Pain threshold in diabetic rats: effects of good versus poor diabetic control Jana Herman

Lee and Richard McCarty

Pain threshold was assessed via tail flick latency in streptozotocin diabetic rats following a l-month Summary period of either good or poor diabetic control. Additionally, tail flick latencies wet-c determined under test conditions of euglycemia (60-120 mg/dl) and hyperglycemia (> 250 mg/dl) for both groups of diabetic rats. Conditions of hyperglycemia resulted in a significant decrease in tail tlick latency in diabetic animals maintained in good as well as poor diabetic control. However, tail flick latencies for animals in the good but not in the poor diabetic control group increased when animals were eug~ycemic at the time of testing. Animals in the poor diabetic control group continued to have reduced tail flick latencies even after acute n~~rmalization of blood glucose levels. These results suggest that chronic states of hyperglycemia that attend prolonged periods of poor diabetic management may lead to persistent alterations in pain threshold. In contrast, the reduced pain threshold of rats maintained in good diabetic control was reversed by a normalization of blood glucose levels. These findings provide evidence for two patterns of hyperalgesia in diabetic rats: (1) a readily reversible form in well-maintained diabetic rats that is altered by reducing circulating blood glucose levels to control values and (2) a more persistent lbrm found in poorly controlled diabetic rats that does not respond to acute normalization of blood glucose. Key words: Streptozotocin;

Pain threshold; GIycemic control; Animal models

introduction Diabetes mellitus is associated with several longterm complications. Prominent among these is peripheral neuropathy, often expressed as hypersensitivity to painful stimuli (Brown et al. 1976). A review of the published work on painful diabetic neuropathy suggests that a significant degree of neuropathic pain is more likely to occur in patients with poorly controiled diabetes (Boulton et al. 1982; Archer et al. 1983; Thomas and Eliasson 1984). It has been suggested that acute biochemical alterations in neural tissue might result from prolonged hyperglycemia and could contribute to the development and maintenance of painful diabetic neuropathy (Thomas and Eliasson 1984).

Corre.spun&we search

Unit,

D-S-West. USA.

The

IO: Jana. Johns

H. Lee,

Hopkins

Francis Scott Key Medical

Behavioral

University Center,

Pharmacology School

Baltimore.

Tel.: (410) 5.50-1273: Fax: (410) S50-003fl.

Re-

of Medicine. MD

2122-I.

The idea that glucose may be an important contributing factor in painful diabetic neuropathy has been confirmed in several clinical studies. Morley and coworkers (1984) demonstrated in nondiabetic humans that a 50-g infusion of glucose resulted in decreases in pain threshold. Additionally, hyperglycemic non-insulin-dependent diabetes mellitus (NIDDM) patients were hyperalgesic when compared to non-diabetic control patients (Morley et al. 1984). It has aiso been demonstrated that recovery from painful diabetic neuropathy is more likely to occur if patients are maintained in good diabetic control. This was particuiariy true for patients with an acute onset of painful symptoms, but was less evident when the onset was insidious and was followed by sensation loss. Boulton and coworkers (1982) demonstrated that maintcnance of euglycemia for 6 weeks, by use of a continuous subcutaneous insulin infusion. resulted in symptomatic relief of painful diabetic neuropathy and was accompanied by a significant improvement in subjcctivc pain ratings. Additi~)nally, long-term m~~intenance

