Age Differences in the Time Course and Magnitude of Changes in Circulating Neuropeptides After Pain Evocation in Humans


      • Older adults had higher baseline levels of substance P and β-endorphin compared with younger adults.
      • Older adults had a more intense initial response for substance P and β-endorphin.
      • A weaker response for β-endorphin among the older participants was not observed.
      • Resolution occurred at similar time points for both younger and older adults.
      • The response patterns differed between cold pressure pain and contact heat.


      This study tested the hypothesis that older adults would have a stronger response for substance P (facilitatory) but weaker response to β-endorphin (inhibitory), in magnitude as well as time course. Eight younger and 9 older adults underwent 3 experimental sessions using well validated laboratory pain models: cold pressor task, contact heat pain, and a nonpainful control. Blood was collected through an indwelling catheter at baseline and 3, 15, 30, 45, and 60 minutes after stimuli administration. Older adults had higher baseline levels of both neuropeptides suggesting increased peripheral activity compared with younger adults. After the cold pressor task, older adults demonstrated a quick and strong release of substance P with dramatic recovery, whereas young adults maintained a constant low-grade response. Unlike substance P, β-endorphin increased between 3 and 15 minutes for both groups with the upsurge substantially higher for older adults. After heat pain, younger adults had an immediate surge in circulating substance P and β-endorphin that was more pronounced than among older adults. However, levels of substance P for younger adults slowly tapered whereas they continued to climb for the older adults through 30 minutes. β-endorphin peaked at 30 minutes for both groups and returned to baseline. No changes were observed during the nonpainful control session.


      Older adults had higher baseline levels of substance P and β-endorphin suggesting increased peripheral activity compared with younger adults. After pain evocation, older adults demonstrated a more intense early response for both neuropeptides suggesting peripheral mechanisms involved in the response to pain may change with age.

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        • Akil H.
        • Shiomi H.
        • Matthews J.
        Induction of the intermediate pituitary by stress: Synthesis and release of a nonopioid form of beta-endorphin.
        Science. 1985; 227: 424-426
        • Bach F.W.
        • Langemark M.
        • Secher N.H.
        • Olesen J.
        Plasma and cerebrospinal fluid beta-endorphin in chronic tension-type headache.
        Pain. 1992; 51: 163-168
        • Bäckryd E.
        • Ghafouri B.
        • Larsson B.
        • Gerdle B.
        Do low levels of beta-endorphin in the cerebrospinal fluid indicate defective top-down inhibition in patients with chronic neuropathic pain? A cross-sectional, comparative study.
        Pain Med. 2014; 15: 111-119
        • Bergman E.
        • Johnson H.
        • Zhang X.
        • Hökfelt T.
        • Ulfhake B.
        Neuropeptides and neurotrophin receptor mRNAs in primary sensory neurons of aged rats.
        J Comp Neurol. 1996; 375: 303-319
        • Blandini F.
        • Martignoni E.
        • Melzi d’Eril G.V.
        • Biasio L.
        • Sances G.
        • Lucarelli C.
        • Rizzo V.
        • Costa A.
        • Nappi G.
        Free plasma catecholamine levels in healthy subjects: A basal and dynamic study. The influence of age.
        Scand J Clin Lab Invest. 1992; 52: 9-17
        • Casale G.
        • Pecorini M.
        • Cuzzoni G.
        • de Nicola P.
        Beta-endorphin and cold pressor test in the aged.
        Gerontology. 1985; 31: 101-105
        • Chiu I.M.
        • von Hehn C.A.
        • Woolf C.J.
        Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology.
        Nat Neurosci. 2012; 15: 1063-1067
        • Cruz-Almeida Y.
        • Aguirre M.
        • Sorenson H.L.
        • Tighe P.
        • Wallet S.M.
        • Riley 3rd, J.L.
        Age differences in cytokine expression under conditions of health using experimental pain models.
        Exp Gerontol. 2015; 72: 150-156
        • Curatolo M.
