Introduction

Complaints of patients with chronic pain may increasewhen the weather changes. Several reports based onpain questionnaires have assessed pain sensitivity tometeorological factors, and conditions reported to be es-pecially sensitive to weather changes are chronic pain inrheumatoid arthritis (Hollander 1962; Rasker et al.1986; Guedi and Weinberger 1990; Gorin et al. 1999),nerve entrapment (Hendler et al. 1995), phantom limbpain (Mitchell 1877), osteoarthritis (Hollander 1962), fi-bromyalgia (Yunus et al. 1981; Fors and Sexton 2002),migraine (Anderson et al. 1965), postherpetic neuralgia(Nurmikko and Bowsher 1990), reflex sympathetic dys-trophy (Hooshmand 1993; Hendler et al. 1995), andlow-back pain (Shutty et al. 1992; Hendler et al. 1995).Various meteorological factors, such as barometric pres-sure, ambient temperature, humidity, sunshine, rain andstorms, have been suspected to contribute to changes inpain (Hollander 1962; Sulman et al. 1970; Jamison et al.1995). Hollander (1961) approached this issue experi-mentally using a climate-controlled room and showedthat arthritic patients report more pain in response to thecombination of increased humidity and decreased baro-metric pressure.

All of the studies cited above demonstrated a consis-tent relation between changes in meteorological factorsand pain intensity. Other studies, however, have failedto find a significant relationship between chronic painand weather. For instance, Clark and Nicholl (1991) ex-amined rheumatoid arthritis patients’ pain levels dailyfor 30 days and found no correlation between pain in-tensity and barometric pressure or humidity. More re-cently, Redelmeier and Tversky (1996) failed to findany relationship between weather conditions and pain.They even suggested that psychological factors contrib-

ute to the belief that chronic pain is related to weatherchange.

Does weather really influence chronic pain? Giventhe many contradictory results and opinions in this field,we were struck by the absence of controlled animalstudies addressing the issue. Such studies could provideclues to help explain the contradiction described aboveas well as essential evidence for uncovering the mecha-nism(s) by which weather induces changes in pain. We decided, therefore, to conduct a behavioral animalstudy to determine whether changes in meteorologicalfactors within the range of the natural environment ag-gravate pain-related behaviors in rats with chronic pain.In this article, the author summarizes the data from hisgroup’s recent behavioral animal studies (Sato et al.1998, 1999, 2000, 2001, 2002; Nagao et al. 2000; Takahashi et al. 2001) and discusses the possible mech-anisms by which weather changes aggravate chronicpain.

The studies

All the experiments were carried out using maleSprague-Dawley (SD) rats in which neuropathy orchronic inflammation of the foot was produced experi-mentally1. The neuropathic animal model was producedby loosely ligating the sciatic nerve (chronic constric-tion injury), according to a method previously described(Bennett and Xie 1988). These rats present varioussymptoms, which approximate the clinical features ofhuman neuropathic pain (Bennett and Xie 1988; Attal etal. 1990). Chronic inflammation in rats was produced bya single injection of Freund’s complete adjuvant into thefoot joint. These rats show swelling of the foot joint andpain-related signs on the hindpaw, and thus are knownto be a model of rheumatoid monoarthritis (Butler et al.1992). Normal SD rats were used as controls.J. Sato (✉)

Department of Neural Regulation, Research Institute of Environmental Medicine, Nagoya University,Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan,e-mail: jun@riem.nagoya-u.ac.jpFax: +81-52-7893889

Int J Biometeorol (2003) 47:55–61DOI 10.1007/s00484-002-0156-9

M I N I - R E V I E W

Jun Sato

Weather change and pain: a behavioral animal study of the influencesof simulated meteorological changes on chronic pain

Published online: 30 January 2003© ISB 2003

1 All the experiments in the present study received approval fromthe Animal Care Committee of Nagoya University, and were per-formed in accordance with the guidelines of the International As-sociation for the Study of Pain (Zimmermann 1983)

All exposure experiments were performed using a cli-mate-controlled room in the Research Institute of Environ-mental Medicine, Nagoya University. The barometric pres-sure was decreased over 8 min to a level 20 mmHg(26.7 hPa) below the atmospheric pressure, and the ambienttemperature was decreased by 7 °C from 22 °C over 30 min(Sato et al. 1999, 2000). A change of 20 mmHg was chosenfor the low-pressure exposure because barometric pressuregradually falls by 10–20 mmHg (13.3–26.7 hPa) during thepassage of the low-pressure systems that occur in naturalweather patterns. A change of 7 °C was chosen for the low-temperature exposure because this value is also within therange typical of natural weather change.

