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Ronald Dubner

Publications and source records attributed to Ronald Dubner.

At least 19 recordsLinked to original sources
PubMed2006

Selective distribution and function of primary afferent nociceptive inputs from deep muscle tissue to the brainstem trigeminal transition zone.

Orofacial injury activates two distinct regions in the spinal trigeminal complex, the subnuclei interpolaris/caudalis (Vi/Vc) transition zone and the laminated Vc, or medullary dorsal horn (MDH). Studies suggest that the Vi/Vc transition zone plays an important role in processing orofacial deep input. To test this hypothesis, we employed a double-tracing strategy to compare central projections of primary afferent neurons that innervate the masseter muscle and the overlying skin. Different tracers were injected either centrally (Fluoro-Gold: ventral Vi/Vc, or MDH) or peripherally (wheat germ agglutinin-conjugated horseradish peroxidase or cholera toxin B: masseter or overlying skin) in the same rat. Trigeminal ganglion tissue sections were processed for single or double immunohistochemistry. The double labeling of ganglion neurons indicates their site of peripheral and central innervations. A population of small to medium-sized neurons was doubly labeled after injections of the tracers into the masseter-Vi/Vc, masseter-MDH, or the skin-MDH. However, only a few double-labeled neurons were occasionally observed after injections of the tracers into the skin-Vi/Vc. Injection of an N-methyl-D-aspartate receptor antagonist, AP-5, into the Vi/Vc and MDH attenuated masseter inflammatory hyperalgesia. In contrast, hyperalgesia after inflammation of the skin overlying the masseter was attenuated by injection of AP-5 into the MDH but not Vi/Vc. These results indicate that while both masseter and cutaneous inputs project to the MDH, masseter afferents provide an additional input to the Vi/Vc. These findings provide further evidence to support a role of the trigeminal transition zone in response to orofacial deep injury.

Afferent Pathways↗
PubMed2006

Demonstration of a trigeminothalamic pathway to the oval paracentral intralaminar thalamic nucleus and its involvement in the processing of noxious orofacial deep inputs.

Using combined retrograde labeling and Fos protein immunohistochemistry, we show that after masseter inflammation, a population of neurons in the dorsal portion of the subnuclei interpolaris/caudalis transition zone at the level of the obex was activated and projected to the oval paracentral nucleus (OPC) of the intralaminar thalamic nuclei. The present findings indicate a trigeminothalamic pathway to the OPC intralaminar nucleus involved in central processing of orofacial deep noxious input.

Animals↗
PubMed2006

Supraspinal brain-derived neurotrophic factor signaling: a novel mechanism for descending pain facilitation.

In the adult mammalian brain, brain-derived neurotrophic factor (BDNF) is critically involved in long-term synaptic plasticity. Here, we show that supraspinal BDNF-tyrosine kinase receptor B (TrkB) signaling contributes to pain facilitation. We show that BDNF-containing neurons in the periaqueductal gray (PAG), the central structure for pain modulation, project to and release BDNF in the rostral ventromedial medulla (RVM), a relay between the PAG and spinal cord. BDNF in PAG and TrkB phosphorylation in RVM neurons are upregulated after inflammation. Intra-RVM sequestration of BDNF and knockdown of TrkB by RNA interference attenuate inflammatory pain. Microinjection of BDNF (10-100 fmol) into the RVM facilitates nociception, which is dependent on NMDA receptors (NMDARs). In vitro studies with RVM slices show that BDNF induces tyrosine phosphorylation of the NMDAR NR2A subunit in RVM via a signal transduction cascade involving IP(3), PKC, and Src. The supraspinal BDNF-TrkB signaling represents a previously unknown mechanism underlying the development of persistent pain. Our findings also caution that application of BDNF for recovery from CNS disorders could lead to undesirable central pain.

Animals↗
PubMed2005

Trigeminal transition zone/rostral ventromedial medulla connections and facilitation of orofacial hyperalgesia after masseter inflammation in rats.

