PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide)

1. Overview

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide belonging to the VIP/secretin/glucagon superfamily, first isolated by Akira Miyata and Akira Arimura in 1989 from ovine hypothalamic extracts based on its ability to stimulate adenylate cyclase activity in rat anterior pituitary cells [1]. PACAP exists in two biologically active forms: PACAP-38 (38 amino acids, the predominant endogenous form comprising approximately 90% of total PACAP) and PACAP-27 (the N-terminal 27 residues, identical to the first 27 residues of PACAP-38) [1][2].

PACAP-27 shares 68% amino acid sequence identity with vasoactive intestinal peptide (VIP), making PACAP the closest known structural relative of VIP [3]. However, the two peptides differ critically in their receptor pharmacology: while both bind VPAC1 and VPAC2 receptors with nanomolar affinity, PACAP binds the PAC1 receptor with approximately 1000-fold greater affinity than VIP (Kd approximately 0.5 nM vs. greater than 500 nM for VIP) [4][5]. This PAC1 selectivity enables PACAP-specific signaling in neuronal populations, adrenal chromaffin cells, and specific immune cell subsets where PAC1 is the predominant receptor.

PACAP is encoded by the ADCYAP1 gene on chromosome 18p11.32. It is widely expressed in the central and peripheral nervous systems, with particularly high concentrations in the hypothalamus, hippocampus, amygdala, brainstem, dorsal root ganglia, trigeminal ganglia, and adrenal medulla [3][15]. PACAP functions as a neurotransmitter, neuromodulator, neurotrophic factor, and vasodilator, with established roles in neuroprotection, pain modulation, stress responses, circadian entrainment, and immune regulation [3][18].

The clinical significance of PACAP has been highlighted by its involvement in migraine pathophysiology, leading to the development of AMG 301 (now Lu AG09222), an anti-PAC1 receptor monoclonal antibody that entered Phase IIa clinical trials for episodic migraine [7]. Additionally, genetic studies have linked the PACAP/PAC1 system to post-traumatic stress disorder (PTSD) [20].

Molecular Weight

4534.3 Da (PACAP-38); 3147.6 Da (PACAP-27)

Sequence (PACAP-27)

HSDGIFTDSYSRYRKQMAVKKYLAAVL-NH2

Gene

ADCYAP1 (18p11.32)

Primary Receptors

PAC1 (Kd ~0.5 nM); VPAC1 (~1 nM); VPAC2 (~1 nM)

Discovery

Miyata & Arimura, 1989 (ovine hypothalamic extracts)

Half-life

~5-10 minutes (PACAP-38); ~2-5 minutes (PACAP-27)

VIP Homology

68% sequence identity with VIP

FDA Status

Not approved. Anti-PACAP antibody Lu AG09222 showed positive Phase 2 results (NEJM 2024); Phase 2b PROCEED trial ongoing; Phase 3 planned H2 2026.

2. Mechanism of Action

Receptor Pharmacology

PACAP signals through three class B (secretin family) G protein-coupled receptors [4][5]:

PAC1 receptor (ADCYAP1R1): The PACAP-selective receptor, with approximately 1000-fold higher affinity for PACAP over VIP. PAC1 exists in multiple splice variants generated by alternative splicing of the "hip" and "hop" cassettes in the third intracellular loop, which determine coupling efficiency to different signaling pathways (Gs/adenylyl cyclase vs. Gq/PLC). PAC1 is expressed on neurons throughout the CNS and PNS, adrenal chromaffin cells, pancreatic beta cells, and specific immune cell populations [4][5][19].

VPAC1 receptor: Shared with VIP, with equal nanomolar affinity for both peptides. Constitutively expressed on immune cells (T lymphocytes, macrophages, dendritic cells), lung epithelium, and gastrointestinal tract [4][16].

VPAC2 receptor: Also shared with VIP. Predominantly expressed on smooth muscle, the suprachiasmatic nucleus, and activated immune cells [4][5].

Signaling Cascades

PAC1 receptor activation triggers multiple intracellular signaling pathways, reflecting its complex splice variant diversity [3][19]:

cAMP/PKA pathway: The canonical cascade involving Gs-mediated adenylyl cyclase activation, cAMP production, and protein kinase A (PKA) activation. PKA phosphorylates CREB, driving transcription of neuroprotective genes including BDNF, Bcl-2, and c-fos [3][9].

