Top

Molecular Pain

Published in:

Open Access 01-12-2011 | Research

Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents

Authors: Alec Okun, Milena DeFelice, Nathan Eyde, Jiyang Ren, Ramon Mercado, Tamara King, Frank Porreca

Published in: Molecular Pain | Issue 1/2011

Abstract

Background

Tissue injury elicits both hypersensitivity to evoked stimuli and ongoing, stimulus-independent pain. We previously demonstrated that pain relief elicits reward in nerve-injured rats. This approach was used to evaluate the temporal and mechanistic features of inflammation-induced ongoing pain.

Results

Intraplantar Complete Freund's Adjuvant (CFA) produced thermal hyperalgesia and guarding behavior that was reliably observed within 24 hrs and maintained, albeit diminished, 4 days post-administration. Spinal clonidine produced robust conditioned place preference (CPP) in CFA treated rats 1 day, but not 4 days following CFA administration. However, spinal clonidine blocked CFA-induced thermal hyperalgesia at both post-CFA days 1 and 4, indicating different time-courses of ongoing and evoked pain. Peripheral nerve block by lidocaine administration into the popliteal fossa 1 day following intraplantar CFA produced a robust preference for the lidocaine paired chamber, indicating that injury-induced ongoing pain is driven by afferent fibers innervating the site of injury. Pretreatment with resiniferatoxin (RTX), an ultrapotent capsaicin analogue known to produce long-lasting desensitization of TRPV1 positive afferents, fully blocked CFA-induced thermal hypersensitivity and abolished the CPP elicited by administration of popliteal fossa lidocaine 24 hrs post-CFA. In addition, RTX pretreatment blocked guarding behavior observed 1 day following intraplantar CFA. In contrast, administration of the selective TRPV1 receptor antagonist, AMG9810, at a dose that reversed CFA-induced thermal hyperalgesia failed to reduce CFA-induced ongoing pain or guarding behavior.

Conclusions

These data demonstrate that inflammation induces both ongoing pain and evoked hypersensitivity that can be differentiated on the basis of time course. Ongoing pain (a) is transient, (b) driven by peripheral input resulting from the injury, (c) dependent on TRPV1 positive fibers and (d) not blocked by TRPV1 receptor antagonism. Mechanisms underlying excitation of these afferent fibers in the early post-injury period will offer insights for development of novel pain relieving strategies in the early post-traumatic period.

Available only for authorised users

King T, Vera-Portocarrero L, Gutierrez T, Vanderah TW, Dussor G, Lai J, Fields HL, Porreca F: Unmasking the tonic-aversive state in neuropathic pain. Nat Neurosci 2009, 12: 1364–1366. 10.1038/nn.2407PubMedCentralPubMedCrossRef

Koltzenburg M, Torebjork HE, Wahren LK: Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 1994, 117: 579–591. 10.1093/brain/117.3.579PubMedCrossRef

Eisenach JC, Rauck RL, Curry R: Intrathecal, but not intravenous adenosine reduces allodynia in patients with neuropathic pain. Pain 2003, 105: 65–70. 10.1016/S0304-3959(03)00158-1PubMedCrossRef

Rice AS, Cimino-Brown D, Eisenach JC, Kontinen VK, Lacroix-Fralish ML, Machin I, Mogil JS, Stohr T: Animal models and the prediction of efficacy in clinical trials of analgesic drugs: a critical appraisal and call for uniform reporting standards. Pain 2008, 139: 243–247. 10.1016/j.pain.2008.08.017PubMedCrossRef

Vierck CJ, Hansson PT, Yezierski RP: Clinical and pre-clinical pain assessment: are we measuring the same thing? Pain 2008, 135: 7–10. 10.1016/j.pain.2007.12.008PubMedCrossRef

Djouhri L, Koutsikou S, Fang X, McMullan S, Lawson SN: Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. J Neurosci 2006, 26: 1281–1292. 10.1523/JNEUROSCI.3388-05.2006PubMedCrossRef

Hurley RW, Hammond DL: The Analgesic Effects of Supraspinal {micro} and delta Opioid Receptor Agonists Are Potentiated during Persistent Inflammation. J Neurosci 2000, 20: 1249–1259.PubMed

Hurley RW, Hammond DL: Contribution of Endogenous Enkephalins to the Enhanced Analgesic Effects of Supraspinal {micro} Opioid Receptor Agonists after Inflammatory Injury. J Neurosci 2001, 21: 2536–2545.PubMed

Ren K, Dubner R: Enhanced descending modulation of nociception in rats with persistent hindpaw inflammation. J Neurophysiol 1996, 76: 3025–3037.PubMed

10.

