- Email: [email protected]
Painful Beginnings
Pain 110 (2004) 508–509 www.elsevier.com/locate/pain
Editorial
Painful Beginnings Much has been written about plasticity and learning in adult pain processing but equally important is how pain processing is learned in the first place. Does pain, like other sensory modalities, require appropriate postnatal experience to shape synaptic connections? Is there a critical developmental period, where exposure to a particular pattern of nociceptive input determines the subsequent development of pain processing? The problem, of course, is that pain is not like other sensory modalities. The newborn mammalian CNS is not normally exposed to nociceptive input. While olfactory, auditory and tactile stimulation is plentiful after birth, nociceptive afferents will be relatively inactive. Nevertheless, considerable fine tuning of nociceptive synaptic connections does occur over this time. Mammals are born with the ability to display robust reflex responses to noxious stimuli but these are poorly organised compared to adults (Fitzgerald and Jennings, 1999; Schouenborg, 2002). For the first 10 days after birth, rat pups have a 75% error rate in the direction of a tail flick on noxious stimulation of the tail, which improves to less than 10% by 21 days (Waldenstrom et al., 2003). An analogous lack of tuning is observed in human withdrawal reflexes (Andrews and Fitzgerald, 1994, 2000; Andrews et al., 2002). In a series of fascinating studies, Schouenborg and co-workers have recently shown that while daily noxious stimulation does not affect this developmental reflex learning, blocking low intensity tactile inputs from the tail during the critical period, completely prevents the learning process. During normal development then, it is tactile input that shapes developing nociceptive circuits using a cross-modality mechanism (Petersson et al., 2003, 2004; Waldenstrom et al., 2003). But what happens if development is not ‘normal’ and somatosensory input during the critical period is not restricted to low intensity inputs? Excessive nociceptive inputs, such as those experienced by infants in intensive care exposed to repeated invasive procedures with limited analgesic therapy (Simons et al., 2003; Stevens et al., 2000), may alter the normal process of postnatal learning and have long-term consequences for pain processing (Anand, 2000; Fitzgerald and Walker, 2003). Research in this area began with a pioneering study by Grunau and co-workers who found that low birth weight children who had been in intensive care had low pain responsiveness and increased ‘somatization’ (Grunau et al.,
1994a,b). Despite a number of confounding factors (see Fitzgerald and Walker (2003) and Grunau (2000) for review) it appeared that early pain experience could reduce future pain responsiveness and perhaps alter the ability to interpret pain appropriately. Nevertheless, noxious stimulation and tissue damage in infancy can also lead to prolonged sensitisation of pain responses. Boys who have been circumcised at birth show increased pain responses to vaccinations at 4 – 6 months (Taddio et al., 1995), which are partially prevented by local anaesthetic treatment before surgery (Taddio et al., 1997). Referred abdominal hypersensitivity in infants with visceral pain persists for months after corrective surgery (Andrews et al., 2002). Animal models have highlighted the complexity of designing and interpreting such long-term studies. One critical factor is the nature of the stimulus. Neonatal exposure to repetitive paw needle prick produces heat hyperalgesia but this does not last into adulthood (Anand et al., 1999). On the other hand, repeated 10% formalin injections leads to a more generalised hypoalgesia in adulthood (Bhutta et al., 2001). Local skin wounds in the first postnatal week, produce a prolonged increase in behavioural mechanical sensitivity and expanded dorsal horn receptive fields in adults (Alvares et al., 2000; Torsney and Fitzgerald, 2003). Stimulus duration is also critical. A high profile report of long-term spinal cord plasticity due to early hindpaw CFA inflammation (Ruda et al., 2000) was confounded by the fact that the neonatal lesion was actually a chronic injury that lasted into adulthood (Walker et al., 2003). Depending on the dose used, lower intensity neonatal hindpaw inflammation either produces no long-term change in behaviour or dorsal horn cell responses (Alvares et al., 2000; Torsney and Fitzgerald, 2003; Walker et al., 2003) or long-term mechanical and heat hypoalgesia and increased re-inflammation hyperalgesia (Lidow et al., 2000). This issue of Pain reports a significant step towards understanding this apparently conflicting data (Ren et al., 2004). By following a large number of groups of animals, subjected to low dose hindpaw inflammation at many different postnatal ages and over a prolonged period, two clear patterns of adult pain behaviour have emerged. Firstly, there is a localised enhancement of the re-inflammationinduced mechanical and thermal hyperalgesia in the affected paw that emerges within the first postnatal week. Secondly, this is accompanied by a generalised reduction of baseline