PLC/PKC pathway: Gq-mediated activation of phospholipase C generates IP3 and DAG, mobilizing intracellular calcium and activating protein kinase C. This pathway is particularly important for PAC1 hop1 splice variant signaling [5][19].

PI3K/Akt pathway: Activation of phosphoinositide 3-kinase and downstream Akt promotes cell survival by phosphorylating and inactivating pro-apoptotic proteins (Bad, caspase-9) [3][9].

MAPK/ERK pathway: PACAP activates ERK1/2 signaling through both cAMP-dependent (Epac/Rap1) and PKC-dependent mechanisms, promoting neuronal differentiation and survival [3].

Neuroprotective Mechanisms

PACAP is considered one of the most potent neuroprotective peptides known, effective at femtomolar to nanomolar concentrations [3][9][13]. Neuroprotection involves inhibition of apoptosis through Bcl-2 upregulation and caspase inhibition, reduction of oxidative stress through induction of antioxidant enzymes (SOD, catalase), suppression of neuroinflammation through microglial deactivation, enhancement of neurotrophic factor expression (BDNF, NGF, ADNP), and maintenance of mitochondrial membrane potential [3][9][13].

Migraine Pathophysiology

PACAP has emerged as a key mediator of migraine alongside CGRP. The migraine-related mechanisms include vasodilation of meningeal blood vessels (particularly the middle meningeal artery) through VPAC1/VPAC2, activation and sensitization of trigeminal nociceptive neurons through PAC1, mast cell degranulation in the dura mater, and central sensitization in the trigeminovascular system [6][8][14].

3. Researched Applications

3.1 Migraine

PACAP's role in migraine was established by Schytz et al. (2009), who demonstrated that intravenous PACAP-38 (10 pmol/kg/min for 20 minutes) provoked delayed migraine-like attacks in 58% of migraine patients vs. 17% with placebo in a randomized double-blind crossover design [6]. This was the first direct evidence of PACAP's migraine-triggering capacity in humans.

Tuka et al. (2013) found that plasma PACAP-38 levels were significantly elevated during migraine attacks compared to interictal periods and controls, with decreased levels in the external jugular vein during attacks suggesting cranial release [8].

These findings prompted development of AMG 301 (subsequently renamed Lu AG09222 after Lundbeck acquisition), a humanized monoclonal antibody that binds to the PACAP ligand with high affinity, preventing PACAP from activating its receptors. The initial Phase IIa trial (Rubio-Beltran et al., 2021) enrolled 343 patients with episodic migraine. While the primary efficacy endpoint (reduction in monthly migraine days) was not met, the antibody demonstrated target engagement and good tolerability, with trends toward benefit in some subgroups [7].

Critically, the subsequent Phase 2 HOPE trial (published in the New England Journal of Medicine in 2024) demonstrated the first positive Phase 2 result for PACAP-targeted migraine prevention [21]. Lu AG09222 at 750 mg IV significantly reduced monthly migraine days by 6.2 versus 4.2 for placebo (difference -2.0 days; 95% CI -3.8 to -0.3; P=0.02) over weeks 1-4. This landmark result validated PACAP as a druggable migraine target independent of CGRP.

Building on the HOPE trial success, Lundbeck initiated the PROCEED Phase 2b dose-finding study in 2025, enrolling approximately 498 patients across Europe, Japan, and the US. Following a planned interim analysis after approximately 75% enrollment in the subcutaneous dosing arm, the trial was expanded to include an intravenous dose-finding arm. Completion is expected in the first half of 2026, with pivotal Phase 3 initiation planned for the second half of 2026.

3.2 Neuroprotection -- Stroke

Ohtaki et al. (2006) provided definitive evidence of PACAP's endogenous neuroprotective role using PACAP-deficient mice. These animals had significantly larger infarct volumes after middle cerebral artery occlusion (MCAO) compared to wild-type mice. Exogenous PACAP-38 (1 mcg, intracerebroventricularly) reduced infarct volume by approximately 50% in wild-type mice through anti-apoptotic and anti-inflammatory mechanisms involving IL-6 signaling [9].

Multiple studies have confirmed PACAP's neuroprotective efficacy in focal and global cerebral ischemia, traumatic brain injury, and excitotoxic neuronal death models [3][13].

