETA Gq/11 Endothelins are involved in the maintenance of vascular tone. Peripheral ETA activation promotes pain-like behavior; ETB receptor activation is analgesic (possibly by endogenous peripheral opioid activation analgesia. 89, 90
ETB Gs,Gi/0,Gq/11
Estrogen + GPER Gs Previously designated as orphan receptor GPR30, the G protein–coupled estrogen receptor functions autonomously from the steroid receptors ERα and ERβ. GPER is expressed in small sensory neurons; its activation increases CFA-induced allodynia in the masseter muscle. 91
Formylpeptide NA FPR1, FPR2 Gi/o Formylpeptide receptors are expressed in brain, spinal cord and peripheral nervous system. A role for the formylpeptide receptors in nociception has not been investigated. 92
FPR3 NA
Frizzled NA FZD1,7 Gq/11, Gi/o Frizzled receptors are important in embryonic development and adult tissue homeostasis; their modulation of bone remodelling may have relevance to arthritis. 93, 94
FZD2,4,6,9,10 Gi/o
FZD3 Gq/11, Gi/o, Gs
FZD5,8 Gq/11
SMO NA
Free fatty acid NA FFA1, FFA2 Gq/11 Free fatty acids as ligands for a family of orphan GPCRs is a new concept in cell surface receptor signaling. Fatty acids are involved in the immune response and may be important in neuroimmune interactions; a role in pain remains to be investigated. 92
FFA3 Gi/o
GPR42 NA
Galanin − GAL1,3 Gi/o Endogenous galanin modulates spinal nociception primarily in an inhibitory manner and is highly upregulated in sensory neurons following peripheral nerve injury. Galanin is also expressed by neurons that send descending projections to spinal cord. 17, 95, 96
GAL2 Gq/11
GABAB − GABAB1, GABAB2 Gi/o The GABAB agonist baclofen is used clinically to treat pain in patients with spasticity, but also has efficacy in neuropathic, stroke, spinal cord injury, and musculoskeletal pain. 6, 18
Ghrelin − Ghrelin Gq/11 Ghrelin has antinociceptive activity following central, systemic, and local peripheral administration. The ghrelin receptor is expressed in the dorsal horn, directly inhibiting spinal neurotransmission. 97, 98
Glucagon − GHRH, GIP, GLP-1, glucagon, secretin Gs Neither glucagon or the glucagon-like peptide have been reported to directly modulate nociception; however, activation of the growth hormone–releasing hormone receptor attenuates inflammatory hypersensitivity. Reduced GHRH levels have been associated with fibromyalgia. 99–101
GLP-2 NA
Glycoprotein hormone +/− FSH, LH, TSH Gs Acute activation of the hypothalamic-pituitary-adrenal axis results in analgesia; chronic activation may enhance pain. Disturbances in the HPA axis are observed in chronic pain. 86, 87, 102
Gonadotrophin- releasing hormone +/− GnRH Gq/11 The GnRH receptor, regulating the biosynthesis and secretion of the gonadotropins, may affect pain thresholds by regulating estrogen and testosterone levels. Altered gonadotropin levels have been detected in spinal fluid from chronic headache patients. 103, 104
GnRH2 NA
Histamine + H1,2 Gq/11 Histamine activates nociceptors, releases pronociceptive neuropeptides, and is painful when injected into skin. It contributes to neurogenic inflammaton and peripheral sensitization. H1 receptor antagonists and other antihistaminics are analgesic. Histamine receptors in the CNS may be involved in nociception. 105
H3,4 Gi/o
KiSS1-derived peptide NA KISS1 Gq/11 Formerly known as the orphan receptor GPR54, KISS1 is expressed in brain and spinal cord. 106
Leukotriene + BLT1,2, CysLT1,2 Gq/11, Gi/o Leukotrienes are pro-inflammatory lipid mediators synthesized by leukocytes, macrophages, and mast cells, and can sensitize nociceptors. 81, 107–109
OXE Gi/o
Lysophospho-lipid + LPA1,2, S1P1–3 Gi/o Lysophospholipids, produced by phospholipase C activity, agonize a newly recognized GPCR family. Lysophospholipids contribute to peripheral sensitization via direct action on LPA1 on sensory neurons, produce hyperalgesia if injected intrathecally, and are required for nerve injury–induced hypersensitivity. Sphingolipid S1P receptor activation is implicated in peripheral sensitization. 110, 111
LPA3 Gq/11
S1P4,5 G12
Melatonin − MT1,2 Gi/o Melatonin receptors are localized in brain and spinal cord; spinal and supraspinal levels of melatonin are antinociceptive in acute, inflammatory, and neuropathic pain. Melatonin inhibits the production of pro-inflammatory cytokines. 112
Melanocortin +/− MC1–5 Gs Peptide agonists encoded by the pro-opiomelanocortin POMC gene activate CNS receptors and are reportedly analgesic, hyperalgesic, and anti-opioid. Variants of the MC1 gene are associated with altered pain sensitivity in humans. 113, 114
