National Institutes of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Funding Opportunity Title
Mechanistic Studies of Pain and Alcohol Dependence (R01)
R01 Research Project Grant
Funding Opportunity Announcement (FOA) Number
Catalog of Federal Domestic Assistance (CFDA) Number(s)
This Funding Opportunity Announcement (FOA) encourages applications that propose to conduct mechanistic studies on the relationship between alcohol drinking, alcohol dependence and pain. An association between chronic pain conditions and alcohol dependence has been revealed in numerous studies with episodes of alcohol abuse antedating chronic pain in some people and alcohol dependence emerging after the onset of chronic pain in others. Pain transmission and alcohol’s reinforcing effects share overlapping neural substrates giving rise to the possibility that chronic pain states significantly affect alcohol use patterns and promote the development of dependence and addiction. In addition, long term alcohol intoxication and alcohol dependence induce pain symptoms and may exacerbate chronic pain arising from other sources. The objective of this FOA is to understand genetic, pharmacological and learning mechanisms underlying the association between the propensity to drink alcohol and pain responses.
July 20, 2011
Open Date (Earliest Submission Date)
September 5, 2011
Letter of Intent Due Date
Application Due Date(s)
Standard dates, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)
Scientific Merit Review
Advisory Council Review
Earliest Start Date(s)
September 8, 2014
Due Dates for E.O. 12372
Required Application Instructions
It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.
Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information
This Funding Opportunity Announcement (FOA), issued by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) encourages Research Project Grant (R01) applications that propose to conduct mechanistic studies on the relationship between alcohol drinking, alcohol dependence and pain. Each year, an estimated 50 million Americans suffer from persistent pain arising from a variety of sources including headaches, joint pain, muscular pain, and neural pain. An association between chronic pain conditions and alcohol dependence has been revealed in numerous studies with episodes of alcohol abuse antedating chronic pain in some people and alcohol dependence emerging after the onset of chronic pain in others. Pain transmission and alcohol’s reinforcing effects share overlapping neural substrates giving rise to the possibility that chronic pain states significantly affect alcohol use patterns and promote the development of dependence and addiction. In addition, long term alcohol intoxication and alcohol dependence induce pain symptoms and may exacerbate chronic pain arising from other sources. The objective of this FOA is to understand genetic, pharmacological and learning mechanisms underlying the association between the propensity to drink alcohol and pain responses. Using the NIH Research Project Grant (R01) funding mechanism, this FOA focuses on discrete, specified, circumscribed projects based upon strong preliminary data.
Related Funding Opportunity: Investigators, who are interested in proposing exploratory and developmental research projects, should submit applications in response to the partner FOA of identical scientific scope (PA-11-268), which uses the NIH R21 grant mechanism.
Alcohol dependence is a complex, heterogeneous disorder involving multiple biological systems including genes, neural circuitry, and behavioral systems. Pain is similarly a complex, multidimensional experience influenced by multiple physiological and psychological factors. The relationship between these phenomena may be explained by three general observations. First, alcohol’s ability to alleviate pain may covary with its reinforcing effects and may be influenced by common genes. Second, neural substrates of alcohol reinforcement and addiction overlap with those involved in some aspects of pain experience. Finally, extensive alcohol exposure may evoke pain through withdrawal-induced hyperalgesia or induce neuropathic pain through actions on neuroimmune pathways as well as through other mechanisms.
Alcohol-induced Analgesia and Alcohol Dependence
Previous studies suggested that heavy alcohol users and people having a positive family history for alcoholism (FHP) are more sensitive to painful stimulation and are more responsive to pain-reducing effects of alcohol than control subjects. Heightened alcohol analgesia in alcoholics may arise from extensive experience through which they come to expect that alcohol temporarily alleviates pain. For example, bourbon whiskey reduced pain perception by alcoholic men, but had no analgesic effect in non-alcoholic subjects. Subsequent research tied alcohol’s ability to reduce pain to drinking experiences such that customary bar drinkers and subjects with a history of sickness after drinking experienced greater pain reduction after drinking alcohol than those who drank with families or who had no history of drinking-related sickness. The maximum level of pain reduction was also associated with preferred alcohol dose (i.e., light drinkers benefited most from the lowest dose tested and heavy drinkers required higher doses for pain reduction).
