Meta-analysis of the impact of physical activity on the recovery of physical function in COVID-19 patients.

Background: The decrease in physical function resulting from COVID-19 infection exerts a substantial negative influence on the quality of life of individuals. Physical activity plays a crucial and irreplaceable role in hastening the elimination of adverse effects on the body caused by acute and chronic diseases. Nevertheless, there have been reports of unfavorable events following physical activity post-COVID-19 infection, sparking debate regarding the efficacy of physical activity as a rehabilitation method to enhance the physical function of COVID-19 patients. Objective: The aim of this study is to investigate the impact of physical activity on promoting the restoration of physical function among individuals with COVID-19, and to offer guidance for the advancement and consideration of physical activity in the rehabilitation treatment of COVID-19 patients. Methods: A search was conducted on the PubMed and Web of Science core collection databases, with the search period set from January 1, 2020, to February 6, 2023. The included literature was assessed for risk of bias and methodological quality according to the Cochrane Handbook for Systematic Reviews of Interventions, utilizing Review Manager 5.1 software. The outcome measures from the included studies were analyzed, and the quality of evidence for the outcome measures was graded using the GRADE classification criteria. Results: The effect of physical activity intervention on improving the 6-Minute Walk Test score in COVID-19 patients was better than that of conventional treatment [WMD = 69.19(95%CI = 39.38, 98.99), I2 = 57%(p = 0.03)]. The effect of physical activity on improving the 30-Second Sit-to-Stand Test score was better than that of conventional treatment [WMD = 2.98(95%CI = 1.91, 4.04), I2 = 0%(p = 0.56)]. There was no significant difference between physical activity and conventional treatment in improving Grip strength in COVID-19 patients [WMD = 2.35(95%CI = -0.49, 5.20), I2 = 0%(p = 0.80)]. The effect of physical activity on improving the Timed Up and Go test score in COVID-19 patients was better than that of conventional treatment [WMD = -1.16(95%CI = -1.98, -0.34), I2 = 4%(p = 0.35)]. The effect of physical activity on improving Forced Vital Capacity in COVID-19 patients was better than that of conventional treatment [WMD = 0.14(95%CI = 0.08, 0.21), I2 = 0%(p = 0.45)]. The effect of physical activity on improving Forced Expiratory Volume in the first second in COVID-19 patients was better than that of conventional treatment [WMD = 0.08(95%CI = 0.02, 0.15), I2 = 52%(p = 0.10)]. Conclusions: Physical activity plays a crucial role in facilitating the recovery of exercise capacity and pulmonary function in COVID-19 patients, helping to expedite the restoration of overall physical health. It is crucial for COVID-19 patients to undergo an accurate assessment of their physical condition before engaging in any physical activity.

Manipulation of retinoic acid signaling in the nucleus accumbens shell alters rat emotional behavior.

Novel targets for depression and anxiety disorders are necessary for the development of more effective pharmacotherapeutics. Our previous study found that the retinoic acid (RA) signaling pathway is the signaling pathway most enhanced in the nucleus accumbens (NAc) shell, a region important for depression, anxiety, and addiction. Genetic manipulations of RA signaling in the NAc affecting addiction-related behavior prompted our study of the role of retinoic acid signaling in depression-related and anxiety-related behavior using in vivo RNA interference. Knockdown of the retinoic acid degradation enzyme cytochrome p450 family 26 subfamily b member 1 (Cyp26b1) in the nucleus accumbens shell increased depression-related behavior while decreasing anxiety-like behavior. Knockdown of the retinoic acid binding protein, cellular RA binding protein 2 (Crabp2), also increased depression-related behavior. Knockdown of another RA binding partner fatty acid binding protein 5 (Fabp5), did not alter these behaviors. These results further support the contention that RA signaling in the NAc shell can affect emotional behavior and that targeting some components of this pathway could be a promising avenue for developing novel treatments for depression and anxiety.

Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell.