Glutamate metabotropic +/− mGlu1,5 Gq/11 All three groups are expressed throughout CNS. Group I (listed first) is pro-nociceptive and contributes to central sensitization. Group II and III receptors produce analgesia both centrally and in the periphery. 18, 115
mGlu2,3 Gi/o
mGlu4,6–8 Gi/o
Melanin-concentrating hormone NA MCH1 Gs,Gi/o,Gq/11 Categorized as orphan receptors prior to 1999, the MCH receptor family is most highly expressed in brain and is implicated in regulating food intake, emotion, stress, and motivation. 116
MCH2 Gq/11
Motilin NA Motilin Injection of motilin induces visceral pain behavior reversed by a selective receptor antagonist. Drugs targeting this receptor may be useful for gastrointestinal disorders such as irritable bowel syndrome. 117, 118
Neurotensin +/− NTS1,2 Gq/11 Activation of neurotensin receptors in the brainstem is pronociceptive. In contrast, intrathecal neurotensin produces antinociception via actions on both spinal cord and dorsal root ganglia neurons. Neurotensin knockout mice display defects in both basal nociceptive responses and stress-induced analgesia. 17, 119
Neuromedin U + NMU1 Gq/11 Intrathecal administration of neuromedin U causes hyperalgesia. Studies in knockout mice suggest that NMU2 mediates these pronociceptive effects. 120, 121
NMU2 NA
Neuropeptide S NA NPS NA The NPS receptor, isolated as an orphan GPCR ligand in 2002, is expressed nearly exclusively in the brain. Central administration of NPS results in increased arousal and an altered anxiolytic profile. 122, 123
Neuropeptide Y +/− Y1,2,5 Gi.o After peripheral nerve injury, there is a dramatic increase of NPY in DRG neurons, especially in larger cells. NPY apparently has both pro- and antinociceptive actions, but the antinocicepive actions appear to dominate. 124, 125
Y4 Gq/11
Neuropeptide W/Neuropeptide B − NPBW1,2 Gi.o Neuropeptides B and W were recently identified as endogenous ligands of the GPR7 NPBW1 and GPR8 NPBW2 receptors. Intrathecal injection of either peptide inhibits inflammation-induced mechanical but not thermal hyperalgesia. 126–128
Neuropeptide FF/neuropeptide AF +/− NPFF1,2 Gi/o NPFF receptors are present in superficial layers of spinal cord and in brain. Supraspinal injection of NPFF analogs results in pronociceptive and anti-opioid activity; intrathecal injection induces analgesia and enhances opioid effects. 129, 130
Nicotinic acid NA GPR81, GPR109A, GPR109B temporary names Gi/o Nicotinic acid was the first orally available drug to treat high cholesterol, but only recently have three GPCRs been identified to recognize this ligand. 131
Opioid − DOP, MOP, KOP, NOP Gi/o Activation of DOP, MOP or KOP reduces nociceptive transmission throughout the CNS. Synthetic agonists are common in pain management, but side effects include constipation and respiratory depression. The long-term use of opioids for non-terminal chronic pain is a topic of intense debate. 18, 132
Orexin − OX1 Gi/o, Gq/11 In the last decade, orexins were identified as endogenous ligands for two orphan GPCRs. Spinal and supraspinal administration of orexins inhibits nociceptive transmission in acute, inflammatory, and neuropathic pain. 18
OX2 Gq/11
P2Y + P2Y1,2,4,6,11 Gq/11 Gq/11- and Gi/o-coupled P2Y receptors are expressed in sensory neurons, including nociceptors, and glia. P2Y2 mediates thermal sensitivity and inflammatory pain. P2Y12 mediates tactile allodynia after nerve injury. Stimulated keratinocytes release ATP, suggesting a role in sensory transduction. 20, 133, 134
P2Y12–14 Gi/o
Parathyroid hormone NA PTH1,2 Gs Parathyroid hormone regulates calcium metabolism and bone growth and remodeling. PTH function in nociception is unclear; its protective effects on bone destruction may reduce arthritic pain. 135
Platelet-activating factor + PAF Gq/11 PAF is a lipid mediator of peripheral inflammation; intrathecal injection induces thermal and mechanical hypersensitivity; inhibition of PAF attenuates inflammatory pain. 136, 137
Prostanoid + DP1, EP2,4, IP1 Gs The COX enzymes participate in prostaglandin and prostanoid synthesis. Prostanoids commonly act as localized pro-inflammatory/pro-nociceptive mediators. Prostanoid receptors on sensory neurons may cause direct excitation. COX inhibitors mediate analgesia mainly by reducing prostaglandin synthesis. 81
DP2, EP3 Gi/o
EP1, FP, TP Gq/11