Recent studies have implicated a role for the trigeminal interpolaris/caudalis (Vi/Vc) transition zone in response to orofacial injury. Using combined neuronal tracing and Fos protein immunocytochemistry, we investigated functional connections between the Vi/Vc transition zone and rostral ventromedial medulla (RVM), a key structure in descending pain modulation. Rats were injected with a retrograde tracer, FluoroGold, into the RVM 7 days before injection of an inflammatory agent, complete Freund's adjuvant, into the masseter muscle and perfused at 2 hours postinflammation. A population of neurons in the ventral Vi/Vc overlapping with caudal ventrolateral medulla, and lamina V of the trigeminal subnucleus caudalis (Vc), exhibited FluoroGold/Fos double staining, suggesting the activation of the trigeminal-RVM pathway after inflammation. No double-labeled neurons were found in the dorsal Vi/Vc and laminae I-IV of Vc. Injection of an anterograde tracer, Phaseolus vulgaris leucoagglutinin, into the RVM resulted in labeling profiles overlapped with the region that showed FluoroGold/Fos double labeling, suggesting reciprocal connections between RVM and Vi/Vc. Lesions of Vc with a soma-selective neurotoxin, ibotenic acid, significantly reduced inflammation-induced Fos expression as well as the number of FluoroGold/Fos double-labeled neurons in the ventral Vi/Vc (P<0.05). Compared with control rats, lesions of the RVM (n=6) or Vi/Vc (n=6) with ibotenic acid led to the elimination or attenuation of masseter hyperalgesia/allodynia developed after masseter inflammation (P<0.05-0.01). The present study demonstrates reciprocal connections between the ventral Vi/Vc transition zone and RVM. The Vi/Vc-RVM pathway is activated after orofacial deep tissue injury and plays a critical role in facilitating orofacial hyperalgesia.

Animals↗
PubMed2005

Neonatal local noxious insult affects gene expression in the spinal dorsal horn of adult rats.

Neonatal noxious insult produces a long-term effect on pain processing in adults. Rats subjected to carrageenan (CAR) injection in one hindpaw within the sensitive period develop bilateral hypoalgesia as adults. In the same rats, inflammation of the hindpaw, which was the site of the neonatal injury, induces a localized enhanced hyperalgesia limited to this paw. To gain an insight into the long-term molecular changes involved in the above-described long-term nociceptive effects of neonatal noxious insult at the spinal level, we performed DNA microarray analysis (using microarrays containing oligo-probes for 205 genes encoding receptors and transporters for glutamate, GABA, and amine neurotransmitters, precursors and receptors for neuropeptides, and neurotrophins, cytokines and their receptors) to compare gene expression profiles in the lumbar spinal dorsal horn (LDH) of adult (P60) male rats that received neonatal CAR treatment within (at postnatal day 3; P3) and outside (at postnatal 12; P12) of the sensitive period. The data were obtained both without inflammation (at baseline) and during complete Freund's adjuvant induced inflammation of the neonatally injured paw. The observed changes were verified by real-time RT-PCR. This study revealed significant basal and inflammation-associated aberrations in the expression of multiple genes in the LDH of adult animals receiving CAR injection at P3 as compared to their expression levels in the LDH of animals receiving either no injections or CAR injection at P12. In particular, at baseline, twelve genes (representing GABA, serotonin, adenosine, neuropeptide Y, cholecystokinin, opioid, tachykinin and interleukin systems) were up-regulated in the bilateral LDH of the former animals. The baseline condition in these animals was also characterized by up-regulation of seven genes (encoding members of GABA, cholecystokinin, histamine, serotonin, and neurotensin systems) in the LDH ipsilateral to the neonatally-injured paw. The largest aberration in gene expression, however, was observed during inflammation of the neonatally injured hindpaws in the ipsilateral LDH, which included thirty-six genes (encoding numerous members of glutamate, serotonin, GABA, calcitonin gene-related peptide, neurotrophin, and interleukin systems). These findings suggest that changes in gene expression may be involved in the long-term nociceptive effects of neonatal noxious insult at the spinal level.

Aging↗
PubMed2005

Antibody array analysis of peripheral and blood cytokine levels in rats after masseter inflammation.