Low-pressure exposure augmented spontaneous pain,and mechanical allodynia and hyperalgesia shownby rats rendered neuropathic or monoarthritic in the foot

All the neuropathic rats held the hindpaw of the affectedside off the floor much of the time, which is suggestiveof spontaneous pain induced by nerve injury (Bennettand Xie 1988). Low-pressure exposure significantly in-creased the cumulative time the injured paw was lifted(Fig. 1). Low-pressure exposure did not alter the sponta-neous postures of sham-operated control rats.

The neuropathic rats showed a lowered withdrawalthreshold (allodynia) and an increased magnitude ofwithdrawal response (hyperalgesia) of the hindpaw fol-lowing mechanical stimulation of the foot skin (Figs. 2,3). These rats also showed a lowered threshold for with-drawal of the hindpaw in response to the application ofradiant heat to the foot (heat allodynia, Fig. 4). Whenthese rats were exposed to the low-pressure environment,the mechanical allodynia and hyperalgesia, as well as theheat allodynia, were aggravated (Figs. 2, 3, 4). Addition-ally, the increase in mechanical allodynia appeared just

after the lowest pressure was reached, and gradually dis-appeared with time in the low-pressure environment(Fig. 5). This observation agrees with the findings of anearlier study, in which many patients reported that theirpain was affected before (52.6%) and during (62.3%)weather changes, rather than after (Jamison et al. 1995).

A low-pressure environment has also been found tohave a similar augmenting effect on the mechanical hy-

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Fig. 1 Increase in spontaneous pain (expressed by guarding be-havior) produced by low-pressure exposure of neuropathic rats. Tomeasure the guarding behavior in a natural setting without inter-vention by the experimenter, neuropathic rats were placed individ-ually in inverted transparent plastic cages with a mesh floor. After5 min of adaptation, the cumulative time that the rat held its footoff the floor during a 5-min period was recorded. pre Shortly be-fore exposure; mid at the lowest pressure; post shortly after expo-sure. Low-pressure exposure significantly increased the cumula-tive time of the injured paw but not the uninjured paw was raised.* P < 0.05, compared with the pre-exposure value [repeated-mea-sures analysis of variance (ANOVA) with Fisher’s PLSD test](from Sato et al. 2001, with permission)

Fig. 2A–C Decrease in nociceptive paw-withdrawal threshold inresponse to mechanical stimulation of neuropathic rats followinglow-pressure exposure. To measure the paw-withdrawal threshold,von Frey filaments were applied to the mid-plantar skin of the in-jured hindpaw in order of increasing stiffness (12–960 g/mm2).The strength of the first hair that evoked at least one positive re-sponse among the five trials was designated the pain threshold.One test was carried out before nerve constriction (CCI) or shamsurgery (control, pre I) and four tests were carried out with low-pressure exposure: 7 min before exposure (pre II), during (mid Iand II, just and 15-min after reaching the lowest pressure respec-tively) and 7 min after a return to the normal pressure (post). Ordi-nate cumulative number of rats responding. Abscissa bendingforce (g/mm2) of von Frey hairs in a logarithmic scale. Low-pres-sure exposure further decreased the withdrawal threshold of neu-ropathic but not control rats. Lumbar sympathectomy inhibited thelow-pressure-induced lowering of the threshold in the CCI rats(SYX+CCI) (from Sato et al. 1999, with permission)