Prokineticin + PKR1 Gq/11 The two newly recognized PKRs are expressed by DRG neurons; prokineticin peptides produce hyperalgesia. PKRs on nociceptors mediate heat hyperalgesia by sensitizing TRPV1. PKR1 mediates pain behavior in mice as well as TRPV1 function. 138–140
PKR2 Gs
Protease-activated +/− PAR1,2,4 Gq/11 The proteolytic generation of an N-terminal “tethered” receptor-stimulating ligand is unique to PARs. The release of proteinases in arthritis orchestrates joint tissue remodeling and degeneration. Activation of PAR subtypes on sensory neurons can be either pronociceptive (i.e., PAR2) or antinociceptive. PAR2 triggers neuropeptide release, neurogenic inflammation, and TRPV1 sensitization. Sub-inflammatory doses of PAR1 and PAR4 activators reduce inflammatory pain. 141–143
PAR3 NA
Prolactin-releasing peptide − PRRP Gi/o PRRP was formerly designated as orphan receptor GPR10. Intracerebral injection of PrRP is normally antinociceptive and reduces allodynia in neuropathic rats. 144
Relaxin NA RXFP1, RXFP2 Gs, Gi/o Relaxins modulate the formation of connective tissue. Serum relaxin levels correlate to pelvic pain during pregnancy but more likely reflect the remodeling of pelvic connective tissue rather than a direct role in nociception. 145
RXFP3, RXFP4 Gi/o
Somatostatin − SST1–5 Gi/o Somatostatin is expressed in non-peptidergic C-fibers; most SST2 receptors are expressed by TRPV1-containing neurons. Peripheral somatostatin, released upon injury, inhibits neuropeptide release and prevents nociceptor sensitization. Peripheral SST receptors may tonically inhibit TRPV1. Intrathecal administration of agonists inhibits inflammatory and neuropathic pain. 18, 146, 147
Tachykinin + NK1–3 Gq/11 Tachykinins (i.e., substance P and neurokinins A and B) are positively implicated in pain modulation. SP and NKA are expressed by small and medium-sized primary sensory neurons. Tachykinins contribute to peripheral and central sensitization. NK1 receptors are expressed by ascending spinal cord neurons; the analgesic inefficacy of NK1 antagonists in humans was unexpected. 148, 149
Thyrotropin-releasing hormone − TRH1 Gq/11 TRH receptors can activate descending inhibitory pathways. A systemically administered TRH analog mediates antinociception at the supraspinal level. 150
Trace amineh NA TA1 Gs Trace amines are metabolites of biogenic amine neurotransmitters. TA modulation of the CNS was only recently linked GCPR signaling. Of nine family members, eight receptors remain orphans with unidentified ligands; the potential for relevant drug targets is unexplored. Ingested TA can precipitate headaches. 151, 152
Urotensin NA UT Gq/11 Urotensin, expressed in brainstem and spinal cord, was recently identified as the ligand for an orphan GPCR. Supraspinal injection reportedly causes anxiogenic and depressant-like effects in mice without altering nociceptive. 153
Vasopressin/oxytocin +/− V1A,1B Gq/11 Vasopressin and oxytocin are synthesized in the hypothalamus and stored in vesicles at the posterior pituitary. Although released predominately into the bloodstream, a fraction acts directly in the brain. V1B receptors appear to have pronociceptive and anti-opioid actions, whereas V1A receptors in the spinal cord are analgesic. 154–156
V2 Gs
OT Gq/11
VIP/PACAP + PAC1, VPAC1,2 Gs Vasoactive intestinal peptide and pituitary adenylate cyclise–activating polypeptide are expressed in nociceptive sensory neurons and are upregulated following nerve injury. PAC1 mediates hyperalgesia in inflammatory and neuropathic pain; VIP and PACAP receptor antagonists are analgesic. 157–159

  • ↵a Family name and nomenclature are based on the recommendations of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification NC-IUPHAR as of July 2009 (49).

  • ↵b Refers only to each receptors primary or preferred α-subunit as provided by IUPHAR or the selected references. In several cases more than one is listed as equally preferred. Note that most GPCRs will couple to more than one Gα with varying affinity.

  • ↵c A family was considered to be positive if at least one study showing a direct action on nociception was identified. In some of the negative cases, appropriate experiments have not yet been performed.

  • ↵d Mixed effects.

  • ↵e Inhibitory.

  • ↵f Excitatory.

  • ↵g None ascertained.

  • ↵h Trace amine associated receptors, TAAR2–9, are currently classified as orphans.

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  1. MI October 2009 vol. 9 no. 5 234-251
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