0304-3959/$20.00 q 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2004.05.022
M. Fitzgerald / Pain 110 (2004) 508–509
mechanical and thermal sensitivity all over the body but this effect is not apparent until the animal is over 4 weeks old. Both the early onset inflammatory hyperalgesia and the later onset baseline hypoalgesia only occur if the original inflammatory stimulus is applied within the first 10 days of life and both last into adulthood. This combination of a localised enhancement of pain responses and an overall baseline depression each with their own time of onset, may very well explain the apparently conflicting reports by different groups in this area. What are the underlying mechanisms for such changes? Effects that are local to the site of injury are easier to explain in terms of activity dependent strengthening and weakening of synapses. Both inhibitory and excitatory neurotransmitter/ receptor systems involved in pain undergo marked changes in subunit composition and function in the first two postnatal weeks, many of which are activity dependent (Pattinson and Fitzgerald, 2004). Less easy to explain at the cellular level is the baseline hypoalgesia. Stress-induced analgesia in adults is a powerful, but poorly understood phenomenon and the longterm effects of neonatal stress are even harder to fathom. Daily handling alone for 14 postnatal days is known to increase nociceptive thresholds in adult male and female rats and to decrease behavioural and analgesic responses to stress in adulthood (Sternberg and Ridgeway, 2003). One possibility then, is that early pain experience enhances stress responses, which in turn increases stress-induced analgesia. Any local sensitisation that might occur at segmental level would be masked by this and require a strong stimulus such as re-inflammation to be observed. A number of us (e.g. Fitzgerald et al., London; Hermann et al., Mannheim) currently studying sensory and nociceptive thresholds in children that have undergone early pain experience need to take note. Pain may be learnt in infancy, but so too is stress and the stress of the situation may mask everything.
References Alvares D, Torsney C, Beland B, Reynolds M, Fitzgerald M. Modelling the prolonged effects of neonatal pain. Prog Brain Res 2000;129:365–73. Anand KJ. Pain, plasticity, and premature birth: a prescription for permanent suffering? Nat Med 2000;6:971–3. Anand KJS, Coskun V, Thrivikraman KV, Nemeroff CB, Plotsky PM. Long-term behavioural effects of repetitive pain in neonatal rat pups. Physiol Behav 1999;66:627 –37. Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation. Pain 1994;56:95–101. Andrews K, Fitzgerald M. Flexion reflex responses in biceps femoris and tibialis anterior in human neonates. Early Hum Dev 2000;57:105– 10. Andrews KA, Desai D, Dhillon HK, Wilcox DT, Fitzgerald M. Abdominal sensitivity in the first year of life: comparison of infants with and without prenatally diagnosed unilateral hydronephrosis. Pain 2002;100:35 –46. Bhutta AT, Rovnaghi C, Simpson PM, Gossett JM, Scalzo FM, Anand KJS. Interactions of inflammatory pain and morphine in infant rats. Longterm behavioural effects. Physiol Behav 2001;73:51–8. Fitzgerald M, Jennings E. The postnatal development of spinal sensory processing. Proc Natl Acad Sci USA 1999;96:7719–22.
509
Fitzgerald M, Walker S. The role of activity in developing pain pathways. In: Dostrovsky JO, Carr DB, editors. Proceedings of the 10th World Congress on Pain. Progress in pain research and management, vol. 24. Seattle, WA: IASP Press; 2003. Grunau RE. Long-term consequences of pain in human neonates. In: Anand KJS, Stevens BJ, McGrath PJ, editors. Pain Res Clin Man, 10.; 2000. p. 101– 34. Grunau R, Whitfield MF, Petrie JH. Pain sensitivity and temperament in extremely lowbirthweight premature toddlers and preterm and fullterm controls. Pain 1994a;58:341– 6. Grunau RVE, Whitfield MF, Petrie JH, Fryer EL. Early pain experience, child and family factors, as precursors of somatization: a prospective study of extremely premature and fullterm children. Pain 1994b;56:353–9. Lidow MS, Song Z-M, Ren K. Long-term effects of short-lasting early local inflammatory insult. Neuroreport 2000;12:399–403. Pattinson D, Fitzgerald M. The neurobiology of infant pain: development of excitatory and inhibitory neurotransmission in the spinal dorsal horn. Reg