The influence of genes and drinking experience on alcohol’s analgesic effects may be complex. For example, in contrast to studies described above, a study that minimized experience-based effects by employing an IV “clamp” procedure to administer ethanol revealed diminished analgesic response to alcohol in young FHP adults. Ethanol administration enhanced tolerance for a painful electric shock only in subjects without a family history of alcoholism. A more comprehensive study found that FHP subjects scoring high for neuroticism were more sensitive to alcohol analgesia than FHP subjects with low neuroticism scores as well as subjects without a family history of alcoholism (FHN) suggesting that alcohol analgesia and predisposition for alcohol dependence may have a common genetic basis in a subset of individuals at risk for alcoholism. Further studies are needed to clarify genetic, personality and experiential variables contributing to alcohol’s analgesic effects.
Studies in rodents selectively bred for differences in alcohol preference provide partial evidence for a shared genetic basis for alcohol preference and pain response. Alcohol-preferring rat strains (P, AA, Maudsley Non-Reactive) had lower pain thresholds in the hot plate test than did their parallel non-preferring strains. Similarly, male alcohol-preferring P rats were more sensitive to thermal pain, as measured by tail-flick latency, than non-preferring NP rats. This relationship was not observed in a subsequent study in which alcohol non-preferring LAD1 rats displayed lower thermal pain sensitivity than the corresponding alcohol-preferring HAD1 strain. No differences in pain sensitivity were observed between inbred P rats and inbred NP rats. None of these studies included measures of alcohol analgesia, however. Studies using these animal models to complement human studies on covariation between alcohol analgesia and alcohol preference are needed to reveal common mechanisms underlying these phenotypes.
Tolerance to alcohol’s analgesic effects has been observed in animal studies. These effects are attributable to both physiological and learning mechanisms. In one study, exposure to alcohol in itself was not sufficient to produce tolerance to alcohol analgesia; i.e., tolerance was observed only in animals receiving repeated pain assessments during IP alcohol administration, but not in animals receiving alcohol, but no analgesia tests during the study. In another study, rats receiving alcohol injections in a distinct context were shown to develop tolerance to alcohol’s analgesic effects regardless of whether they also received tail-flick tests in the context. Learning mechanisms do not appear to operate when rats receive alcohol in a liquid diet because comparable levels of tolerance to alcohol analgesia were observed regardless of whether repeated pain tests were given during alcohol administration.
The preceding studies suggest that environmental and biological variables interact to determine analgesic responses to alcohol administration. The genetic relationship between alcohol analgesia (and basal pain sensitivity) and alcohol reinforcement and reward remains to be fully studied. This includes assessing alcohol preference and alcohol analgesia in relevant selectively-bred animals and in genetic reference populations such as BXD recombinant inbred strains. Studies of pain responses and alcohol reinforcement and analgesia are also needed in FHP subjects as well as people having genetic polymorphisms associated with aberrant pain processing. To explore possible gene-environment interactions, studies of experimentally controlled exposure to alcohol smell and taste and the role of learning mechanisms on the maintenance and abolishment of alcohol analgesia and reward in these subjects are also needed.
Mechanisms of Alcohol Analgesia and Reinforcement
Some evidence suggests that alcohol’s analgesic effects are mediated by neurotransmitter receptor systems involved in alcohol reinforcement. For example, alcohol-induced analgesia was reversed by administration of naloxone and other opiate antagonists, and alcohol analgesia in an arthritis model was associated with neuronal ß-endorphin release in the hypothalamus and a-neoendorphin release in the spinal cord. Despite this, naloxone failed to reverse alcohol analgesia in other reports leaving in question the range of conditions under which endogenous opioids contribute to alcohol’s analgesic effects. Ethanol inhibition of NMDA-activated neurotransmission may also mediate alcohol analgesia as intrathecal alcohol administration attenuated persistent pain in two models of NMDA-mediated thermal pain. G protein-coupled inwardly rectifying potassium 2 (GIRK2) channels are implicated as a major signal transduction mechanism for analgesic actions of many different drug classes including ethanol. Ethanol’s analgesic effects were abolished in GIRK2 null-mutant mice and diminished in weaver mice having a point mutation of the GIRK2 channel. Similarly, stress-induced analgesia known to be mediated by opioid receptors was absent in GIRK2 null-mutant mice suggesting that ethanol-induced analgesic responses mediated by opioid receptors may also involve GIRK2 channel activation. On the other hand, NMDA-receptor mediated analgesia occurs independently of GIRK2 channels as ketamine analgesia is intact in GIRK2 -/- mice. GIRK channels may also have a role in the acute rewarding effects of alcohol. Although GIRK2 -/- mice drink more ethanol than wild-type mice, they failed to acquire place preferences conditioned to ethanol suggesting diminished sensitivity to ethanol’s rewarding effects. The mutual reduction in ethanol analgesia and reward observed in GIRK2 knockout mice is consistent with a positive relationship between ethanol’s reinforcing and pain reducing effects.