Fig. 3A, B Increase in nociceptive paw-withdrawal response tomechanical stimulation of the neuropathic rat following low-pres-sure exposure. To measure mechanical hyperalgesia, the point of asafety pin was applied to the mid-plantar surface of the hindpawthrough an elevated grid floor, and the duration of the evokedpaw-withdrawal was timed with a stopwatch. A measurement cut-off of 15 s was applied. The figures show the average durations ofthe nociceptive withdrawal response in neuropathic rats with[SYX(+)] and without (SYX(–)) lumbar sympathectomy. pre 52 minbefore exposure; mid just after reaching the lowest pressure; post97 min after returning to the normal pressure. * P < 0.05, com-pared with each pre-exposure value (repeated-measures ANOVAfollowed by a post hoc analysis). Low-pressure exposure in-creased the duration of withdrawal in the neuropathic but not inthe sympathectomized neuropathic rats (from Sato et al. 1999,with permission)

Fig. 5 Time course of the increased mechanical allodynia inducedby the low-pressure exposure. To measure the paw-withdrawalthreshold, von Frey filaments were applied to the mid-plantar skin of the injured hindpaw in order of increasing stiffness(12–69 g/mm2). The strength of the first hair that evoked at leastone positive response among the five trials was designated thepain threshold. The barometric pressure was kept at the lowestlevel for 3 h and the threshold was measured every 60 min beforea return to atmospheric pressure. Ordinate cumulative number ofrats responding. Abscissa bending force of hairs in a logarithmicscale. The thresholds measured immediately after the lowest pres-sure was reached (0 min) were significantly lower than the base-line value (pre). This increased hypersensitivity gradually disap-peared with time (60–180 min) in the low-pressure environment(from Sato et al. 1999, with permission)

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Fig. 4 Low-pressure exposure augmented heat allodynia in theneuropathic rats. The figure shows the average latency of the noci-ceptive paw-withdrawal response evoked by a radiant heat appliedto the mid-plantar area of the injured hindpaw. pre 20 min beforeexposure; mid 27 min after reaching the lowest pressure; post I and II 7 and 27 min after returning to the normal pressure. * P < 0.05, compared to PRE (repeated-measures ANOVA withFisher’s PLSD test) (from Sato et al. 1998, with permission)

peralgesia in rheumatoid arthritic rats. By 3 weeks afteradjuvant injection into the foot joint, the rats showedmechanical hyperalgesia of the hindpaw skin (Takahashiet al. 2001). When these arthritic rats were exposed tothe low-pressure environment, this neuropathic symptomwas significantly aggravated. These results show that,with all other meteorological parameters constant, a dropin barometric pressure of 20 mmHg (within the range ofnatural environmental change) aggravates chronic painexhibited by neuropathic and rheumatic animals.

The sympathetic nervous system contributes to aggravation of neuropathic pain in a low-pressureenvironment

It has been reported that acute hypobaric conditions acti-vate muscle sympathetic activity in normal human sub-jects (Saito et al. 1988). We therefore examined whethersympathetic nervous activity is increased during low-pressure exposure, and whether such increased sympa-thetic activity augments the pain-related behaviors ofrats. Before the nerve or sham surgery, we performedsurgical lumbar sympathectomy. This surgical pretreat-ment blocked the aggravating effect of low-pressure ex-posure on the mechanical allodynia and hyperalgesia inthe neuropathic rats, but did not alter any nociceptive re-sponses in sham-operated control rats (Figs. 2, 3). Thisindicates that sympathetic nervous activity plays an im-portant role in the mechanism underlying the augment-ing effect of low-pressure exposure. Additionally, thisobservation led us to speculate that low-pressure expo-sure activates the sympathetic nervous system only in aneuropathic condition. We therefore tested the influenceof low-pressure exposure on systemic blood pressure andheart rate (as indicators of autonomic response) in ratsboth before and after nerve injury. As a result, low-pres-sure exposure was shown to cause even larger increasesin both sympathetic parameters before nerve injury thanit did after nerve injury (Fig. 6). Additionally, we foundthat both plasma noradrenaline release and renal sympa-thetic nerve activity in normal rats were clearly in-creased during low-pressure exposure (Sato et al. 2002).These observations imply that low-pressure exposureprovokes autonomic responses; in other words, it mayactivate the sympathetic nervous system in both groups