Anesth Pain Med 2004;29:36–44. Petersson P, Waldenstrom A, Fahraeus C, Schouenborg J. Spontaneous muscle twitches during sleep guide spinal self-organization. Nature 2003;424:72–5. Petersson P, Granmo M, Schouenborg J. Properties of an adult spinal sensorimotor circuit shaped through early postnatal experience [Epub ahead of print]. J Neurophysiol 2004;February 25. Ren K, Anseloni V, Zou S-P, Wade EB, Novikova SI, Ennis M, Traub RJ, Gold MS, Dubner R, Lidow MS. Characterization of basal and re-inflammation-associated long-term alteration in pain responsively following short-lasting neonatal local inflammatory insult. Pain 2004; 110(3):588–96. Ruda MA, Ling Q-D, Hohmann AG, Peng YB. Tachibana T altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science 2000;289:628–30. Schouenborg J. Modular organisation and spinal somatosensory imprinting. Brain Res Brain Res Rev 2002;40:80– 91. Simons SH, van Dijk M, Anand KS, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med 2003;157:1058–64. Sternberg WF, Ridgway CG. Effects of gestational stress and neonatal handling on pain, analgesia, and stress behavior of adult mice. Physiol Behav 2003;78:375–83. Stevens B, Gibbins S, Franck LS. Treatment of pain in the neonatal intensive care unit. Pediatr Clin North Am 2000;47:633–50. Taddio A, Goldbach M, Ipp M, Stevens B, Koren G. Effect of neonatal circumcision on pain responses during vaccination in boys. Lancet 1995;345:291–2. Taddio A, Stevens B, Craig K, Rastogi P, Ben-David S, Shennan A, Mulligan P, Koren G. Efficacy and safety of lidocaine–prilocaine cream for pain during circumcision. N Engl J Med 1997;336:1197– 201. Torsney C, Fitzgerald M. Spinal dorsal horn cell receptive field size is increased in adult rats following neonatal hindpaw skin injury. J Physiol 2003;550:255–61. Waldenstrom A, Thelin J, Thimansson E, Levinsson A, Schouenborg J. Developmental learning in a pain-related system: evidence for a crossmodality mechanism. J Neurosci 2003;23:7719–25. Walker S, Meredith-Middleton J, Cooke-Yarborough C, Fitzgerald M. Neonatal inflammation and primary afferent terminal plasticity in the rat dorsal horn. Pain 2003;105:185– 95.
Maria Fitzgerald* Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK E-mail address: [email protected] * Tel.: þ 44-207-391-1303; fax: þ44-207-383-0929.
Editorial
Painful Beginnings Much has been written about plasticity and learning in adult pain processing but equally important is how pain processing is learned in the first place. Does pain, like other sensory modalities, require appropriate postnatal experience to shape synaptic connections? Is there a critical developmental period, where exposure to a particular pattern of nociceptive input determines the subsequent development of pain processing? The problem, of course, is that pain is not like other sensory modalities. The newborn mammalian CNS is not normally exposed to nociceptive input. While olfactory, auditory and tactile stimulation is plentiful after birth, nociceptive afferents will be relatively inactive. Nevertheless, considerable fine tuning of nociceptive synaptic connections does occur over this time. Mammals are born with the ability to display robust reflex responses to noxious stimuli but these are poorly organised compared to adults (Fitzgerald and Jennings, 1999; Schouenborg, 2002). For the first 10 days after birth, rat pups have a 75% error rate in the direction of a tail flick on noxious stimulation of the tail, which improves to less than 10% by 21 days (Waldenstrom et al., 2003). An analogous lack of tuning is observed in human withdrawal reflexes (Andrews and Fitzgerald, 1994, 2000; Andrews et al., 2002). In a series of fascinating studies, Schouenborg and co-workers have recently shown that while daily noxious stimulation does not affect this developmental reflex learning, blocking low intensity tactile inputs from the tail during the critical period, completely prevents the learning process. During normal development then, it is tactile input that shapes developing nociceptive circuits using a cross-modality mechanism (Petersson et al., 2003, 2004; Waldenstrom et al., 2003). But what happens if development is not ‘normal’ and somatosensory input during the critical period is not restricted to low intensity inputs? Excessive nociceptive inputs, such as those experienced by infants in intensive care exposed to repeated invasive procedures with limited analgesic therapy (Simons et al., 2003; Stevens et al., 2000), may alter the normal process of postnatal learning and have long-term consequences for pain processing (Anand, 2000; Fitzgerald and Walker, 2003). Research in this area began with a pioneering study by Grunau and co-workers who found that low birth weight children who had been in intensive care had low pain responsiveness and increased ‘somatization’ (Grunau et al.,