of good diabetic control has been reported to improve nerve conduction velocity and vibration sensation in patients with diabetic neuropathy (Service et al. 1985; Jakobsen et al. 1988). Animal research studies have provided findings consistent with the view that glucose may be an important mediating factor in pain mechanisms. For example, elevated blood glucose fevefs have been reported to after the response to opiate agonists and antagonists, which indicates that serum glucose IeveIs may modulate responsiveness to endogenous opiates (Davis et al. 19.55;Simon and Dewey 1981; Raz et al. 1988). Forman and coworkers (1986) reported that plasma, neuro-intermediate lobe, and hypothalamic levels of the endogenous opioid peptide P-endorphin were reduced significantly in female rats 8 weeks following the induction of diabetes with streptozotocin. Diabetic female rats’ also exhibited decreased latencies to paw lick or jump when subjected to hot plate testing (Forman et al. 1986). Recent work from our laboratory has demonstrated that h~er~lycemic diabetic rats have decreased taif ffick latencies as compared to euglycemic control animals. However, tail flick Iatencies of diabetic rats were similar to values for controls following acute normalization of blood glucose values (Lee and McCarty 1990; Lee et al. 1990). Finally, tail flick latencies decreased significantly in control non-diabetic rats following a single glucose injection (Lee and McCarty 1990). In contrast to these findings, Raz and coworkers (1988) reported that neither acute nor chronic states of hyperglycemia altered pain threshofds of laboratory rats as measured by hot plate testing. However, both chronic and acute states of hypergiycemia were rtported to decrease significantly the analgesic effects of morphine. Additionally, Levine and coworkers ( 1982) reported increased tail flick Iatencies to a radiant heat stimulus in streptozotocin diabetic rats. There may be several explanations for the inconsistent findings reported in the preclinical literature. For instance, several different methods have been used to assess pain threshofd and some studies have used various strains of diabetic rats and others diabetic mice. More importantIy, several studies fail to report whether diabetic animals received insuIin replacement and, if so, how much and what type. Previous work from our laboratory has shown that the amount and type of insulin administered will affect pain threshold. Finally, few if any published reports have manipulated diabetic control chronically. The clinical literature clearly supports the view that poor diabetic control is associated with several long-term complications, including painful diabetic neuropathy (Thomas and Eliasson 1984). Yet, this issue has been addressed infrequently in laboratory studies. In the present study with laboratory rats, we exam-

ined the role of good versus poor diabetic contrc~f OSI pain threshold. We were particularIy interested in comparing pain threshold levels of diabetic rats following :t l-month period of either poor or good diabetic control and then again following acute normalization of blood glucose levels in both groups.

Methods AnimaIs AdultII,& Ililhop ally

Sprague-Dawley

Breeding

m plastic

cm).

The

dark

boxes

that

vivarium

cycle

on

chow

and

was at

(325-350

Scottdale.

contained

room

(light\

I:lh 0.8). However, body weights of STZdiabetic rats were reduced significantly at 72 h following administration of STZ (I’ < 0.05). Within 1 week after treatment with STZ, animals in the GDC group had body weights that matched control values, whereas animals in the PDC group had significantly reduced body weights. Animals in the GDC group had body weights that were comparable to control animals for the entire l-month period of treatment whereas body weights for animals in the PDC group remained signifi-

ii

J

I

GDC

CON Fig. 2. Tail flick latencies (XC) of the experiment. lower

Hyperglycemic

tail flick latencies Values

for all treatment STZ-diahetlc

than euglycemic

are means and vertical

CON

PDC groups at the onset rats had significantly rats (*

lines denote

P < 0.001).

1 S.E.M.

1

CON

100

CRC

0

PRC

Fig. 3. Tail flick latencies (set) for CON and STZ-diabetic rats at the end of 1 month. Hyperglycemic GDC and PDC rats both showed a significant reduction in tail flick latency as compared to euglycemic CON rats (* P < 0.01). Euglycemic GDC rats had tail flick lateacies that matched CON values. In contrast, euglycemic PDC rats showed a reduction in tail flick iatencies (* P < 0.01). Values are means and vertical lines denote 1 S.E.M.

tested under condition of euglycemia. Finally, animals in the PDC group revealed a persistent depression in tail flick Iatencies even during euglycemic test conditions (P < 0.09. Fig. 4 presents blood ghrcose values for diabetic and control animals 72 h after treatment with either ST2 or 0.9% safine. Blood glucose values at the onset of the experiment were equal for both diabetic groups and these values were significantly higher than control vatues (F (2, 37) = 44.4, P < 0.001). After 1 month, hyperglycemic blood glucose values for PDC and GDC rats were significantly greater than blood glucose levels for controls (F (2, 33) = 237, P < 0.001). Blood glucose values obtained during euglycemic test conditions were slightly higher for ani-

CON

mais in the PDC group as compared to animak in the GDC group (F (2, 32) = 9.3, P < 0.01; Fig. 5). Fig. 6 summarizes HbAl values at the conclusion of the experiment. Animals in the PDC group had HbAl levels that were significantly greater than those of control and CDC animals (F (2, 29) = 25.8, P < 0.0011.