Psychiatric disorders such as anxiety, depression and addiction are often comorbid brain pathologies thought to share common mechanistic biology. As part of the cortico-limbic circuit, the nucleus accumbens shell (NAcSh) plays a fundamental role in integrating information in the circuit, such that modulation of NAcSh circuitry alters anxiety, depression, and addiction-related behaviors. Intracellular kinase cascades in the NAcSh have proven important mediators of behavior. To investigate glycogen-synthase kinase 3 (GSK3) beta signaling in the NAcSh in vivo we knocked down GSK3beta expression with a novel adeno-associated viral vector (AAV2) and assessed changes in anxiety- and depression-like behavior and cocaine self-administration in GSK3beta knockdown rats. GSK3beta knockdown reduced anxiety-like behavior while increasing depression-like behavior and cocaine self-administration. Correlative electrophysiological recordings in acute brain slices were used to assess the effect of AAV-shGSK3beta on spontaneous firing and intrinsic excitability of tonically active interneurons (TANs), cells required for input and output signal integration in the NAcSh and for processing reward-related behaviors. Loose-patch recordings showed that TANs transduced by AAV-shGSK3beta exhibited reduction in tonic firing and increased spike half width. When assessed by whole-cell patch clamp recordings these changes were mirrored by reduction in action potential firing and accompanied by decreased hyperpolarization-induced depolarizing sag potentials, increased action potential current threshold, and decreased maximum rise time. These results suggest that silencing of GSK3beta in the NAcSh increases depression- and addiction-related behavior, possibly by decreasing intrinsic excitability of TANs. However, this study does not rule out contributions from other neuronal sub-types.

Transcriptomics of Environmental Enrichment Reveals a Role for Retinoic Acid Signaling in Addiction.

There exists much variability in susceptibility/resilience to addiction in humans. The environmental enrichment paradigm is a rat model of resilience to addiction-like behavior, and understanding the molecular mechanisms underlying this protective phenotype may lead to novel targets for pharmacotherapeutics to treat cocaine addiction. We investigated the differential regulation of transcript levels using RNA sequencing of the rat nucleus accumbens after environmental enrichment/isolation and cocaine/saline self-administration. Ingenuity Pathways Analysis and Gene Set Enrichment Analysis of 14,309 transcripts demonstrated that many biofunctions and pathways were differentially regulated. New functional pathways were also identified for cocaine modulation (e.g., Rho GTPase signaling) and environmental enrichment (e.g., signaling of EIF2, mTOR, ephrin). However, one novel pathway stood out above the others, the retinoic acid (RA) signaling pathway. The RA signaling pathway was identified as one likely mediator of the protective enrichment addiction phenotype, an interesting result given that nine RA signaling-related genes are expressed selectively and at high levels in the nucleus accumbens shell (NAcSh). Subsequent knockdown of Cyp26b1 (an RA degradation enzyme) in the NAcSh of rats confirmed this role by increasing cocaine self-administration as well as cocaine seeking. These results provide a comprehensive account of enrichment effects on the transcriptome and identify RA signaling as a contributing factor for cocaine addiction.

Convergent transcriptomics and proteomics of environmental enrichment and cocaine identifies novel therapeutic strategies for addiction.

Transcriptomic and proteomic approaches have separately proven effective at identifying novel mechanisms affecting addiction-related behavior; however, it is difficult to prioritize the many promising leads from each approach. A convergent secondary analysis of proteomic and transcriptomic results can glean additional information to help prioritize promising leads. The current study is a secondary analysis of the convergence of recently published separate transcriptomic and proteomic analyses of nucleus accumbens (NAc) tissue from rats subjected to environmental enrichment vs. isolation and cocaine self-administration vs. saline. Multiple bioinformatics approaches (e.g. Gene Ontology (GO) analysis, Ingenuity Pathway Analysis (IPA), and Gene Set Enrichment Analysis (GSEA)) were used to interrogate these rich data sets. Although there was little correspondence between mRNA vs. protein at the individual target level, good correspondence was found at the level of gene/protein sets, particularly for the environmental enrichment manipulation. These data identify gene sets where there is a positive relationship between changes in mRNA and protein (e.g. glycolysis, ATP synthesis, translation elongation factor activity, etc.) and gene sets where there is an inverse relationship (e.g. ribosomes, Rho GTPase signaling, protein ubiquitination, etc.). Overall environmental enrichment produced better correspondence than cocaine self-administration. The individual targets contributing to mRNA and protein effects were largely not overlapping. As a whole, these results confirm that robust transcriptomic and proteomic data sets can provide similar results at the gene/protein set level even when there is little correspondence at the individual target level and little overlap in the targets contributing to the effects.