        • Petersen-Felix S.
        • Arendt-Nielsen L.
        Sensory assessment of regional analgesia in humans—A review of methods and applications.
        Anesthesiology. 2000; 93: 1517-1530
        • Davis K.D.
        Cold-induced pain and prickle in the glabrous and hairy skin.
        Pain. 1998; 75: 47-57
        • De Souza E.B.
        • Van Loon G.R.
        Rate-sensitive glucocorticoid feedback inhibition of adrenocorticotropin and beta-endorphin/beta-lipotropin secretion in rats.
        Endocrinology. 1989; 125: 2927-2934
        • Elahy M.
        • Jackaman C.
        • Mamo J.C.
        • Lam V.
        • Dhaliwal S.S.
        • Giles C.
        • Nelson D.
        • Takechi R.
        Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment.
        Immunol Ageing. 2015; 12: 2
        • Elliott A.M.
        • Smith B.H.
        • Penny K.I.
        • Smith W.C.
        • Chambers W.A.
        The epidemiology of chronic pain in the community.
        Lancet. 1999; 354: 1248-1252
        • Facchinetti F.
        • Petraglia F.
        • Nappi G.
        • Martignoni E.
        • Antoni G.
        • Parrini D.
        • Genazzani A.R.
        Different patterns of central and peripheral beta EP, beta LPH and ACTH throughout life.
        Peptides. 1983; 4: 469-474
        • Fillingim R.B.
        • King C.D.
        • Ribeiro-Dasilva M.C.
        • Rahim-Williams B.
        • Riley 3rd, J.L.
        Sex, gender, and pain: A review of recent clinical and experimental findings.
        J Pain. 2009; 10: 447-485
        • Franceschi C.
        • Bonafe M.
        • Valensin S.
        • Olivieri F.
        • De Luca M.
        • Ottaviani E.
        • De Benedictis G.
        Inflamm-aging. An evolutionary perspective on immunosenescence.
        Ann N Y Acad Sci. 2000; 908: 244-254
        • Fruhstorfer H.
        • Lindblom U.
        Vascular participation in deep cold pain.
        Pain. 1983; 17: 235-241
        • Gibson S.J.
        • Farrell M.
        A review of age differences in the neurophysiology of nociception and the perceptual experience of pain.
        Clin J Pain. 2004; 20: 227-239
        • Gorlé N.
        • Van Cauwenberghe C.
        • Libert C.
        • Vandenbroucke R.E.
        The effect of aging on brain barriers and the consequences for Alzheimer’s disease development.
        Mamm Genome. 2016; 27: 407-420
        • Graven-Nielsen T.
        • Arendt-Nielsen L.
        Peripheral and central sensitization in musculoskeletal pain disorders: An experimental approach.
        Curr Rheumatol Rep. 2002; 4: 313-321
        • Greenhouse S.W.
        • Geisser S.
        On methods in the analysis of profile data.
        Psychometrika. 1959; 24: 95-112
        • Hargreaves K.M.
        • Dionne R.A.
        • Mueller G.P.
        Plasma beta endorphin-like immunoreactivity, pain and anxiety following administration of placebo in oral surgery patients.
        J Dent Res. 1983; 62: 1170-1173
        • Hua S.
        • Cabot P.J.
        Mechanisms of peripheral immune-cell-mediated analgesia in inflammation: Clinical and therapeutic implications.
        Trends Pharmacol Sci. 2010; 31: 427-433
        • Hughes A.M.
        • Rhodes J.
        • Fisher G.
        • Sellers M.
        • Growcott J.W.
        Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers.
        Br J Clin Pharmacol. 2002; 53: 604-612
        • Johannes C.B.
        • Le T.K.
        • Zhou X.
        • Johnston J.A.
        • Dworkin R.H.
        The prevalence of chronic pain in United States adults: Results of an Internet-based survey.
        J Pain. 2010; 11: 1230-1239
        • Julius D.
        • Basbaum A.I.