Enhanced alcohol analgesia observed in alcoholics and FHP people may be partially influenced by genes that enhance alcohol’s reinforcing effects. The A118G variant of the µ-Opioid Receptor 1 (OPRM1) gene may be an obvious candidate although evidence for a relationship between the A118G OPRM1 and alcohol dependence is mixed. A118G carriers have diminished pain sensitivity and may be predicted to have altered analgesic and reinforcement responses to alcohol. Although analgesic effects of alcohol have not been studied as a function of OPRM1 status, a number of studies suggest carriers of the A118G variant or a functionally equivalent polymorphism show enhanced alcohol preference and euphoria and enhanced striatal dopamine response to alcohol a response often associated with drug reward. The val158met polymorphism of the catechol-O-methyl-transferase (COMT) gene could be another link between alcohol analgesia and alcohol reinforcement. The val158met genotype results in higher COMT enzyme levels, lower D2 receptor-mediated neurotransmission and elevated activation of the µ-opioid system. The met158 allele is associated with higher subjective and brain responses to pain and suppressed µ-opioid neurotransmitter response to pain. Whether the COMT met158 allele influences alcohol dependence remains unclear with some studies suggesting that the met158 allele contributes to the development of late-onset and early onset alcoholism and other studies failing to find an association between COMT variation and alcohol dependence. Male COMT -/- mice were found to drink more ethanol than wildtype mice; however, it cannot be determined from the methods used in this study whether this reflect higher or lower reinforcing effects.
Analgesia may contribute to alcohol’s reinforcing effects under some conditions. The most direct test of this hypothesis would be to examine the effects of analgesia blockade on ethanol’s rewarding and reinforcing effects as assessed in place conditioning and self-administration studies; however, the ability to independently block alcohol analgesia and reward may be complicated because overlapping neural systems may support pain transmission and reinforcement. Nevertheless, the possible association between alcohol’s analgesic and reinforcing effects implicates pain systems in the initiation of alcohol drinking and the development of alcohol dependence. This relationship requires further investigation, however, as there are few studies testing analgesic and reinforcing effects of alcohol in the same subjects. In addition, animal studies have focused primarily on pain measured in the spinally-mediated tail-flick assay to the exclusion of other models such as inflammatory or spontaneous pain models. In light of alcohol’s complex pharmacodynamics, additional studies are needed to examine alcohol’s effects at a range of doses in multiple pain modalities. In light of distinct neural effects of self-administered alcohol in regions implicated in pain perception, examining effects of self-administered alcohol on pain is also desirable.
Overlapping Neural Systems and the Development of Alcohol Dependence
As pain modulation networks continue to be identified, it is notable that brain regions that play a critical role in pain experience are not uniquely dedicated to pain and are also involved in other behavioral, sensory, cognitive and emotional experiences. This implies that dysregulation of so-called pain pathways would also influence other functions such as emotional experience. Conversely, dysregulation of neural substrates of emotion may alter pain perception. Such a relationship has been observed between pain and many affective disorders including depression and anxiety. This raises the question whether the relationship between pain and alcohol dependence arises because the two conditions share common neural substrates.
Neuroanatomical regions involved in pain transmission have been shown to play an important role in the development of alcohol dependence and addiction. For example, prolonged, excessive alcohol ingestion and repeated withdrawal episodes alter GABAergic neurotransmission in the central nucleus of the amygdala (CeA). This contributes to excessive alcohol drinking and negative affect associated with alcohol dependence and is proposed to arise from alcohol-induced allostatic changes in a larger network of brain reward, arousal and stress systems of which the CeA is a part. Evidence from electrophysiological, imaging and behavioral studies implicate the CeA as an integral part of the pain system via its connections with limbic structures, and have an important role in the enhancement and inhibition of pain. The activation and sensitization of CeA neurons would be expected to affect not only pain transmission, but also alcohol drinking and emotional states. This prediction remains to be tested.