Xiao WH, Bennett GJ: C-fiber spontaneous discharge evoked by chronic inflammation is suppressed by a long-term infusion of lidocaine yielding nanogram per milliliter plasma levels. Pain 2008, 137: 218–228. 10.1016/j.pain.2008.02.018PubMedCrossRef

11.

Brennan TJ, Zahn PK, Pogatzki-Zahn EM: Mechanisms of incisional pain. Anesthesiol Clin North America 2005, 23: 1–20. 10.1016/j.atc.2004.11.009PubMedCrossRef

12.

Xiao W-HMD, Bennett GJPD: Persistent Low-frequency Spontaneous Discharge in A-fiber and C-fiber Primary Afferent Neurons during an Inflammatory Pain Condition. Anesthesiology 2007, 107: 813–821. 10.1097/01.anes.0000286983.33184.9cPubMedCrossRef

13.

Xu J, Brennan TJ: Guarding Pain and Spontaneous Activity of Nociceptors after Skin versus Skin Plus Deep Tissue Incision. Anesthesiology 2010, 112: 153–164. 10.1097/ALN.0b013e3181c2952ePubMedCentralPubMedCrossRef

14.

Szallasi A, Joo F, Blumberg PM: Duration of desensitization and ultrastructural changes in dorsal root ganglia in rats treated with resiniferatoxin, an ultrapotent capsaicin analog. Brain Res 1989, 503: 68–72. 10.1016/0006-8993(89)91705-8PubMedCrossRef

15.

Ossipov MH, Bian D, Malan TP, Lai J, Porreca F: Lack of involvement of capsaicin-sensitive primary afferents in nerve-ligation injury induced tactile allodynia in rats. Pain 1999, 79: 127–133. 10.1016/S0304-3959(98)00187-0PubMedCrossRef

16.

Gavva NR, Tamir R, Qu Y, Klionsky L, Zhang TJ, Immke D, Wang J, Zhu D, Vanderah TW, Porreca F, et al.: AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties. J Pharmacol Exp Ther 2005, 313: 474–484. 10.1124/jpet.104.079855PubMedCrossRef

17.

Xu J, Richebe P, Brennan TJ: Separate groups of dorsal horn neurons transmit spontaneous activity and mechanosensitivity one day after plantar incision. Eur J Pain 2009, 13: 820–828. 10.1016/j.ejpain.2008.10.005PubMedCrossRef

18.

Sufka KJ: Conditioned place preference paradigm: a novel approach for analgesic drug assessment against chronic pain. Pain 1994, 58: 355–366. 10.1016/0304-3959(94)90130-9PubMedCrossRef

19.

Ren K, Dubner R: Descending modulation in persistent pain: an update. Pain 2002, 100: 1–6. 10.1016/S0304-3959(02)00368-8PubMedCrossRef

20.

Andrew D, Greenspan JD: Mechanical and heat sensitization of cutaneous nociceptors after peripheral inflammation in the rat. J Neurophysiol 1999, 82: 2649–2656.PubMed

21.

Aubrun F, Langeron O, Quesnel C, Coriat P, Riou B: Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous morphine titration. Anesthesiology 2003, 98: 1415–1421. 10.1097/00000542-200306000-00017PubMedCrossRef

22.

Moiniche S, Dahl JB, Erichsen CJ, Jensen LM, Kehlet H: Time course of subjective pain ratings, and wound and leg tenderness after hysterectomy. Acta Anaesthesiol Scand 1997, 41: 785–789. 10.1111/j.1399-6576.1997.tb04784.xPubMedCrossRef

23.

Beilin BMD, Bessler HPD, Mayburd EMD, Smirnov GMD, Dekel AMD, Yardeni IMD, Shavit YPD: Effects of Preemptive Analgesia on Pain and Cytokine Production in the Postoperative Period. Anesthesiology 2003, 98: 151–155. 10.1097/00000542-200301000-00024PubMedCrossRef

24.

Southworth S, Peters J, Rock A, Pavliv L: A multicenter, randomized, double-blind, placebo- controlled trial of intravenous ibuprofen 400 and 800 mg every 6 hours in the management of postoperative pain. Clinical Therapeutics 2009, 31: 1922–1935. 10.1016/j.clinthera.2009.08.026PubMedCrossRef

25.