Overexpression of DeltaFosB in nucleus accumbens mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment.

Environmental enrichment produces protective addiction and depression phenotypes in rats. ΔFosB is a transcription factor that regulates reward in the brain and is induced by psychological stress as well as drugs of abuse. However, the role played by ΔFosB in the protective phenotypes of environmental enrichment has not been well studied. Here, we demonstrate that ΔFosB is differentially regulated in rats reared in an isolated condition (IC) compared to those in an enriched condition (EC) in response to restraint stress or cocaine. Chronic stress or chronic cocaine treatment each elevates ΔFosB protein levels in the nucleus accumbens (NAc) of IC rats, but not of EC rats due to an already elevated basal accumulation of ΔFosB seen under EC conditions. Viral-mediated overexpression of ΔFosB in the NAc shell of pair-housed rats (i.e., independent of environmental enrichment/isolation) increases operant responding for sucrose when motivated by hunger, but decreases responding in satiated animals. Moreover, ΔFosB overexpression decreases cocaine self-administration, enhances extinction of cocaine seeking, and decreases cocaine-induced reinstatement of intravenous cocaine self-administration; all behavioral findings consistent with the enrichment phenotype. In contrast, however, ΔFosB overexpression did not alter responses of pair-housed rats in several tests of anxiety- and depression-related behavior. Thus, ΔFosB in the NAc the shell mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment.

Environmental enrichment alters protein expression as well as the proteomic response to cocaine in rat nucleus accumbens.

Prior research demonstrated that environmental enrichment creates individual differences in behavior leading to a protective addiction phenotype in rats. Understanding the mechanisms underlying this phenotype will guide selection of targets for much-needed novel pharmacotherapeutics. The current study investigates differences in proteome expression in the nucleus accumbens of enriched and isolated rats and the proteomic response to cocaine self-administration using a liquid chromatography mass spectrometry (LCMS) technique to quantify 1917 proteins. Results of complementary Ingenuity Pathways Analyses (IPA) and gene set enrichment analyses (GSEA), both performed using protein quantitative data, demonstrate that cocaine increases vesicular transporters for dopamine and glutamate as well as increasing proteins in the RhoA pathway. Further, cocaine regulates proteins related to ERK, CREB and AKT signaling. Environmental enrichment altered expression of a large number of proteins implicated in a diverse number of neuronal functions (e.g., energy production, mRNA splicing, and ubiquitination), molecular cascades (e.g., protein kinases), psychiatric disorders (e.g., mood disorders), and neurodegenerative diseases (e.g., Huntington's and Alzheimer's diseases). Upregulation of energy metabolism components in EC rats was verified using RNA sequencing. Most of the biological functions and pathways listed above were also identified in the Cocaine X Enrichment interaction analysis, providing clear evidence that enriched and isolated rats respond quite differently to cocaine exposure. The overall impression of the current results is that enriched saline-administering rats have a unique proteomic complement compared to enriched cocaine-administering rats as well as saline and cocaine-taking isolated rats. These results identify possible mechanisms of the protective phenotype and provide fertile soil for developing novel pharmacotherapeutics. Proteomics data are available via ProteomeXchange with identifier PXD000990.

Functional status of the serotonin 5-HT2C receptor (5-HT2CR) drives interlocked phenotypes that precipitate relapse-like behaviors in cocaine dependence.

Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues ('cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5-HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors.

Differential phosphoproteome regulation of nucleus accumbens in environmentally enriched and isolated rats in response to acute stress.