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Fig. 6A–D Time courses ofchanges in systemic bloodpressure (BP: A, B) and heartrate (HR: C, D) of rats before(A, C) and after (B, D) nerveinjury during low-pressure ex-posure. Average values of in-stantaneous BP and HR read-ings taken for 3 s every 5 minare plotted. Each 45-min periodpre-, mid- (shaded area) andpost- exposure contains ninesampling points (B1–B9,L1–L9 and A1–A9 respectively)* P < 0.05, compared with B9of each group (repeated-mea-sures ANOVA with Fisher’sPLSD test). Low-pressure ex-posure increased BP and HR inboth groups of rats (from Satoet al. 2001, with permission)

Fig. 7 Possible mechanism for chronic pain increased induced bylowering the barometric pressure. For explanation see text

of rats (normal and neuropathic) similarly. It is also sug-gested that the pain-aggravating process involves mecha-nisms (described below) other than the sympathetic ef-ferent excitation that works only in neuropathic rats.

The underlying mechanism by which a low-pressure environment aggravates chronic pain

In the following, possible mechanisms for the increase inchronic pain under a low-pressure environment are dis-cussed (Fig. 7).

1. Increased sympathetic nerve activity aggravates pain vialocal vasoconstriction. If skin sympathetic nerves are ac-tivated by a drop of 20 mmHg in barometric pressure,then an increase in sympathetic nerve discharges mayinduce vasoconstriction and result in ischemia, whichwould increase background pain (Drummond 1996). Wefound, however, that low-pressure exposure did not in-duce any definite changes in the hindpaw skin tempera-

ture of the rats tested (Sato et al. 1999). This suggeststhat local vasoconstriction and ischemia do not play amajor role in the mechanism of the sympathetic-relatedchanges in the painful behaviors of neuropathic rats.

2. Catecholamines were released from the adrenal me-dulla as a result of the low-pressure exposure. Thesecirculating hormones might have activated the periph-eral nociceptive and/or mechanoreceptive fibers in theinjured sciatic nerve, resulting in increasing pain. Ithas been reported that cutaneous nociceptive fibersbecome responsive to adrenaline and noradrenalineafter nerve injury (Sato and Perl 1991; Bossut andPerl 1995; O’Halloran et al. 1996).

3. Low-pressure might have directly increased sympa-thetic nerve activity in the injured sciatic nerve. Sym-pathetic nerve volleys activate and sensitize nocicep-tive primary afferents through the mechanism ofsympatho-nociceptor interactions that are developedafter nerve injury (Bossut et al. 1996). Such a processcould be based on the sympathetic supersensitivity ofnociceptive fibers induced by denervation of sympa-thetic fibers (Birder and Perl 1999).

Low-temperature exposure augmented spontaneous pain and mechanical allodynia and hyperalgesia shownin rats rendered neuropathic or monoarthritic in the foot

We investigated whether lowering the ambient tempera-ture also aggravates pain-related behaviors in neuropathicand rheumatoid arthritic rats. Low-temperature exposuresignificantly increased the cumulative time of the guard-ing behavior in the neuropathic rats (Sato et al. 2000),similar to results following low-pressure exposure.

When the neuropathic rats were exposed to the low-temperature environment, a further decrease was seen inthe already decreased paw-withdrawal thresholds in re-sponse to pressure stimulation to the hindpaw skin (me-chanical allodynia) (Figs. 8, 9). The paw withdrawal inresponse to painful stimulation, already prolonged by the

nerve injury (mechanical hyperalgesia), was further pro-longed during low-temperature exposure (Fig. 10).

By 3 weeks following adjuvant injection into the footjoint, the rats showed a lowered paw-withdrawal thresh-old (allodynia) and increased magnitude of the paw-withdrawal response (hyperalgesia) to the mechanicalstimulation to the foot skin as described above. Whenthese arthritic rats were exposed to the low-temperature

environment, these pain-related behaviors were also sig-nificantly aggravated (Takahashi et al. 2001).