This study was undertaken to evaluate the changes in cytokine levels in response to orofacial deep tissue inflammation. Inflammation was induced by injecting complete Freund's adjuvant (CFA, 0.05 ml 1:1 oil/saline suspension) into the masseter of the male Sprague-Dawley rat under brief halothane anesthesia. At 30 min, 5 h and 24 h after CFA injection (n = 3-4/time point), tissues were dissected from masseter and total proteins isolated. Rat Cytokine Antibody Array 1.1 (RayBiotech) coated with 19 specific cytokine antibodies were probed with protein samples and the relative cytokine levels were compared. Compared to saline-injected rats, there were significant increases (p < 0.05-0.01) in the levels of seven cytokines in the masseter tissue after CFA, including interleukin (IL)-1beta (5 h), IL-6 (5 h), tumor necrosis factor-alpha (5 h), monocyte chemoattractant protein-1 (5 h, 24 h), cytokine-induced neutrophil chemoattractant-2 and -3 (5 h, 24 h), and tissue inhibitor of metalloproteinase-1 (5 h, 24 h). All 19 cytokines were detected in the blood samples, but they did not show significant changes after inflammation. Masseter hyperalgesia and allodynia occurred at 30 min and persisted at 5-24 h after inflammation, as assessed by probing the skin above the masseter with von Frey filaments. The present results indicate selective localized cytokine responses to masseter inflammation. Although different cytokines exist in the blood, their levels did not mirror, nor did not appear to depend on, the local cytokine levels. The findings provide specific targets for further studying the involvement of cytokines in orofacial inflammation and hyperalgesia.

Animals↗
PubMed2004

Group I metabotropic glutamate receptor NMDA receptor coupling and signaling cascade mediate spinal dorsal horn NMDA receptor 2B tyrosine phosphorylation associated with inflammatory hyperalgesia.

Hindpaw inflammation induces tyrosine phosphorylation (tyr-P) of the NMDA receptor (NMDAR) 2B (NR2B) subunit in the rat spinal dorsal horn that is closely related to the initiation and development of hyperalgesia. Here, we show that in rats with Freund's adjuvant-induced inflammation, the increased dorsal horn NR2B tyr-P is blocked by group I metabotropic glutamate receptor (mGluR) antagonists [7-(hydroxyimino)cyclopropa[b] chromen-1a-carboxylate ethyl ester (CPCCOEt) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP), by the Src inhibitor CGP 77675, but not by the MAP kinase inhibitor 2'-amino-3'-methoxyflavone. Analysis of the calcium pathways shows that the in vivo NR2B tyr-P is blocked by an IP3 receptor antagonist 2-aminoethoxydiphenylborate (2APB) but not by antagonists of ionotropic glutamate receptors and voltage-dependent calcium channels, suggesting that the NR2B tyr-P is dependent on intracellular calcium release. In a dorsal horn slice preparation, the group I (dihydroxyphenylglycine), but not group II [(2R,4R)-4-aminopyrrolidine-2,3-dicarboxylate] and III [L-AP 4 (L-(+)-2-amino-4-phosphonobutyric acid)], mGluR agonists, an IP3 receptor (D-IP3) agonist, and a PKC (PMA) activator, induces NR2B tyr-P similar to that seen in vivo after inflammation. Coimmunoprecipitation indicates that Shank, a postsynaptic density protein associated with mGluRs, formed a complex involving PSD-95 (postsynaptic density-95), NR2B, and Src in the spinal dorsal horn. Double immunofluorescence studies indicated that NR1 is colocalized with mGluR5 in dorsal horn neurons. mGluR5 also coimmunoprecipitates with NR2B. Finally, intrathecal pretreatment of CPCCOEt, MPEP, and 2APB attenuates inflammatory hyperalgesia. Thus, inflammation and mGluR-induced NR2B tyr-P share similar mechanisms. The group ImGluR-NMDAR coupling cascade leads to phosphorylation of the NMDAR and appears necessary for the initiation of spinal dorsal horn sensitization and behavioral hyperalgesia after inflammation.

Animals↗
PubMed2004

Changes in AMPA receptor phosphorylation in the rostral ventromedial medulla after inflammatory hyperalgesia in rats.

To study the glutamatergic mechanisms underlying changes in excitability in the brain stem pain modulatory circuitry after injury, we examined GluR1 serine 831 phosphorylation in the rostral ventromedial medulla (RVM) after complete Freund's adjuvant-induced hindpaw inflammation. Western blots indicated a rapid and prolonged (30 min and 7 days post-inflammation) increase in phosphoserine 831 GluR1 protein levels in the RVM. The upregulated GluR1 phosphorylation was blocked by pretreatment, but not by post-treatment, with the local anesthetic, lidocaine, at the site of inflammation. The upregulation of phosphoserine 831 GluR1 was attenuated by pretreatment with chelerythrine, a selective PKC inhibitor, KN-93, a selective CaMKII inhibitor, and two NMDA receptor antagonists, MK-801 and APV. These findings provide new evidence linking in vivo AMPA receptor phosphorylation in the RVM pain modulatory circuitry to the enhanced descending pain modulation after inflammation.