Yardeni IZ, Beilin B, Mayburd E, Levinson Y, Bessler H: The effect of perioperative intravenous lidocaine on postoperative pain and immune function. Anesthesia and Analgesia 2009, 109: 1464–1469. 10.1213/ANE.0b013e3181bab1bdPubMedCrossRef

26.

Gould HJ: Complete Freund's adjuvant-induced hyperalgesia: a human perception. Pain 2000, 85: 301–303. 10.1016/S0304-3959(99)00289-4PubMedCrossRef

27.

Capdevila X, Ponrouch M, Choquet O: Continuous peripheral nerve blocks in clinical practice. Current Opinion in Anaesthesiology 2008, 21: 619–623. 10.1097/ACO.0b013e32830c66c2PubMedCrossRef

28.

Immke DC, Gavva NR: The TRPV1 receptor and nociception. Seminars in Cell & Developmental Biology 2006, 17: 582–591.CrossRef

29.

Honore P, Chandran P, Hernandez G, Gauvin DM, Mikusa JP, Zhong C, Joshi SK, Ghilardi JR, Sevcik MA, Fryer RM, et al.: Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia. Pain 2009, 142: 27–35. 10.1016/j.pain.2008.11.004PubMedCrossRef

30.

Xu XJ, Farkas-Szallasi T, Lundberg JM, Hokfelt T, Wiesenfeld-Hallin Z, Szallasi A: Effects of the capsaicin analogue resiniferatoxin on spinal nociceptive mechanisms in the rat: behavioral, electrophysiological and in situ hybridization studies. Brain Res 1997, 752: 52–60. 10.1016/S0006-8993(96)01444-8PubMedCrossRef

31.

Kang S, Wu C, Banik RK, Brennan TJ: Effect of capsaicin treatment on nociceptors in rat glabrous skin one day after plantar incision. Pain 2010, 148: 128–140. 10.1016/j.pain.2009.10.031PubMedCentralPubMedCrossRef

32.

Hamalainen MM, Subieta A, Arpey C, Brennan TJ: Differential Effect of Capsaicin Treatment on Pain-Related Behaviors After Plantar Incision. The Journal of Pain 2009, 10: 637–645. 10.1016/j.jpain.2009.01.003PubMedCentralPubMedCrossRef

33.

Wu C, Gavva NR, Brennan TJ: Effect of AMG0347, a transient receptor potential type V1 receptor antagonist, and morphine on pain behavior after plantar incision. Anesthesiology 2008, 108: 1100–1108. 10.1097/ALN.0b013e31817302b3PubMedCrossRef

34.

Yaksh TL, Rudy TA: Analgesia mediated by a direct spinal action of narcotics. Science 1976, 192: 1357–1358. 10.1126/science.1273597PubMedCrossRef

35.

Kadiyala RK, Ramirez A, Taylor AE, Saltzman CL, Cassell MD: The blood supply of the common peroneal nerve in the popliteal fossa. J Bone Joint Surg Br 2005, 87: 337–342. 10.1302/0301-620X.87B3.15694PubMedCrossRef

36.

Dixon WJ: Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol 1980, 20: 441–462. 10.1146/annurev.pa.20.040180.002301PubMedCrossRef

37.

Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53: 55–63. 10.1016/0165-0270(94)90144-9PubMedCrossRef

38.

Xu J, Brennan TJ: Comparison of skin incision vs. skin plus deep tissue incision on ongoing pain and spontaneous activity in dorsal horn neurons. Pain 2009, 144: 329–339. 10.1016/j.pain.2009.05.019PubMedCentralPubMedCrossRef

Title: Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents
Authors: Alec Okun
Milena DeFelice
Nathan Eyde
Jiyang Ren
Ramon Mercado
Tamara King
Frank Porreca
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2011
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-7-4

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2011

Visceral hyperalgesia induced by forebrain-specific suppression of native Kv7/KCNQ/M-current in mice

Hypotonicity modulates tetrodotoxin-sensitive sodium current in trigeminal ganglion neurons

AKAP150-mediated TRPV1 sensitization is disrupted by calcium/calmodulin

Dynorphin is expressed primarily by GABAergic neurons that contain galanin in the rat dorsal horn

Identification and characterization of seven new exon 11-associated splice variants of the rat mu opioid receptor gene, OPRM1

Are voltage-gated sodium channels on the dorsal root ganglion involved in the development of neuropathic pain?