Increasing evidence shows that stress contributes to the pathogenesis of major depressive disorder which is a severe neuropsychiatric disorder and influences over 10% of the world's population. Our previous studies revealed that rats reared in an enriched environment display less depression-related behavior compared to rats raised in an isolated environment, which implies that environmental enrichment produces an antidepressant-like behavioral phenotype. However, the molecular mechanisms are not fully understood. Protein phosphorylation rapidly changes signaling pathway function and alters the function of proteins associated with the stress-induced depressive disorder. Thus, in this study, a phosphoproteomic approach was used to uncover differential phosphoprotein regulation in rat nucleus accumbens between isolated (IC) and enriched environmental conditions (EC) under basal conditions, and in response to acute stress. We found 23 phosphoproteins were regulated in EC vs. IC rats under basal conditions; 10 phosphoproteins regulated by stress in IC rats; and 15 regulated by stress in EC rats. Among all significantly regulated phosphoproteins, 11 of them were represented in at least two conditions. The regulated phosphoproteins represent signaling pathway proteins (including ERK2), enzymes, transcriptional regulators, protein translation regulators, transporters, chaperones and cytoskeletal proteins. These findings provide a global view for further understanding the contribution of protein phosphorylation in depression pathogenesis and antidepressant action.

Dynamic proteomics of nucleus accumbens in response to acute psychological stress in environmentally enriched and isolated rats.

Our prior research has shown that environmental enrichment (i.e. rats reared in an environment with novel objects, social contact with conspecifics) produces a protective antidepressant-like phenotype in rats and decreases neurobiological effects of acute psychological stress. Although CREB activity has been identified as a major player, the downstream molecular mechanisms remain largely unexplored. Thus, the current study investigates proteomic differences in the accumbens of rats raised in an enriched condition (EC) versus those raised in an isolated control condition (IC) under basal conditions and after 30 min of acute restraint stress. Results showed that under basal conditions, EC rats generally expressed less mitochondria-related proteins, particularly those involved in TCA cycle and electron transport compared to IC rats. After 30 min of acute stress, EC rats displayed increased expression of energy metabolism enzymes (among others) while IC rats exhibited decreased expression of similar proteins. Further, network and pathway analyses also identified links to AKT signaling proteins, 14-3-3 family proteins, heat-shock proteins, and ubiquitin-interacting proteins. The protein ENO1 showed marked differential expression and regulation; EC rats expressed higher levels under basal conditions that increased subsequent to stress, while the basal IC expression was lower and decreased further still after stress. The results of this study define differential protein expression in a protective rat model for major depression and additionally identify a dynamic and coordinated differential response to acute stress between the two groups. These results provide new avenues for exploration of the molecular determinants of depression and the response to acute stress.

Minocycline inhibits the enhancement of antidromic primary afferent stimulation-evoked vasodilation following intradermal capsaicin injection.

Neurogenic inflammation is induced by inflammatory mediators released in peripheral tissue from primary afferent nociceptors. Our previous studies suggest that neurogenic inflammation induced by intradermal injection of capsaicin results from the enhancement of dorsal root reflexes (DRRs), which involve antidromic activation of dorsal root ganglion (DRG) neurons. Numerous studies have reported the important role of glial modulation in pain. However, it remains unclear whether glial cells participate in the process of neurogenic inflammation-induced pain. Here we tested the role of DRG satellite glial cells (SGCs) in this process in anesthetized rats by administration of a glial inhibitor, minocycline. Electrical stimuli (ES, frequency 10 Hz; duration 1 ms; strength 3 mA) were applied to the cut distal ends of the L4-5 dorsal roots. The stimuli evoked antidromic action potentials designed to mimic DRRs. Local cutaneous blood flow in the hindpaw was measured using a Doppler flow meter. Antidromic ES for 10 min evoked a significant vasodilation that could be inhibited dose-dependently by local administration of the calcitonin gene-related peptide receptor antagonist, CGRP8-37. Pretreatment with capsaicin intradermally injected into the hindpaw 2h before the ES enhanced greatly the vasodilation evoked by antidromic ES, and this enhancement could be reversed by minocycline pretreatment. Our findings support the view that neurogenic inflammation following capsaicin injection involves antidromic activation of DRG neurons via the generation of DRRs. Inhibition of neurogenic inflammation by minocycline is suggested to be associated with its inhibitory effect on SGCs that are possibly activated following capsaicin injection.