        Molecular mechanisms of nociception.
        Nature. 2001; 413: 203-210
        • Kask A.
        • Rageo L.
        • Harro J.
        NPY Y-sub-1 receptors in the dorsal periaqueductal gray matter regulate anxiety in the social interaction test.
        Neuroreport. 1998; 9: 2713-2716
        • Kieffer B.L.
        • Evans C.J.
        Opioid receptors: From binding sites to visible molecules in vivo.
        Neuropharmacology. 2009; 56: 205-212
        • Klement W.
        • Arndt J.O.
        The role of nociceptors of cutaneous veins in the mediation of cold pain in man.
        J Physiol. 1992; 449: 73-83
        • Kondo I.
        • Marvizon J.C.
        • Song B.
        • Salgado F.
        • Codeluppi S.
        • Hua X.Y.
        • Yaksh T.L.
        Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release.
        J Neurosci. 2005; 25: 3651-3660
        • LaMotte R.H.
        • Thalhammer J.G.
        Response properties of high-threshold cutaneous cold receptors in the primate.
        Brain Res. 1982; 244: 279-287
        • Latremoliere A.
        • Woolf C.J.
        Central sensitization: A generator of pain hypersensitivity by central neural plasticity.
        J Pain. 2009; 10: 895-926
        • Lautenbacher S.
        Experimental approaches in the study of pain in the elderly.
        Pain Med. 2012; 13: S44-S50
        • Littlejohn G.
        Neurogenic neuroinflammation in fibromyalgia and complex regional pain syndrome.
        Nat Rev Rheumatol. 2015; 11: 639-648
        • Lovallo W.
        The cold pressor test and autonomic function: A review and integration.
        Psychophysiology. 1975; 12: 268-282
        • Machelska H.
        Targeting of opioid-producing leukocytes for pain control.
        Neuropeptides. 2007; 41: 355-363
        • Mauchly J.W.
        Significance test for sphericity of n-variate normal population.
        Ann Math Stat. 1940; 11: 204-209
        • McCormack K.
        • Prather P.
        • Chapleo C.
        Some new insights into the effects of opioids in phasic and tonic nociceptive tests.
        Pain. 1998; 78: 79-98
        • Morley J.E.
        Neuropeptides, behavior and aging.
        J Am Geriatr Soc. 1988; 34: 52-62
        • Muñoz M.
        • Coveñas R.
        Involvement of substance P and the NK-1 receptor in human pathology.
        Amino Acids. 2014; 46: 1727-1750
        • Nyman M.J.
        • Eskola O.
        • Kajander J.
        • Vahlberg T.
        • Sanabria S.
        • Burns D.
        • Hargreaves R.
        • Solin O.
        • Hietala J.
        Gender and age affect NK1 receptors in the human brain—a positron emission tomography study with [18F]SPA-RQ.
        Int J Neuropsychopharmacol. 2007; 10: 219-229
        • O’Connor T.M.
        • O’Connell J.
        • O’Brien D.I.
        • Goode T.
        • Bredin C.P.
        • Shanahan F.
        The role of substance P in inflammatory disease.
        J Cell Physiol. 2004; 201: 167-180
        • Portenoy R.K.
        • Ugarte C.
        • Fuller I.
        • Haas G.
        Population-based survey of pain in the United States: Differences among white, African American, and Hispanic subjects.
        J Pain. 2004; 5: 317-328
      1. Purves D. Augustine G.J. Fitzpatrick D. Katz L.C. Lamantia A.S. McNamara J.O. Williams M. Neuroscience. 2nd ed. Sinauer Associates, Sunderland, MA2001
        • Rohleder N.
        • Wolf J.M.
        • Herpfer I.
        • Fiebich B.L.
        • Kirschbaum C.
        • Lieb K.
        No response of plasma substance P, but delayed increase of interleukin-1 receptor antagonist to acute psychosocial stress.
        Life Sci. 2006; 78: 3082-3089
        • Rolandi E.