Discussion The data presented in this study indicate that hyperglycemia can affect pain threshold in Iaborato~ rats. More importantly, these findings support the concept that two processes related to pain sensitivity may exist

35

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Fig. 5. Blood glucose values (mg/dl) at the end ot I nwnrtl tol diabetic and control animals under hyperglycetnic test condition\. Hyperglycemic blood glucose values for both CiDC and PDC WI\ were significantly higher than blood glucose ievefs for CON tats (* * P < 0.~1~. Euglycemic blood glucose values were higher for rats in PDC rats as compared to GDC and CON rats ( * P . Pawn. 10 (1990) 105-107. Levine. AS., Morley, J.E., Wilcox, G.. Brown, l>.M. and Handweger. B.S.. Tail pinch behavior and analgesia in diabetic mice. Physiol. Behav.. 2X (I 982) 39-43. Morley. G.K.. Mooradian, A.D.. Levine. A.?;. and Morley, J.f.. Mechanism of pain in diabetic peripheral ncuropathy: effect 01 glucose on pain perception in humans, Am. J. Med.. 77 (lYX4) 79-82. Raz, I.. Hasdai, D.. Seltzer, Z. and Melmed. R.N.. Effect of hypcrglycemia on pain perception and on efficacy of morphine analgesia in rats. Diabetes, 37 (19X8) 1253-1259. Service, F.J., Rizza, R.A., Daube, J.R.. O’Brien. PC and Dyck, P.J.. Near normoglycaemia improved nerve conduction and vibration sensation in diabetic neuropathy, Diabetologia, 2X (1985) 722-727. Sharma, A.K., Duguid, I.G.M.. Blanchard, D.S. and Thomas. P.K.. The effect of insulin treatment on myelinated nerve fibre maturation and integrity and on body growth in streptozotocin-diabetic rats. J. Neural. Sci., 74 (19X6) 5567. Shook, J.E. and Dewey, W.L., Morphine dependence and diabetes: the development of morphine dependence in streptozotocin-diabetic rats and spontaneously diabetic CS7B/KsJ mice, J. Pharmacol. Exp. Ther.. 237 (1986) X41 -X47. Shook, J.E., Kachur, J.F.. Brase, D.A. and Dewey. W.L.. Morphine dependence and diabetes. II. Alterations of normorphine potency in the guinea-pig ileum and mouse vas deferens and of ileal morphine dependency by changes in glucose concentration. J. Pharmacol. Exp. Ther., 237 (1986) 84X-852. Simon, G.S. and Dewey, W.L., Narcotics and diabetes. I. The effects of streptozotocin-induced diabetes on the antinociceptive potency of morphine, J. Pharmacol. Exp. Ther.. 218 (lYK1) 31X-323. Simon, G.S., Borzelleca. J. and Dewey, W.L., Narcotics and diabetes\. II. Streptozotocin-induced diabetes selectively alters the potency of certain narcotic analgesics: mechanism of diabetes: morphine interaction. J. Pharmacol. Exp. Ther., 218 (lYXl)324-32Y. Thomas, P.K. and Eliasson, S.G.. Diabetic neuropathy. In:. P.J. Dyck. P.K. Thomas, E.H. Lambert and R. Bunge (Eds.), Peripheral Neuropathy. Vol. III, Sanders. Philadelphia, PA. IYXJ, pp. 1773-1810.

Pain threshold in diabetic rats: effects of good versus poor diabetic control.

Pain threshold was assessed via tail flick latency in streptozotocin diabetic rats following a 1-month period of either good or poor diabetic control...
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