The effects of sympathetic outflow on upregulation of vanilloid receptors TRPV(1) in primary afferent neurons evoked by intradermal capsaicin.

The vanilloid receptor TRPV(1) is a key nociceptive molecule located in primary afferent nociceptive neurons in dorsal root ganglia (DRG) for initiating neurogenic inflammation and pain. Our recent study demonstrates that up-regulation of TRPV(1) receptors by intradermal injection of capsaicin is modulated by activation of the protein kinase C (PKC) cascade. Neurogenic inflammation and pain resulting from capsaicin injection are sympathetically dependent, responding to norepinephrine, adenosine 5'-triphosphate (ATP) and/or neuropeptide Y released from sympathetic efferents. In a rat model of acute neurogenic inflammatory pain produced by capsaicin injection, we used immunofluorescence and Western blots combined with pharmacology and surgical sympathectomies to analyze whether the capsaicin-evoked up-regulation of TRPV(1) in DRG neurons is affected by sympathetic outflow by way of activating the PKC cascade. Sympathetic denervation reduced significantly the capsaicin-evoked expressions of TRPV(1), calcitonin gene-related peptide and/or phosphorylated PKC and their co-expression. These reductions could be restored by exogenous pretreatment with an analog of ATP, alpha,beta-methylene ATP. Inhibition of PKC with chelerythrine chloride prevented the ATP effect. Consistent results were obtained from experiments in which capsaicin-evoked changes in cutaneous inflammation (vasodilation and edema) were examined after sympathetic denervation, and the effects of the above pharmacological manipulations were evaluated. Our findings suggest that the capsaicin-evoked up-regulation of TRPV(1) receptors in DRG neurons is modulated sympathetically by the action of ATP released from sympathetic efferents to activate the PKC cascade. Thus, this study proposes a potential new mechanism of sympathetic modulation of neurogenic inflammation.

Increases in transient receptor potential vanilloid-1 mRNA and protein in primary afferent neurons stimulated by protein kinase C and their possible role in neurogenic inflammation.

A recent study by our group demonstrates pharmacologically that the transient receptor potential vanilloid-1 (TRPV(1)) is activated by intradermal injection of capsaicin to initiate neurogenic inflammation by the release of neuropeptides in the periphery. In this study, expression of TRPV(1), phosphorylated protein kinase C (p-PKC), and calcitonin gene-related peptide (CGRP) in dorsal root ganglion (DRG) neurons was visualized by using immunofluorescence, real-time PCR, and Western blots to examine whether increases in TRPV(1) mRNA and protein levels evoked by capsaicin injection are subject to modulation by the activation of PKC and to analyze the role of this process in the pathogenesis of neurogenic inflammation. Capsaicin injection into the hindpaw skin of anesthetized rats evoked increases in the expression of TRPV(1), CGRP and p-PKC in mRNA and/or protein levels and in the number of single labeled TRPV(1), p-PKC, and CGRP neurons in ipsilateral L4-5 DRGs. Coexpressions of TRPV(1) with p-PKC and/or CGRP in DRG neurons were also significantly increased after CAP injection. These evoked expressions at both molecular and cellular levels were significantly inhibited after TRPV(1) receptors were blocked by 5'-iodoresiniferatoxin (5 microg) or PKC was inhibited by chelerythrine chloride (5 microg). Taken together, these results provide evidence that up-regulation of TRPV(1) mRNA and protein levels under inflammatory conditions evoked by capsaicin injection is subject to modulation by the PKC cascade in which increased CGRP level in DRG neurons may be related to the initiation of neurogenic inflammation. Thus, up-regulation of TRPV(1) receptors in DRG neurons seems critical for initiating acute neurogenic inflammation.