        • Franceschini R.
        • Marabini A.
        • Messina V.
        • Cataldi A.
        • Salvemini M.
        • Barreca T.
        Twenty-four-hour beta-endorphin secretory pattern in the elderly.
        Acta Endocrinol (Copenh). 1987; 115: 441-446
        • Rosa C.
        • Ghione S.
        • Mezzasalma L.
        • Pellegrini M.
        • Fasolo B.
        • Giaconi S.
        • Gazzetti P.
        • Ferdeghini M.
        Relationship between pain sensitivity, cardiovascular reactivity to cold pressor test, and indexes of activity of the adrenergic and opioid system.
        Clin Exp Theory. 1988; A10: 383-390
        • Schedlowski M.
        • Flüge T.
        • Richter S.
        • Tewes U.
        • Schmidt R.E.
        • Wagner T.O.
        Beta-endorphin, but not substance-P, is increased by acute stress in humans.
        Psychoneuroendocrinology. 1995; 20: 103-110
        • Smith H.S.
        Peripherally-acting opioids.
        Pain Physician. 2008; 11: S121-S132
        • Staud R.
        Evidence for shared pain mechanisms in osteoarthritis, low back pain, and fibromyalgia.
        Curr Rheumatol Rep. 2011; 13: 513-520
        • Stein C.
        The control of pain in peripheral tissue by opioids.
        N Engl J Med. 1995; 332: 1685-1690
        • Stein C.
        • Clark J.D.
        • Oh U.
        • Vasko M.R.
        • Wilcox G.L.
        • Overland A.C.
        • Vanderah T.W.
        • Spencer R.H.
        Peripheral mechanisms of pain and analgesia.
        Brain Res Rev. 2009; 60: 90-113
        • Stein C.
        • Schafer M.
        • Machelska H.
        Attacking pain at its source: New perspectives on opioids.
        Nat Med. 2003; 9: 1003-1008
        • Stein C.
        • Zollner C.
        Opioids and sensory nerves.
        Handb Exp Pharmacol. 2009; 194: 495-518
      2. Strand FL: Neuropeptides. Regulators of Physiological Processes. Cambridge, MA, Bradford Books, 1999

        • Streff A.
        • Kuehl L.K.
        • Michaux G.
        • Anton F.
        Differential physiological effects during tonic painful hand immersion tests using hot and ice water.
        Eur J Pain. 2010; 14: 266-272
        • Tassorelli C.
        • Miciell G.
        • Osipova V.
        • Rossi R.
        • Nappi G.
        Pupillary and cardiovascular responses to the cold-pressor test.
        J Auton Nerv Syst. 1995; 55: 45-49
        • Varatharaj A.
        • Galea I.
        The blood-brain barrier in systemic inflammation.
        Brain Behav Immunol. 2016; 60: 1-12
        • Veening J.G.
        • Gerrits P.O.
        • Barendregt H.P.
        Volume transmission of beta-endorphin via the cerebrospinal fluid; a review.
        Fluids Barriers CNS. 2012; 9: 16
        • Vierck C.J.
        • Mauderli A.P.
        • Riley 3rd, J.L.
        Relationships between the intensity and duration of Peltier heat stimulation and pain magnitude.
        Exp Brain Res. 2013; 225: 339-348
        • Yaksh T.L.
        Substance P release from knee joint afferent terminals: Modulation by opioids.
        Brain Res. 1988; 458: 319-324
        • Yarnitsky D.
        • Ochoa J.L.
        Release of cold-induced burning pain by block of cold-specific afferent input.
        Brain. 1990; 113: 893-902
        • Young E.A.
        Induction of the intermediate lobe pro-opiomelanocortin system with chronic swim stress and beta-adrenergic modulation of this induction.
        Neuroendocrinology. 1990; 52: 405-414
        • Young E.
        • Akil H.
        Changes in releasability of ACTH and beta-endorphin with chronic stress.
        Neuropeptides. 1985; 5: 545-548