1994a,b). Despite a number of confounding factors (see Fitzgerald and Walker (2003) and Grunau (2000) for review) it appeared that early pain experience could reduce future pain responsiveness and perhaps alter the ability to interpret pain appropriately. Nevertheless, noxious stimulation and tissue damage in infancy can also lead to prolonged sensitisation of pain responses. Boys who have been circumcised at birth show increased pain responses to vaccinations at 4 – 6 months (Taddio et al., 1995), which are partially prevented by local anaesthetic treatment before surgery (Taddio et al., 1997). Referred abdominal hypersensitivity in infants with visceral pain persists for months after corrective surgery (Andrews et al., 2002). Animal models have highlighted the complexity of designing and interpreting such long-term studies. One critical factor is the nature of the stimulus. Neonatal exposure to repetitive paw needle prick produces heat hyperalgesia but this does not last into adulthood (Anand et al., 1999). On the other hand, repeated 10% formalin injections leads to a more generalised hypoalgesia in adulthood (Bhutta et al., 2001). Local skin wounds in the first postnatal week, produce a prolonged increase in behavioural mechanical sensitivity and expanded dorsal horn receptive fields in adults (Alvares et al., 2000; Torsney and Fitzgerald, 2003). Stimulus duration is also critical. A high profile report of long-term spinal cord plasticity due to early hindpaw CFA inflammation (Ruda et al., 2000) was confounded by the fact that the neonatal lesion was actually a chronic injury that lasted into adulthood (Walker et al., 2003). Depending on the dose used, lower intensity neonatal hindpaw inflammation either produces no long-term change in behaviour or dorsal horn cell responses (Alvares et al., 2000; Torsney and Fitzgerald, 2003; Walker et al., 2003) or long-term mechanical and heat hypoalgesia and increased re-inflammation hyperalgesia (Lidow et al., 2000). This issue of Pain reports a significant step towards understanding this apparently conflicting data (Ren et al., 2004). By following a large number of groups of animals, subjected to low dose hindpaw inflammation at many different postnatal ages and over a prolonged period, two clear patterns of adult pain behaviour have emerged. Firstly, there is a localised enhancement of the re-inflammationinduced mechanical and thermal hyperalgesia in the affected paw that emerges within the first postnatal week. Secondly, this is accompanied by a generalised reduction of baseline
0304-3959/$20.00 q 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2004.05.022
M. Fitzgerald / Pain 110 (2004) 508–509
mechanical and thermal sensitivity all over the body but this effect is not apparent until the animal is over 4 weeks old. Both the early onset inflammatory hyperalgesia and the later onset baseline hypoalgesia only occur if the original inflammatory stimulus is applied within the first 10 days of life and both last into adulthood. This combination of a localised enhancement of pain responses and an overall baseline depression each with their own time of onset, may very well explain the apparently conflicting reports by different groups in this area. What are the underlying mechanisms for such changes? Effects that are local to the site of injury are easier to explain in terms of activity dependent strengthening and weakening of synapses. Both inhibitory and excitatory neurotransmitter/ receptor systems involved in pain undergo marked changes in subunit composition and function in the first two postnatal weeks, many of which are activity dependent (Pattinson and Fitzgerald, 2004). Less easy to explain at the cellular level is the baseline hypoalgesia. Stress-induced analgesia in adults is a powerful, but poorly understood phenomenon and the longterm effects of neonatal stress are even harder to fathom. Daily handling alone for 14 postnatal days is known to increase nociceptive thresholds in adult male and female rats and to decrease behavioural and analgesic responses to stress in adulthood (Sternberg and Ridgeway, 2003). One possibility then, is that early pain experience enhances stress responses, which in turn increases stress-induced analgesia. Any local sensitisation that might occur at segmental level would be masked by this and require a strong stimulus such as re-inflammation to be observed. A number of us (e.g. Fitzgerald et al., London; Hermann et al., Mannheim) currently studying sensory and nociceptive thresholds in children that have undergone early pain experience need to take note. Pain may be learnt in infancy, but so too is stress and the stress of the situation may mask everything.