3.3 Retinal Protection

Rat et al. (2011) demonstrated that intravitreal PACAP-38 (100 pmol) protected retinal ganglion cells and inner nuclear layer neurons against ischemic damage following bilateral carotid artery occlusion. The mechanism involved reduction of apoptotic markers, oxidative stress, and inflammatory mediator production [12]. PACAP's retinal neuroprotection has been replicated across multiple models including diabetic retinopathy, glaucoma, and UV-induced retinal damage.

3.4 Renal Protection

Reglodi et al. (2012) showed that PACAP-38 pretreatment protected against renal ischemia-reperfusion injury in rats, reducing tubular necrosis and improving renal function through anti-apoptotic and anti-inflammatory mechanisms [11]. PACAP-deficient mice show increased susceptibility to renal injury, confirming an endogenous protective role.

3.5 Stress Response and PTSD

Ressler et al. (2011) published a landmark study in Nature demonstrating a sex-specific association between ADCYAP1R1 (PAC1 receptor gene) polymorphisms and PTSD in women. The PAC1 receptor SNP rs2267735 was associated with PTSD diagnosis, dark-enhanced startle response, and altered PAC1 mRNA expression in blood and brain tissue [20]. This finding links PACAP signaling to stress-related psychiatric disorders and may explain sex differences in PTSD prevalence.

3.6 Circadian Entrainment

Hannibal et al. (2002) demonstrated that PACAP is co-expressed with glutamate in melanopsin-containing retinal ganglion cells that project to the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract. PACAP modulates light-induced phase shifts of circadian rhythms, acting through PAC1 receptors on SCN neurons [10]. While VIP acts as the primary synchronizer within the SCN (via VPAC2), PACAP conveys photic information from the retina to the clock.

4. Comparison with VIP

| Feature | PACAP | VIP | |---|---|---| | Length | 38 or 27 amino acids | 28 amino acids | | Sequence identity | 68% (PACAP-27 vs. VIP) | 68% | | PAC1 affinity | ~0.5 nM | greater than 500 nM | | VPAC1/VPAC2 affinity | ~1 nM each | ~1 nM each | | Predominant CNS receptor | PAC1 | VPAC1/VPAC2 | | Primary neuroprotective role | Direct neuronal survival (PAC1) | Indirect (anti-inflammatory) | | Circadian role | Photic entrainment (RHT to SCN) | SCN synchronization (VPAC2) | | Migraine role | Triggers migraine; drug target | Limited evidence | | Clinical development | Anti-PAC1 antibody (migraine) | Aviptadil (ARDS, PAH) |

5. Clinical Evidence Summary

6. Dosing in Published Research

7. Pharmacokinetics

PACAP's pharmacokinetics are characterized by rapid enzymatic degradation and form-dependent differences between PACAP-38 and PACAP-27 [3][14][15].

Plasma Half-Life: PACAP-38 has a plasma half-life of approximately 5-10 minutes, while PACAP-27 is degraded more rapidly with a half-life of approximately 2-5 minutes [3][14]. The shorter half-life of PACAP-27 is attributed to greater susceptibility to dipeptidyl peptidase IV (DPP-IV/CD26), which cleaves the N-terminal His1-Ser2 dipeptide from both forms, generating inactive PACAP(3-38) and PACAP(3-27) metabolites. The 11 additional C-terminal residues of PACAP-38 may provide partial steric protection against some degrading enzymes.

DPP-IV Degradation: DPP-IV is the principal degrading enzyme for PACAP in circulation, recognizing the N-terminal His-Ser dipeptide motif (also present in GLP-1, GIP, and other peptides in the VIP/secretin superfamily) [3][5]. DPP-IV cleavage generates PACAP(3-38) and PACAP(3-27), which have dramatically reduced PAC1 receptor affinity (greater than 100-fold reduction) and may act as partial antagonists [3][4]. Other contributing peptidases include neutral endopeptidase (NEP/neprilysin) and mast cell tryptase.