Functional neuroimaging studies examining responses to physically induced pain as well as abnormal pain evoked by innocuous stimuli (allodynia) reveal the insular cortex to be the most consistently activated region during painful experiences in humans. These observations are consistent with studies in epilepsy patients in which direct electrical stimulation of distinct regions within the posterior insula evoked somatotopically specific pain sensations, and with neuroanatomical studies showing that the dorsal posterior insula receives pain input from a spinothamocoritical circuit. The anterior insula appears to integrate information about the salience of an impending painful stimulus. Aberrant misreading of such stimuli has been hypothesized to be a possible factor in the transition from acute to chronic pain. The role of the insula in addiction was widely publicized in a study showing that smokers with brain damage involving the insula were more likely to quit smoking without difficulty. A recent fMRI study showed that subjects with a family history of alcohol dependence and a variant of the GABRA2 gene associated with alcoholism had an elevated response in the insula when anticipating rewards and losses. Whether the insula’s involvement in aspects of alcohol dependence is correlated with pain transmission remains unknown.
The likelihood that pain transmission and alcohol reinforcement share overlapping neural substrates suggests that pain would alter the pharmacology and neurochemistry of alcohol self-administration. Further studies are needed to examine ethanol self-administration, particularly dose-response functions, and ethanol’s ability to support place conditioning in chronic pain models. Functional neuroimaging studies are needed to examine potential differences in brain processing of painful stimulation associated with risk for alcohol dependence as well as experience with alcohol. Such studies could provide clues regarding shared neural systems affecting pain and alcohol pharmacology. Intravenous ethanol administration procedures are well suited for functional imaging studies of alcohol effects. In addition, studies that examine interactions between chronic pain states and neuroadaptation to chronic intermittent alcohol exposure would reveal the possible contribution of pain transmission systems to the development of alcohol dependence.
Long-term Alcohol Use and Chronic Pain
Long term alcohol intoxication and alcohol dependence may induce pain symptoms and may exacerbate chronic pain arising from other sources. These effects, which persist after alcohol administration is discontinued, are associated with acute hyperalgesia following alcohol withdrawal, PKC-epsilon dependent peripheral neuropathy, and neuropathic pain activated by spinal cord glia. In addition to alcoholic neuropathy caused by excessive drinking, long-term low to moderate alcohol consumption may have important effects on pain sensitivity without any apparent hyperalgesia or neuropathic pain especially in vulnerable population. Although most people who consume alcohol do not become alcohol dependent or do not develop explicit alcoholic neuropathy, they may be prone to developing neuropathic pain when pain modulating system is perturbed at different levels. Neuropathic pain can be caused by several underlying conditions such as post-stroke pain, spinal cord injury, multiple sclerosis, painful diabetic poly-neuropathy, HIV neuropathy, post-operative neuralgia, peripheral nerve injury pain, trigeminal neuralgia, and cancer neuropathic pain. Whether such co-morbid pain conditions interact with alcohol use to induce hyperalgesia and exacerbate the pain sensitivity has not been studied. The consumption of low to moderate alcohol in these subjects could cause an increase in the severity of pain and/or make them resistant to analgesic treatment. There is a critical need to understand how alcohol use influences comorbid neuropathic pain conditions as such studies have not been reported in human or in animal models. Moreover, the influence of prior chronic alcohol use and withdrawal on neuropathic pain development and expression needs to be investigated. There are several animal models of neuropathic pain that closely reproduce human conditions. For example, diabetic neuropathy, sciatic nerve injury, spinal cord injury are well-established animal models of chronic neuropathic pain. The effects of different doses of alcohol (acute and chronic) in these animal models will provide valuable information on the role of alcohol intake on neuropathic pain development and severity. It is especially critical to understand the effects of low to moderate doses of alcohol on hyperalgesia development and severity. These studies could reveal how alcohol sensitizes pain transmission even before the development of neuropathic pain due to variety of underlying disease conditions. These issues are also important from a treatment perspective as many chronic neuropathic pain patients fail to respond to various treatment options. Prior and current chronic alcohol consumption may play a role in the treatment outcome of chronic neuropathic pain subjects. Furthermore, identification of possible mechanisms of action of alcohol in regulating pain sensitivity in these conditions could help to understand why certain patients fail to respond to analgesic medications.