Sensitization of primary afferent nociceptors induced by intradermal capsaicin involves the peripheral release of calcitonin gene-related Peptide driven by dorsal root reflexes.

UNLABELLED: Neuropeptides released from axons of primary afferent nociceptive neurons are the key elements for the incidence of neurogenic inflammation and their release is associated with dorsal root reflexes (DRRs). However, whether the release is due to the triggering of DRRs and plays a role in inflammation-induced pain still remain to be determined. The present study assessed the role of calcitonin gene-related peptide (CGRP) in sensitization of primary afferent nociceptors induced by activation of transient receptor potential vanilloid-1 (TRPV(1)) after intradermal injection of capsaicin and determined if this release is due to activation of primary afferent neurons antidromically by triggering of DRRs. Under dorsal root intact conditions, primary afferent nociceptive fibers recorded in anesthetized rats could be sensitized by capsaicin injection, as shown by an increase in afferent responses and lowering of the response threshold to mechanical stimuli. After DRRs were removed by dorsal rhizotomy, the capsaicin-evoked sensitization was significantly reduced. In dorsal root intact rats, peripheral pretreatment with a CGRP receptor antagonist could dose-dependently reduce the capsaicin-induced sensitization. Peripheral post-treatment with CGRP could dose-dependently restore the capsaicin-induced sensitization under dorsal rhizotomized conditions. Capsaicin injection evoked increases in numbers of single and double labeled TRPV(1) and CGRP neurons in ipsilateral dorsal root ganglia (DRG). After dorsal rhizotomy, these evoked expressions were significantly inhibited. PERSPECTIVE: These data indicate that the DRR-mediated neurogenic inflammation enhances sensitization of primary afferent nociceptors induced by capsaicin injection. The underlying mechanism involves antidromic activation of DRG neurons via upregulation of TRPV(1) receptors whereby CGRP is released peripherally.

Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin.

BACKGROUND: Acute cutaneous neurogenic inflammation initiated by activation of transient receptor potential vanilloid-1 (TRPV1) receptors following intradermal injection of capsaicin is mediated mainly by dorsal root reflexes (DRRs). Inflammatory neuropeptides are suggested to be released from primary afferent nociceptors participating in inflammation. However, no direct evidence demonstrates that the release of inflammatory substances is due to the triggering of DRRs and how activation of TRPV1 receptors initiates neurogenic inflammation via triggering DRRs. RESULTS: Here we used pharmacological manipulations to analyze the roles of TRPV1 and neuropeptidergic receptors in the DRR-mediated neurogenic inflammation induced by intradermal injection of capsaicin. The degree of cutaneous inflammation in the hindpaw that followed capsaicin injection was assessed by measurements of local blood flow (vasodilation) and paw-thickness (edema) of the foot skin in anesthetized rats. Local injection of capsaicin, calcitonin gene-related peptide (CGRP) or substance P (SP) resulted in cutaneous vasodilation and edema. Removal of DRRs by either spinal dorsal rhizotomy or intrathecal administration of the GABAA receptor antagonist, bicuculline, reduced dramatically the capsaicin-induced vasodilation and edema. In contrast, CGRP- or SP-induced inflammation was not significantly affected after DRR removal. Dose-response analysis of the antagonistic effect of the TRPV1 receptor antagonist, capsazepine administered peripherally, shows that the capsaicin-evoked inflammation was inhibited in a dose-dependent manner, and nearly completely abolished by capsazepine at doses between 30-150 mug. In contrast, pretreatment of the periphery with different doses of CGRP8-37 (a CGRP receptor antagonist) or spantide I (a neurokinin 1 receptor antagonist) only reduced the inflammation. If both CGRP and NK1 receptors were blocked by co-administration of CGRP8-37 and spantide I, a stronger reduction in the capsaicin-initiated inflammation was produced. CONCLUSION: Our data suggest that 1) the generation of DRRs is critical for driving the release of neuropeptides antidromically from primary afferent nociceptors; 2) activation of TRPV1 receptors in primary afferent nociceptors following intradermal capsaicin injection initiates this process; 3) the released CGRP and SP participate in neurogenic inflammation.