Endogenous Distribution: PACAP is widely distributed in the CNS and PNS, with the highest concentrations in the hypothalamus (approximately 30-40 pmol/g tissue), followed by the hippocampus, amygdala, brainstem, trigeminal ganglia, dorsal root ganglia, and adrenal medulla [3][15]. PACAP-38 constitutes approximately 90% of total PACAP in most tissues, with PACAP-27 representing the remaining 10% [1][2]. Circulating plasma levels of PACAP-38 are in the low picomolar range (5-20 pM) under normal conditions, with significant elevations during migraine attacks [8].

Route-Dependent Kinetics: In the migraine provocation paradigm, intravenous PACAP-38 infusion at 10 pmol/kg/min for 20 minutes achieved plasma levels sufficient to cause sustained meningeal artery dilation and delayed migraine-like attacks, with vasodilatory effects persisting well beyond the infusion period despite rapid peptide clearance [6]. This temporal dissociation between peptide clearance and biological effect suggests that PACAP triggers sustained receptor signaling cascades (potentially through PAC1 receptor internalization and endosomal signaling) that outlast the ligand's physical presence [19].

Intracerebroventricular Administration: Ohtaki et al. (2006) administered PACAP-38 (1 mcg) by ICV injection, achieving direct CNS exposure that bypassed the blood-brain barrier and DPP-IV degradation in plasma [9]. This route provided neuroprotective concentrations in brain tissue within minutes, reducing infarct volume by approximately 50%.

Blood-Brain Barrier Penetration: PACAP-38 has limited but measurable blood-brain barrier penetration, primarily through a saturable transport system (PTS-6) [3]. However, the rapid systemic degradation limits the fraction reaching the CNS after peripheral administration. Intravitreal delivery for retinal applications bypasses this limitation [12].

Tissue Storage and Release: PACAP is stored in dense-core vesicles in nerve terminals and released in a calcium-dependent manner upon neuronal depolarization [3][15]. In the trigeminal system, PACAP is released from perivascular trigeminal nerve endings during migraine attacks, contributing to meningeal vasodilation and neurogenic inflammation [6][8][14].

8. Dose-Response Relationships

Migraine Provocation: Schytz et al. (2009) used intravenous PACAP-38 at 10 pmol/kg/min for 20 minutes, inducing delayed migraine-like attacks in 58% of migraine patients versus 17% with placebo [6]. This dose was selected based on earlier studies showing that lower doses (1-5 pmol/kg/min) produced vasodilation without reliable migraine provocation, while the 10 pmol/kg/min dose consistently triggered clinically recognizable migraine attacks. VIP at the same molar dose produced only vasodilation without migraine, demonstrating that the migraine-triggering effect is specific to PACAP's PAC1 receptor engagement rather than VPAC-mediated vasodilation [6][14].

Neuroprotection -- Stroke: Ohtaki et al. (2006) demonstrated that a single ICV injection of 1 mcg PACAP-38 reduced infarct volume by approximately 50% after MCAO [9]. In vitro neuroprotection studies show PACAP activity at femtomolar to nanomolar concentrations, with maximal neuronal survival enhancement at approximately 0.1-10 nM -- an extraordinarily potent dose-response reflecting the high-affinity PAC1 receptor interaction (Kd approximately 0.5 nM) [3][9][13].

Retinal Protection: Rat et al. (2011) used intravitreal PACAP-38 at 100 pmol (single injection), which significantly protected retinal ganglion cells against ischemic damage [12]. Dose-ranging studies in retinal ischemia models have shown neuroprotective effects from 1 pmol to 100 pmol, with maximal protection at 100 pmol and the dose-response curve plateauing above this concentration.

Renal Protection: Reglodi et al. (2012) demonstrated dose-dependent renal protection with intravenous PACAP-38, testing 10-100 mcg/kg as single pretreatment doses [11]. The higher dose (100 mcg/kg) provided greater reduction in tubular necrosis and better preservation of renal function, consistent with a progressive dose-response without apparent ceiling effect at the doses tested.

Adenylate Cyclase Stimulation: The defining biochemical property of PACAP is its extraordinary potency in stimulating adenylate cyclase. In the original characterization, Miyata et al. (1989) showed that PACAP-38 stimulated cAMP production in rat anterior pituitary cells approximately 1000-fold more potently than VIP, with an EC50 in the low picomolar range [1].