Animals↗
PubMed2004

The neurobiology of persistent pain and its clinical implications.

Descending modulation of nociception is enhanced following tissue injury. These changes include suppression and facilitation of nocifensive behavior and spinal dorsal horn hyperexcitability originating at brain stem sites. Evidence has been presented that such descending modulation undergoes time-dependent changes following persistent inflammation. There is an initial decrease and a subsequent increase in the excitability of neurons in the RVM involving facilitation and inhibition. The enhanced descending modulation includes changes in the activation and gene expression of the NMDA and AMPA excitatory amino acid receptors. In vivo electrophysiological recordings further reveal a change in the response profile of RVM neurons during the development of inflammation: cells previously unresponsive to nociceptive stimuli, exhibit response profiles characteristic of pain-modulating neurons. These findings demonstrate activity-dependent plasticity in brain stem circuits that includes changes in excitatory amino acid receptor activation and sensitivity and a phenotypic switch of some RVM neurons.

Animals↗
PubMed2004

Brainstem mechanisms of persistent pain following injury.

Nerve signals arising from sites of tissue or nerve injury lead to long-term changes in the central nervous system and contribute to hyperalgesia and the amplification and persistence of pain. These nociceptor activity-dependent changes are referred to as central sensitization. Central sensitization involves an increase in the excitability of medullary dorsal horn (subnucleus caudalis) and spinal dorsal horn neurons brought about by a series of events including neuronal depolarization; removal of the voltage-dependent magnesium block of the N-methyl-D-aspartate (NMDA) receptor; release of calcium from intracellular stores; phosphorylation of the NMDA, alpha amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA), and neurokinin (NK) 1 receptors via activation of protein kineses; a change in the neuron's excitability; and an increase in synaptic strength. Central sensitization occurs in trigeminal nociceptive pathways, and more robust neuronal hyperexcitability occurs following deep tissue stimulation than cutaneous stimulation. Utilizing Fos protein immunocytochemistry, it has been found that 2 distinct regions are activated in the trigeminal brainstem sensory nuclei, the subnuclei interpolaris/caudalis transition zone (Vi/Vc) and the caudal part of the subnucleus caudalis. The latter is very similar to the spinal dorsal horn and is involved in the sensory discriminative aspects of pain. In contrast, the ventral pole of the Vi/Vc is unique. In addition to its role in the nociceptive sensory processing of deep tissues, it is involved bilaterally in somatovisceral and somatoautonomic processing, activation of the pituitary-adrenal axis, and descending modulatory control. The findings support our overall hypothesis that the ventral pole of Vi/Vc is involved in the coordination of bilateral sensorimotor functions of the trigeminal system associated with the response to deep tissue injury.

Animals↗
PubMed2003

Differential rostral projections of caudal brainstem neurons receiving trigeminal input after masseter inflammation.

To understand the functional significance of orofacial injury-induced neuronal activation, this study examined the rostral projection of caudal brainstem neurons that were activated by masseteric inflammation. Rats were injected with a retrograde tracer, Fluorogold, into the nucleus submedius of the thalamus (Sm), parabrachial nucleus (PB), lateral hypothalamus (LH), or medial ventroposterior thalamic nucleus (VPM) 7 days before injection of an inflammatory agent, complete Freund's adjuvant (CFA), into the masseter muscle. Rats were perfused at 2 hours after inflammation, and brainstem tissues were processed for Fos-Fluorogold double immunocytochemistry. Although there was no difference in Fos expression among the four groups (n=4 per site), the rostral projection of Fos-positive neurons showed dramatic differences. In the ventral portion of the trigeminal subnuclei interpolaris/caudalis (Vi/Vc) transition zone, the percentage of Fos-positive neurons projecting to the Sm (39.7%) was significantly higher than that projecting to the LH (5.4%) or VPM (5.6%; P<.001). The anesthesia alone also induced Fos expression in ventral Vi/Vc neurons, but these neurons did not project to Sm. In the caudal laminated Vc and dorsal Vi/Vc, the PB was the major site of rostral projection of Fos-positive neurons. In the caudal ventrolateral medulla and nucleus tractus solitarius, Fos-positive neurons projected to the Sm, PB, and LH. Most VPM-projecting neurons examined did not show Fos-like immunoreactivity after masseter inflammation. These findings emphasize the importance of the trigeminal Vi/Vc transition zone in response to orofacial deep tissue injury. Furthermore, the results differentiate the ventral and dorsal portions of the Vi/Vc transition zone, in that the Sm received projection mainly from activated neurons in the ventral Vi/Vc. The activation of Vi/Vc neurons and associated ascending pathways may facilitate somatoautonomic and somatovisceral integration and descending pain modulation after orofacial deep tissue injury.