References Alvares D, Torsney C, Beland B, Reynolds M, Fitzgerald M. Modelling the prolonged effects of neonatal pain. Prog Brain Res 2000;129:365–73. Anand KJ. Pain, plasticity, and premature birth: a prescription for permanent suffering? Nat Med 2000;6:971–3. Anand KJS, Coskun V, Thrivikraman KV, Nemeroff CB, Plotsky PM. Long-term behavioural effects of repetitive pain in neonatal rat pups. Physiol Behav 1999;66:627 –37. Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human neonates: sensitization, receptive fields, and the effects of contralateral stimulation. Pain 1994;56:95–101. Andrews K, Fitzgerald M. Flexion reflex responses in biceps femoris and tibialis anterior in human neonates. Early Hum Dev 2000;57:105– 10. Andrews KA, Desai D, Dhillon HK, Wilcox DT, Fitzgerald M. Abdominal sensitivity in the first year of life: comparison of infants with and without prenatally diagnosed unilateral hydronephrosis. Pain 2002;100:35 –46. Bhutta AT, Rovnaghi C, Simpson PM, Gossett JM, Scalzo FM, Anand KJS. Interactions of inflammatory pain and morphine in infant rats. Longterm behavioural effects. Physiol Behav 2001;73:51–8. Fitzgerald M, Jennings E. The postnatal development of spinal sensory processing. Proc Natl Acad Sci USA 1999;96:7719–22.
509
Fitzgerald M, Walker S. The role of activity in developing pain pathways. In: Dostrovsky JO, Carr DB, editors. Proceedings of the 10th World Congress on Pain. Progress in pain research and management, vol. 24. Seattle, WA: IASP Press; 2003. Grunau RE. Long-term consequences of pain in human neonates. In: Anand KJS, Stevens BJ, McGrath PJ, editors. Pain Res Clin Man, 10.; 2000. p. 101– 34. Grunau R, Whitfield MF, Petrie JH. Pain sensitivity and temperament in extremely lowbirthweight premature toddlers and preterm and fullterm controls. Pain 1994a;58:341– 6. Grunau RVE, Whitfield MF, Petrie JH, Fryer EL. Early pain experience, child and family factors, as precursors of somatization: a prospective study of extremely premature and fullterm children. Pain 1994b;56:353–9. Lidow MS, Song Z-M, Ren K. Long-term effects of short-lasting early local inflammatory insult. Neuroreport 2000;12:399–403. Pattinson D, Fitzgerald M. The neurobiology of infant pain: development of excitatory and inhibitory neurotransmission in the spinal dorsal horn. Reg Anesth Pain Med 2004;29:36–44. Petersson P, Waldenstrom A, Fahraeus C, Schouenborg J. Spontaneous muscle twitches during sleep guide spinal self-organization. Nature 2003;424:72–5. Petersson P, Granmo M, Schouenborg J. Properties of an adult spinal sensorimotor circuit shaped through early postnatal experience [Epub ahead of print]. J Neurophysiol 2004;February 25. Ren K, Anseloni V, Zou S-P, Wade EB, Novikova SI, Ennis M, Traub RJ, Gold MS, Dubner R, Lidow MS. Characterization of basal and re-inflammation-associated long-term alteration in pain responsively following short-lasting neonatal local inflammatory insult. Pain 2004; 110(3):588–96. Ruda MA, Ling Q-D, Hohmann AG, Peng YB. Tachibana T altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science 2000;289:628–30. Schouenborg J. Modular organisation and spinal somatosensory imprinting. Brain Res Brain Res Rev 2002;40:80– 91. Simons SH, van Dijk M, Anand KS, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med 2003;157:1058–64. Sternberg WF, Ridgway CG. Effects of gestational stress and neonatal handling on pain, analgesia, and stress behavior of adult mice. Physiol Behav 2003;78:375–83. Stevens B, Gibbins S, Franck LS. Treatment of pain in the neonatal intensive care unit. Pediatr Clin North Am 2000;47:633–50. Taddio A, Goldbach M, Ipp M, Stevens B, Koren G. Effect of neonatal circumcision on pain responses during vaccination in boys. Lancet 1995;345:291–2. Taddio A, Stevens B, Craig K, Rastogi P, Ben-David S, Shennan A, Mulligan P, Koren G. Efficacy and safety of lidocaine–prilocaine cream for pain during circumcision. N Engl J Med 1997;336:1197– 201. Torsney C, Fitzgerald M. Spinal dorsal horn cell receptive field size is increased in adult rats following neonatal hindpaw skin injury. J Physiol 2003;550:255–61. Waldenstrom A, Thelin J, Thimansson E, Levinsson A, Schouenborg J. Developmental learning in a pain-related system: evidence for a crossmodality mechanism. J Neurosci 2003;23:7719–25. Walker S, Meredith-Middleton J, Cooke-Yarborough C, Fitzgerald M. Neonatal inflammation and primary afferent terminal plasticity in the rat dorsal horn. Pain 2003;105:185– 95.
Maria Fitzgerald* Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK E-mail address: [email protected] * Tel.: þ 44-207-391-1303; fax: þ44-207-383-0929.