These results indicate that lowering the ambient tem-perature by 7 °C can aggravate behavioral abnormalitiesdisplayed in a model of chronic pain.

The sympathetic nervous system is not a predominantfactor in the mechanism by which the response to chronicpain is augmented by low-temperature exposure

Since sympathetic activities underlie the mechanism bywhich low-pressure exposure augments the pain-related

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Fig. 8A–D Augmenting effectof low-temperature exposureon the mechanical allodynia inneuropathic rats. The presenta-tion is the same as in Fig. 2, ex-cept for the abscissa showingthe bending force (g) of vonFrey hairs in a logarithmicscale. pre I Before neuropathicor sham surgery; pre II 60 minbefore exposure; mid 30 minafter reaching the lowest tem-perature; post 90 min after re-turning to the normal tempera-ture. Low-temperature expo-sure further decreased the with-drawal threshold of neuropathic(CCI) but not control rats.Lumbar sympathectomy didnot influence the low-tempera-ture-induced lowering of thethreshold in the neuropathicrats (SYX+CCI) (from Sato etal. 2000, with permission)

Fig. 9 Decrease in nociceptive paw-withdrawal threshold in re-sponse to pressure stimulation of the neuropathic rats followinglow-temperature exposure. For the paw-pressure stimulation, aconstantly increasing pressure was applied to the area between thethird and fourth metatarsi of the dorsal part of the hindpaw untilthe rat withdrew its paw. The nociceptive threshold was defined asthe force (g) at which the rat withdrew its paw. Ordinate the aver-age threshold of the nociceptive hindpaw withdrawal response. BSbefore neuropathic or sham surgery; POD 26 and POD 33 26 and33 days after the surgery respectively. pre 60 min before exposure;mid 30 min after reaching the lowest temperature; post 90 min af-ter returning to the normal temperature. Low-temperature expo-sure decreased the threshold of the withdrawal response in theneuropathic rats, but not that in the control rats, on both postopera-tive days. +P < 0.05, * P < 0.05, compared with BS and each pre-exposure value respectively (repeated-measures ANOVA with apost hoc analysis). # P < 0.05, compared to each control value(unpaired t-test) (from Sato et al. 2000, with permission)

Fig. 10 Augmenting effect of low-temperature exposure on themechanical hyperalgesia in the neuropathic rats. The figure showsthe average durations of the nociceptive withdrawal responseevoked by a pinprick applied to the mid-planter area of the injuredhindpaw. pre 60 min before exposure; mid 30 min after reachingthe lowest temperature; post 90 min after returning to the normaltemperature. * P < 0.05, compared with each pre-exposure value(repeated-measures ANOVA followed by a post hoc analysis).Low-temperature exposure increased the duration of withdrawal inboth the sympathectomized neuropathic rats (SYX+CCI) and theneuropathic rats but not that in the control and sympathectomized(SYX) rats (from Sato et al. 2000, with permission)

behaviors in neuropathic rats, we again performed sym-pathectomy to see whether this was true with low-tem-perature exposure as well. As shown in Figs. 8 and 10,lumbar sympathectomy did not inhibit low-temperature-induced augmentations of pain-related behaviors in theneuropathic rats. These results suggest a fundamentaldifference in the mechanisms by which low-pressure andlow-temperature exposures aggravate pain-related be-haviors. They would seem at first to indicate that sympa-thetic nerve activity does not play a significant role inthe aggravating effect of low-temperature exposure.This, however, is highly unlikely, since exposure to acold environment is known to be associated with activa-tion of the sympathetic nervous system (indicated by in-creasing skin or muscle sympathetic nerve activities andother effects) (Delius et al. 1972a, b; Bini et al. 1980;Okamoto et al. 1994) and an increase in plasma norad-renaline level (Benedict et al. 1977). Additionally, wehave recently found that the low-temperature exposureincreased the systemic blood pressure, heart rate andplasma noradrenaline level of normal and arthritic rats(unpublished observation). These facts lead us to specu-late that there is some other mechanism involved thatmasks the effects of sympathetic nerve activities.