PAC1 vs. VPAC Dose-Response Separation: The clinical relevance of PACAP signaling in migraine is underscored by the dose-response separation between PAC1 and VPAC pathways. VIP, which activates only VPAC1/2 (not PAC1), produces vasodilation at equivalent doses but does not trigger migraine, establishing that PAC1-specific signaling is required for the migraine-provoking effect [6][14].

9. Comparative Effectiveness

PACAP Pathway vs. CGRP Pathway in Migraine

The PACAP and CGRP (calcitonin gene-related peptide) pathways represent the two most validated neuropeptide targets in migraine therapeutics, with important differences in clinical development trajectory and mechanistic understanding [6][7][8][14].

Clinical Evidence: CGRP pathway drugs (erenumab, fremanezumab, galcanezumab, eptinezumab -- anti-CGRP or anti-CGRP receptor antibodies; rimegepant, ubrogepant -- small molecule CGRP receptor antagonists) have achieved FDA approval and demonstrated robust efficacy in Phase III trials with 50% responder rates of 40-60% for episodic migraine. The anti-PAC1 antibody AMG 301 (Lu AG09222) did not meet its primary efficacy endpoint in Phase IIa, though it showed trends toward benefit and confirmed target engagement [7].

Mechanistic Complementarity: CGRP and PACAP are co-released from trigeminal nerve endings during migraine, and they activate overlapping but distinct downstream pathways. CGRP acts through CGRP receptors (CLR/RAMP1) to cause meningeal vasodilation and trigeminovascular sensitization. PACAP acts primarily through PAC1 to activate trigeminal neurons, with additional vasodilatory effects through VPAC1/2 [6][8][14]. The failure of VIP to trigger migraine (despite sharing VPAC receptors with PACAP) confirms that PAC1-specific signaling drives PACAP's migraine-provoking effect. This suggests that PACAP/PAC1 blockade may benefit patients who respond incompletely to CGRP-targeted therapy.

Non-Responder Potential: Approximately 30-40% of migraine patients do not respond adequately to CGRP-targeted therapies. The PACAP/PAC1 pathway represents the leading alternative target for this population. The rationale is supported by the finding that PACAP and CGRP may trigger migraine through partially independent mechanisms, meaning that some patients' migraine may be more PACAP-driven than CGRP-driven [7][14].

AMG 301 (Lu AG09222) Trial Analysis

The Phase IIa trial (Rubio-Beltran et al., 2021) enrolled 343 patients with episodic migraine and tested AMG 301 at a single dose versus placebo [7]. The primary endpoint (change in monthly migraine days) was not met, though several factors may have contributed: the single-dose design may not have provided adequate PAC1 receptor occupancy over the full treatment period; the trial enrolled an unselected migraine population rather than CGRP non-responders who might be enriched for PACAP-dependent migraine; and the dose may not have been optimized. Development continues with modified trial designs and optimized candidates.

PACAP vs. VIP as Therapeutic Targets

Despite 68% sequence homology and shared VPAC receptors, PACAP and VIP have divergent clinical development paths [3][4][16]. PACAP's clinical significance centers on migraine and neuroprotection through PAC1, while VIP's clinical development (aviptadil) focuses on ARDS and pulmonary hypertension through VPAC2 on smooth muscle. VIP does not trigger migraine, confirming that VPAC-mediated vasodilation alone is insufficient for migraine pathogenesis. For neuroprotection, PACAP is the more potent agent by orders of magnitude, reflecting PAC1-mediated direct neuronal survival signaling versus VIP's indirect anti-inflammatory neuroprotection through VPAC1/2 [3][9][13].

10. Enhanced Safety Profile

Human Administration Data

Direct PACAP administration in humans is limited to the migraine provocation paradigm [6]. Schytz et al. (2009) reported that intravenous PACAP-38 infusion (10 pmol/kg/min for 20 minutes) produced the following effects: transient flushing and warmth (consistent with vasodilation, occurring in most subjects), headache progressing to migraine-like attacks in susceptible individuals (the intended experimental outcome), mild transient hypotension (reflecting systemic vasodilation), and nausea in some subjects [6]. These effects were self-limiting and resolved after infusion cessation, consistent with PACAP's short half-life.

Anti-PAC1 Antibody Safety

AMG 301 (Lu AG09222) demonstrated good tolerability in the Phase IIa trial, with adverse event rates comparable to placebo and no serious drug-related adverse events [7]. This is encouraging, though longer-term safety monitoring is required to assess potential effects of chronic PAC1 blockade.