Anesthetics, Local↗
PubMed2003

Inflammation-induced upregulation of AMPA receptor subunit expression in brain stem pain modulatory circuitry.

Our previous study demonstrated an increase in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor sensitivity in the rostral ventromedial medulla (RVM) associated with enhanced net descending inhibition after inflammatory hyperalgesia. The present study further studied the time-dependent changes in AMPA-produced inhibition after inflammation and the underlying molecular mechanisms. Inflammation was induced by intraplantar injection of complete Freund's adjuvant (CFA, 0.2ml). There was a significant increase in AMPA-produced inhibition at 5h that was further enhanced at 24h (P<0.05), as compared to that at 3h post-inflammation. The AMPA-produced inhibition returned to the control level at 14 days post-inflammation. We analyzed mRNA and protein levels of the GluR1 and GluR2 AMPA receptor subunits in the RVM at 2h to 14 days post-inflammation. AMPA receptor subunits exist in the two 'flip' and 'flop' isoforms that differentially affect the desensitization properties of the receptor. Reverse transcription-polymerase chain reaction analysis indicated that there was a significant upregulation of mRNAs encoding the GluR1-flip (5-24h), GluR2-flip (24h) and GluR2-flop (24h) isoforms in the RVM after inflammation, whereas the levels of GluR1-flop mRNAs showed no significant change. Western blots demonstrated that the GluR1 protein levels were significantly upregulated at 24h-3 days (P<0.05) post-inflammation, compared to that of naive animals. GluR2 protein levels remained unchanged. Immunohistochemistry further demonstrated an increase in GluR1-like immunoreactivity localized to the RVM at 24h post-inflammation. These findings suggest that AMPA receptors in the RVM undergo selective transcriptional and translational modulation following inflammation and may contribute to activity-dependent plasticity in descending pain modulatory systems after prolonged noxious input.

Animals↗
PubMed2002

Tyrosine phosphorylation of the NR2B subunit of the NMDA receptor in the spinal cord during the development and maintenance of inflammatory hyperalgesia.

The present study examined the levels of NMDA receptor NR2 subunit tyrosine phosphorylation in a rat model of inflammation and correlated it with the development of inflammation and hyperalgesia. Hindpaw inflammation and hyperalgesia were induced by intraplantar injection of complete Freund's adjuvant. Proteins from the spinal cord (L4-L5) were immunoprecipitated with anti-NR2A or anti-NR2B antibodies and used for subsequent analysis using 4G-10, a specific anti-phosphotyrosine antibody. Compared with naive rats, there was a rapid and prolonged increase in tyrosine phosphorylation of the NR2B, but not NR2A, subunit after inflammation. The increase in NR2B tyrosine phosphorylation was dependent on primary afferent drive because (1) the phosphorylation correlated with the temporal profile of inflammation and hyperalgesia, (2) shorter-duration noxious stimulation produced a rapid and shorter-lasting increase in phosphorylation, and (3) local anesthetic block of the injected paw reversibly blocked inflammation-induced NR2B tyrosine phosphorylation and delayed hyperalgesia. The increase in NR2B tyrosine phosphorylation was abolished by intrathecal pretreatment with genistein, a tyrosine kinase inhibitor; PP2, an Src family tyrosine kinase inhibitor; AIDA, a group I metabotropic glutamate receptor antagonist; L733,060, an NK1 tachykinin receptor antagonist, and chelerythrine, a protein kinase C inhibitor. In addition, intrathecal PP2 delayed the onset of mechanical hyperalgesia and allodynia. These findings correlate in vivo NMDA receptor tyrosine phosphorylation with the development and maintenance of inflammatory hyperalgesia and suggest that signal transduction upstream to NR2B tyrosine phosphorylation involves G-protein-coupled receptors and PKC and Src family protein tyrosine kinases.

