. 2009 Oct;9(5):234–251. doi: 10.1124/mi.9.5.7

Table 1.

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

GPCR family^a	Role^c	Subtype(s)	G protein(s)^a, ^b	Description	Source
5-HT (Serotonin)	+/−^d	5-HT_1A,B,D,E,F	G_i/o	Descending facilitation and inhibition; peripheral sensitization. 5-HT₁ agonists are used to treat migraine.	17, 51

		5-HT_2A,B,C	G_q/11

		5-HT_4,5A,6,7	G_s
Acetylcholine (muscarinic)	−^e	M₂,M₅	G_i/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	G_q/11
Adenosine	−	A₁	G_i/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

		A_2A,B	G_s

		A₃	G_i/o
Adrenergic	+/−	α_1A,B,D	G_q/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

		α_2A,B,C	G_i/o

		β_1,2,3	G_s
Angiotensin	+^f	AT₁	G_q/11,G_i/o	Supraspinal angiotensin is pronociceptive. Spinal administration appears ineffective.	61, 62

		AT₂	G_i/o
Anaphylatoxin	+	C3a	G_i/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	G_i/o, G₁₆

		C5L2	NA
Apelin	−	APJ	G_i/o	One study, linking the apelin receptor to nociception, reports that supraspinal administration of apelin-13 produced antinociception and potentiated morphine.	67
Bile aid	NA^g	GPBA	G_s	Bile acids induce visceral pain, but GPBA is not nociceptive per se; levels of GPBA are low in CNS.	68, 69
Bombesin	+/−	BB_1–3	G_q/11	Bombesin receptors exist throughout CNS. Supraspinal bombesin receptors produce antinociception, but spinal activation results in hypersensitivity.	70, 71
Bradykinin	+	B₁	G_i/o, G_q/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	G_s,G_i/0,G_q/11
Calcitonin	+/−	CT, AMY_1–3, CGRP, AM_1,2w	G_s	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	−	CB_1,2	G_i/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	G_i/o, G_q/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	G_q/11
Chemokine	+	CCR_1–10, CXCR_1–6, CX3CR1, XCR1	G_i/0	Chemokine receptors modulate calcium channel activity through G_i/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	+	CCK_1,2	G_q/11	Activation of CCK receptors has pronociceptive and/or antiopioid activity at several levels along the neuroaxis.	17, 84
Corticotropin-releasing factor	+/−	CRF_1,2	G_s	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	+/−	D_1,5	G_q/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

		D_2–4	G_i/0
Endothelin	+/−	ET_A	G_q/11	Endothelins are involved in the maintenance of vascular tone. Peripheral ET_A activation promotes pain-like behavior; ET_B receptor activation is analgesic (possibly by endogenous peripheral opioid activation analgesia.	89, 90

		ET_B	G_s,G_i/0,G_q/11
Estrogen	+	GPER	G_s	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	G_i/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	FZD_1,7	G_q/11, G_i/o	Frizzled receptors are important in embryonic development and adult tissue homeostasis; their modulation of bone remodelling may have relevance to arthritis.	93, 94

		FZD_2,4,6,9,10	G_i/o

		FZD₃	G_q/11, G_i/o, G_s

		FZD_5,8	G_q/11

		SMO	NA
Free fatty acid	NA	FFA₁, FFA₂	G_q/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	G_i/o

		GPR42	NA
Galanin	−	GAL_1,3	G_i/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	G_q/11
GABA_B	−	GABA_B1, GABA_B2	G_i/o	The GABA_B 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	G_q/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	G_s	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	G_s	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	G_q/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	+	H_1,2	G_q/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

		H_3,4	G_i/o
KiSS1-derived peptide	NA	KISS₁	G_q/11	Formerly known as the orphan receptor GPR54, KISS₁ is expressed in brain and spinal cord.	106
Leukotriene	+	BLT_1,2, CysLT_1,2	G_q/11, G_i/o	Leukotrienes are pro-inflammatory lipid mediators synthesized by leukocytes, macrophages, and mast cells, and can sensitize nociceptors.	81, 107–109

		OXE	G_i/o
Lysophospho-lipid	+	LPA_1,2, S1P_1–3	G_i/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	G_q/11

		S1P_4,5	G₁₂
Melatonin	−	MT_1,2	G_i/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	+/−	MC_1–5	G_s	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	+/−	mGlu_1,5	G_q/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

		mGlu_2,3	G_i/o

		mGlu_4,6–8	G_i/o
Melanin-concentrating hormone	NA	MCH₁	G_s,G_i/o,G_q/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	G_q/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	+/−	NTS_1,2	G_q/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	G_q/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	+/−	Y_1,2,5	G_i.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	G_q/11
Neuropeptide W/Neuropeptide B	−	NPBW_1,2	G_i.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	+/−	NPFF_1,2	G_i/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	G_i/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	G_i/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	G_i/o, G_q/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	G_q/11
P2Y	+	P2Y_1,2,4,6,11	G_q/11	G_q/11- and G_i/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

		P2Y_12–14	G_i/o
Parathyroid hormone	NA	PTH_1,2	G_s	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	G_q/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, EP_2,4, IP₁	G_s	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	G_i/o

		EP₁, FP, TP	G_q/11
Prokineticin	+	PKR₁	G_q/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	G_s
Protease-activated	+/−	PAR_1,2,4	G_q/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	G_i/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	G_s, G_i/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	G_i/o
Somatostatin	−	SST_1–5	G_i/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	+	NK_1–3	G_q/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	G_q/11	TRH receptors can activate descending inhibitory pathways. A systemically administered TRH analog mediates antinociception at the supraspinal level.	150
Trace amine^h	NA	TA₁	G_s	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	G_q/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	+/−	V_1A,1B	G_q/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. V_1B receptors appear to have pronociceptive and anti-opioid actions, whereas V_1A receptors in the spinal cord are analgesic.	154–156

		V₂	G_s

		OT	G_q/11
VIP/PACAP	+	PAC₁, VPAC_1,2	G_s	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

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).

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.

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.

Mixed effects.

Inhibitory.

Excitatory.

None ascertained.

Trace amine associated receptors, TAAR_2–9, are currently classified as orphans.