Theoretical Concerns with Chronic PAC1 Blockade

PACAP serves essential endogenous functions that could theoretically be compromised by sustained PAC1 blockade [3][14][18]:

Neuroprotection: PACAP is one of the most potent endogenous neuroprotective factors. PACAP-knockout mice show increased vulnerability to stroke (larger infarct volumes after MCAO) [9]. Chronic PAC1 blockade could theoretically reduce endogenous neuroprotective reserve, increasing vulnerability to ischemic and neurodegenerative insults.

Stress Response: The PACAP/PAC1 system mediates stress adaptation, and genetic variants in PAC1 (ADCYAP1R1) are associated with PTSD susceptibility [20]. Long-term PAC1 blockade might alter stress resilience, though this has not been observed in clinical trials.

Circadian Function: PACAP mediates photic entrainment of circadian rhythms through the retinohypothalamic tract [10]. Disruption of this pathway could theoretically affect sleep-wake cycle regulation, though anti-PAC1 antibodies may not penetrate the CNS sufficiently to affect this function.

Reproductive Function: PACAP is involved in gonadal function and spermatogenesis. PACAP-knockout mice show reproductive abnormalities [18]. Fertility effects should be monitored in long-term clinical trials.

Metabolic Effects: PACAP regulates pancreatic beta-cell insulin secretion through PAC1 [3][15]. Chronic PAC1 blockade could theoretically affect glucose homeostasis, warranting metabolic monitoring.

Comparative Safety -- PACAP vs. CGRP Pathway Drugs

Anti-CGRP drugs have established a favorable long-term safety profile with several years of post-marketing surveillance. The potential safety concerns with anti-PAC1 therapy differ from those with anti-CGRP therapy because PACAP's endogenous roles (neuroprotection, circadian regulation, stress adaptation) are distinct from CGRP's (vasodilation, bone metabolism). The safety profile of chronic PAC1 blockade will need to be evaluated independently rather than extrapolated from CGRP pathway experience [7][14].

11. Safety and Side Effects

Direct PACAP administration in human studies has been limited primarily to the migraine provocation paradigm. Schytz et al. (2009) reported that intravenous PACAP-38 infusion (10 pmol/kg/min for 20 minutes) was generally well tolerated, with the most common effects being transient flushing and warmth, headache (expected given the study design), mild hypotension (transient), and nausea in some subjects [6].

The anti-PAC1 antibody AMG 301 demonstrated good tolerability in the Phase IIa trial, with no significant safety signals and adverse event rates comparable to placebo [7].

PACAP's role as an essential endogenous neuroprotective factor raises theoretical concerns about chronic PAC1 blockade. Long-term safety monitoring in anti-PAC1 antibody trials will need to assess potential effects on stress resilience, neuroprotection, and circadian function [14][18].

12. Historical Context

• 1989: Miyata and Arimura isolate PACAP-38 from 4,000 ovine hypothalami [1]
• 1990: PACAP-27 identified as the N-terminal 27-residue form [2]
• 1993: PAC1 receptor cloned; splice variants characterized
• 1998: Arimura publishes comprehensive neuroendocrine perspective [15]
• 2002: PACAP identified in retinohypothalamic tract mediating circadian entrainment [10]
• 2006: PACAP-knockout mice show increased stroke vulnerability [9]
• 2009: Vaudry et al. publish 20th anniversary comprehensive review [3]; Schytz et al. demonstrate PACAP triggers migraine in humans [6]
• 2011: PACAP/PAC1 genetically linked to PTSD [20]
• 2013: Elevated plasma PACAP confirmed during migraine attacks [8]
• 2018: Anti-PAC1 antibody AMG 301 enters clinical trials
• 2021: Phase IIa AMG 301 results published; primary endpoint not met but development continues [7]
• 2024: Phase 2 HOPE trial of Lu AG09222 published in New England Journal of Medicine; first positive Phase 2 for PACAP-targeted migraine prevention [21]
• 2025: PROCEED Phase 2b dose-finding trial underway; pivotal Phase 3 planned for H2 2026

13. Related Peptides

See also: Vasoactive Intestinal Peptide (VIP), CGRP (Calcitonin Gene-Related Peptide), Substance P, Secretin

14. References

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