Afferent Pathways↗
PubMed2002

Age-dependency of analgesia elicited by intraoral sucrose in acute and persistent pain models.

Treatment of pain in newborns is associated with problematic drug side effects. Previous studies demonstrate that an intraoral infusion of sucrose and other sweet components of mother's milk are effective in alleviating pain in infant rats and humans. These findings are of considerable significance, as sweet tastants are used in pain and stress management in a number of clinical procedures performed in human infants. The ability of sweet stimuli to induce analgesia is absent in adult rats, suggesting that this is a developmentally transient phenomenon. However, the age range over which intraoral sucrose is capable of producing analgesia is not known. We investigated the effects of intraoral sucrose (7.5%) on nocifensive withdrawal responses to thermal and mechanical stimuli in naive and inflamed rats at postnatal days (P) P0-21. In some rats, Complete Freund's adjuvant (CFA) was injected in a fore- or hindpaw to produce inflammation. In non-inflamed animals, for noxious thermal stimuli, sucrose-induced analgesia emerged at P3, peaked at P7-10, then progressively declined and was absent at P17. For mechanical forepaw stimuli, sucrose-induced analgesia emerged, and was maximal at approximately P10, then declined and was absent at P17. By contrast, maximal sucrose-induced analgesia for mechanical hindpaw stimuli was delayed (P13) compared to that for the forepaw, although it was also absent at P17. In inflamed animals, sucrose reduced hyperesthesia and hyperalgesia assessed with mechanical stimuli. Sucrose-induced analgesia in inflamed animals was initially present at P3 for the forepaw and P13 for the hindpaw, and was absent by P17 for both limbs. Intraoral sucrose produced significantly greater effects on responses in fore- and hindpaws in inflamed rats than in naive rats indicating that it reduces hyperalgesia and allodynia beyond its effects on responses in naive animals. These findings support the hypothesis that sucrose has a selective influence on analgesic mechanisms and that an enhanced sucrose effect takes place in hyperalgesic, inflamed animals as compared to naive animals. Taken together, these results indicate that intraoral sucrose alleviates transient pain in response to thermal and mechanical stimuli, and also effectively reduces inflammatory hyperalgesia and allodynia. Sucrose-induced analgesia is age-dependent and limited to the pre-weaning period in rats. The age-dependency of sucrose-induced analgesia and its differential maturation for the fore- and hindpaw may be due to developmental changes in endogenous analgesic mechanisms and developmental modulation of the interaction between gustatory and pain modulatory pathways.

Acute Disease↗
PubMed2002

Attenuation of pain in a randomized trial by suppression of peripheral nociceptive activity in the immediate postoperative period.

UNLABELLED: Peripheral neuronal barrage from tissue injury produces central nervous system changes that contribute to the maintenance of postoperative pain. The therapeutic approaches to blocking these central changes remain controversial, because previous studies have not differentiated presurgical interventions from those administered after tissue injury, yet before pain onset. In this study, we evaluated the relative contributions of blockade of nociceptive input during surgery or during the immediate postoperative period on pain suppression. Subjects were randomly allocated to one of four groups: preoperative 2% lidocaine, postoperative 0.5% bupivacaine, both, or placebo injections. General anesthesia was induced and third molars extracted. Pain was assessed over 4 h and at 24 and 48 h. The beta-endorphin in blood samples increased twofold during surgery, which is indicative of activation of the peripheral nociceptive barrage in response to painful stimuli. Pain was decreased in the immediate postoperative period in the bupivacaine groups, whereas it increased in the lidocaine group over time. Pain intensity was less 48 h after surgery in the groups whose postoperative pain was blocked by the administration of bupivacaine, but no effect was demonstrated for the preoperative administration of lidocaine alone. These results in the oral surgery pain model suggest that minimizing the peripheral nociceptive barrage during the immediate postoperative period decreases pain at later time periods. In contrast, blocking the intraoperative nociceptive barrage does not appear to contribute significantly to the subsequent reduction in pain. IMPLICATIONS: Suppression of postoperative pain immediately after surgery attenuates the pain experienced 1 to 2 days after surgery. These findings suggest that pain after minor surgery can be prevented by blocking the development of pain processes that amplify pain for days after surgery.

Acetaminophen↗