Glial cells play an active role within the nervous system, being central to many metabolic and immune functions, as well as modulating neuronal activity, through uptake and release of transmitter substances. Recent studies have shown that microglia and astrocytes contribute to neuropathic pain by releasing pro- and anti-nociceptive (e.g. TNF-a, GDNF, IL-4, IL-10) factors. The effects of alcohol on glial cell functions such as the release of neuromodulators (e.g. adenosine), neurotropic factors (GDNF, thrombospondin) and pro/anti-inflammatory cytokines could play a critical role in alcoholic neuropathy as well as during co morbid neuropathic pain conditions. Recent data indicate that critical involvement of innate and adaptive immune responses following nerve injury. Activation of immune and immune-like glial cells in the brain, dorsal root ganglia and spinal cord results in the release of both pro- and anti-inflammatory cytokines, the balance of which determines whether chronic pain condition is established. Alcohol exposure even at low doses could tilt this balance towards excess of pro inflammatory cytokines resulting in hyperalgesia and increased neuronal damage. Studies are needed to investigate this possibility.
Appropriate topics include but are not limited to:
Studying pharmacological mechanisms of acute alcohol analgesia in multiple pain assays and their relationship to alcohol reinforcement and reward.
Identifying shared genetic influences on pain measures and alcohol dependence phenotypes.
Using functional neuroimaging studies to examine brain processing of painful stimulation and ethanol effects on pain transmission in subjects at risk for alcohol dependence.
Identifying pharmacological and learning mechanisms of alcohol analgesia and tolerance in multiple pain assays.
Studying effects of pain on alcohol’s rewarding and reinforcing effects.
Examining effects of chronic pain on neuroadaptation to chronic alcohol intoxication and repeated withdrawal and behavioral phenotypes associated with alcohol dependence.
Studying the interaction between chronic moderate alcohol consumption and the development of neuropathic pain in animal models.
Examining the role of glial cells in alcohol induced neuropathic pain.
Identifying neuroimmune pathways involved in hyperalgesia resulting from chronic alcohol exposure.
Application Types Allowed
The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards
The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications.
Application budgets are not limited, but need to reflect actual needs of the proposed project.
Award Project Period
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
All Program Directors/Principal Investigators (PD/PIs) must
also work with their institutional officials to register with the eRA Commons
or ensure their existing eRA Commons account is affiliated with the eRA Commons
account of the applicant organization.
All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.
Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director/Principal
Investigator (PD/PI) is invited to work with his/her organization to develop an
application for support. Individuals from underrepresented racial and ethnic
groups as well as individuals with disabilities are always encouraged to apply
for NIH support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed. Resubmission applications may be submitted, according to the NIH Policy on Resubmission Applications from the SF 424 (R&R) Application Guide.
Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.
It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.
The forms package associated with this FOA includes all applicable components, mandatory and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Resource Sharing Plan
Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies; GWAS) as provided in the SF424 (R&R) Application Guide.
Do not use the appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
Foreign (non-US) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.
Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.
Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.
Applicants are responsible for viewing their application in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.
All PD/PIs must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the Central Contractor Registration (CCR). Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.
Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NIH program staff at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF 424 (R&R) Application Guide.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.
Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.
Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be
If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.
Protections for Human Subjects
For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.
Inclusion of Women, Minorities, and Children
When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.
For Renewals, the committee will consider the progress made in the last funding period.
For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.
Applications from Foreign Organizations
Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s), in accordance with NIH peer
review policy and procedures, using the stated review
criteria. Review assignments will be shown in the eRA Commons.
As part of the scientific peer review, all applications:
Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate advisory council or boardl. The following will be considered in making funding decisions:
After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Cooperative Agreement Terms and Conditions of Award
When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.
A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
GrantsInfo (Questions regarding application instructions and
process, finding NIH grant resources)
eRA Commons Help Desk(Questions regarding eRA Commons
registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
Mark Egli, Ph.D.
Division of Neuroscience and Behavior
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Soundar Regunathan, Ph.D.
Division of Neuroscience and Behavior
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).
Ms. Judy Fox
Chief, Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
Department of Health
and Human Services (HHS)
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