The underlying mechanism by which a low-temperatureenvironment aggravates chronic pain

In the following, possible mechanisms that mask thesympathetic effects in a low-temperature environmentare discussed:

1. Decreased local skin temperature during low-temper-ature exposure itself may stimulate and sensitize cuta-neous nociceptive fibers and increase pain.

2. Stress hormones (ACTH, adrenaline, etc.) released inresponse to the cold environment could have inducedvasoconstriction, resulting in decreases in the localtemperature and ischemia, which in turn would in-duce the aggravation of pain-related behaviors. An-other possibility is that circulating adrenaline activat-ed and sensitized nociceptive fibers in the injured sci-atic nerve (O’Halloran et al. 1996).

3. Low-temperature exposure activates non-neuronal cells,such as mast cells, which might then release algesicsubstances (Juhlin and Shelly 1961; Ringkamp et al.1994) that heighten nociceptive fiber activities (Lang etal. 1990; Mizumura et al. 1994; Koda et al. 1996).

Summary and conclusions

1. It has been long observed that weather change is asso-ciated with increased complaints of pain, although theexact mechanism for this phenomenon remains un-clear. To clarify this issue, we have used a climate-controlled room to examine the effects of exposure tolow barometric pressure (20 mmHg lower than thenatural atmospheric pressure) and low ambient tem-

perature (a 7 °C decrease from 22 °C) on the pain-related behaviors of rats rendered neuropathic orrheumatoid arthritic.

2. When these rats were exposed to a low-pressure orlow-temperature environment, mechanical allodyniaand hyperalgesia, and heat allodynia were aggravated.The spontaneous pain-related behavior was also en-hanced during both exposures.

3. Lumbar sympathectomy inhibited the low-pressure-induced, but not the low-temperature-induced, aug-mentation of mechanical allodynia and hyperalgesiain nerve-injured rats. Even after sympathectomy, me-chanical allodynia aggravated by low-temperature ex-posure was seen in the neuropathic rats.

4. These results show that low-pressure and low-temper-ature exposures intensify abnormalities in the pain-related behaviors of neuropathic or arthritic rats. Ad-ditionally, our data suggest that sympathetic nervousactivity makes an important contribution to the low-pressure effect, while it does not appear to be impor-tant for the low-temperature effect.

This hypothesis is partially supported by the fact that, af-ter nerve injuries, some nociceptive fibers related to cuta-neous pain become sensitive to sympathetic nerve activi-ty or catecholamines (Sato and Perl 1991; Bossut andPerl 1995; O’Halloran et al. 1996). We cannot, however,deny the possibility that low-pressure exposure stimulatescertain areas in the central nervous system or non-neuro-nal peripheral tissues directly (Jamison 1996), thereby ac-tivating other processes. At the moment, we have no de-finitive evidence that any special organ senses changes inbarometric pressure. Further studies are needed.

In conclusion, the experiments described form the firstanimal behavioral study to show that low barometricpressure and low ambient temperature augment pain in-tensity. These observations support reports from humanswith several pathological conditions that pain is aggravat-ed by an approaching low-pressure system or exposure toa mildly cold environment (Ochoa and Yarnitsky 1994).

Acknowledgements I am grateful to Professor K. Mizumura forsupporting this study and to M. Aoyama, A. Ito, T. Kobayashi, H.Morimae, T. Nagao, T. Okada, S. Okumura, S. Omura, Y. Seino,N. Suzuki, K. Takanari, M. Watanabe and M. Yamazaki for theircooperation in some of the experiments mentioned here. Thiswork was supported in part by Grants-in-Aid for Scientific Re-search from the Japanese Ministry of Education, Science and Culture, the Kato Ryutaro Foundation at Nagoya University, a part of the “Ground Research for Space Utilization” promoted byNASDA and Japan Space Forum, and a Grant-in-Aid for Scien-tific Collaboration Project with Industries (DENSO Corporation).

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