James A. McCubbin

Diet-Induced Type II Diabetes in C57BL/6J Mice

We investigated the effects of diet-induced obesity on glucose metabolism in two strains of mice, C57BL/6J and A/J. Twenty animals from each strain received ad libitum exposure to a high–fat high-simple-carbohydrate diet or standard Purina Rodent Chow for 6 mo. Exposure to the high-fat, high-simple-carbohydrate, low-fiber diet produced obesity in both A/J and C57BL/6J mice. Whereas obesity was associated with only moderate glucose intolerance and insulin resistance in A/J mice, obese C57BL/6J mice showed clear-cut diabetes with fasting blood glucose levels of >240 mg/dl and blood insulin levels of >150 μU/ml. C57BL/6J mice showed larger glycemic responses to stress and epinephrine in the lean state than AJ mice, and these responses were exaggerated by obesity. These data suggest that the C57BL/6J mouse carries a genetic predisposition to develop non-insulin-dependent (type II) diabetes. Futhermore, altered glycemic response to adrenergic stimulation may be a biologic marker for this genetic predisposition to develop type II diabetes.

The relationship between resting blood pressure and acute pain sensitivity in healthy normotensives and chronic back pain sufferers: the effects of opioid blockade

&NA; Resting blood pressure is inversely correlated with acute pain sensitivity in healthy normotensives. This study tested: (1) whether endogenous opioid activity is necessary for this adaptive relationship to occur, (2) whether this relationship is altered in chronic low back pain (LBP), and (3) whether endogenous opioid dysfunction underlies any such alterations. Fifty‐one pain‐free normotensives and 44 normotensive chronic LBP sufferers received opioid blockade (8 mg naloxone i.v.) or placebo blockade (saline) in randomized, counterbalanced order in separate sessions. During each session, subjects participated in a 1‐min finger pressure (FP) pain task followed by an ischemic (ISC) forearm pain task. Among pain‐free normotensives, elevated resting systolic (SBP) and diastolic (DBP) blood pressure were associated with significantly higher ISC pain thresholds (P values <0.05). Elevated SBP was also associated with significantly lower FP pain ratings (P<0.05). Opioid blockade had no significant effect on the BP–pain relationships detected (P values >0.10). In combined groups analyses, a significant subject type×SBP interaction (P<0.005) was found on ISC pain threshold: elevated SBP was associated with higher pain threshold in pain‐free controls, but with lower pain threshold in LBP subjects. Although subject type×BP interactions on FP and ISC pain ratings were not significant, inclusion of LBP subjects in these analyses resulted in the overall relationship between BP and pain sensitivity becoming positive (P values <0.05). Opioid blockade exerted no significant main or interaction effects in these combined groups analyses (p values >0.10). Higher DBP was associated with greater clinical pain intensity among the LBP subjects (P<0.001). Overall, these results suggest: (1) endogenous opioids do not mediate the inverse relationship between resting blood pressure and acute pain sensitivity in pain‐free normotensives; (2) the BP–pain sensitivity relationship is altered in chronic pain, suggesting dysfunction in pain regulatory systems, and (3) these alterations are not related to opioid dysfunction.

Theoretical review : altered pain regulatory systems in chronic pain

This review synthesizes the existing literature regarding the relationship between resting blood pressure and pain sensitivity, and the literature indicating possible endogenous opioid dysfunction in chronic pain. Adaptive interactions between the cardiovascular and pain regulatory systems occur in healthy individuals, with greater blood pressure associated with decreased acute pain sensitivity. Endogenous opioids appear necessary for full expression of this relationship. There is ample evidence indicating diminished endogenous opioid CSF/plasma levels in chronic pain patients, yet little is known about the functional effects of these opioid changes. A theoretical model is proposed based upon the literature reviewed suggesting progressive dysfunction in endogenous opioid systems with increasing chronic pain duration. This dysfunction is hypothesized to result in dysregulation of normally adaptive relationships between the cardiovascular and pain regulatory systems, resulting in increased chronic pain intensity and increased acute pain sensitivity among chronic pain patients. Preliminary data are consistent with the hypothesis of progressive opioid changes resulting in dysfunctional alterations in the adaptive blood pressure-pain relationship. Clinical implications of this theory are discussed.

Behavioral Manipulation of the Diabetic Phenotype in ob/ob Mice

The genetically obese mouse (C57BL/6J ob/ob) is a commonly used model of non-insulin-dependent diabetes mellitus. However, our studies demonstrate that, while the animal is significantly hyperinsulinemic, it in fact does not show consistent hyperglycemia in the resting state. During stress, both obese animals and their lean littermates become hyperglycemie, but the magnitude of the hyperglycemia is exaggerated in the obese mice. Obese animals also show an exaggerated plasma glucose increase in response to epinephrine injection. This increase in plasma glucose is accompanied by a decrease in plasma insulin in response to both stress and epinephrine. Our findings suggest that environmental stimuli influence the expression of diabetes in the C57BL/6J obese mouse and therefore must be considered in studies of this animal model of diabetes.

Altered pituitary hormone response to naloxone in hypertension development.

&NA; Endogenous opioid regulation of blood pressure is altered during stress in young adults at risk for hypertension. We studied the effects of the opioid antagonist naloxone on the secretion of corticotropin and &bgr;‐endorphin during psychological stress in young adults with mildly elevated casual arterial pressures. Naloxone‐induced secretion of both corticotropin and &bgr;‐endorphin was significantly diminished in persons at enhanced risk for hypertension compared with the low blood pressure control group. Results suggest that opioidergic inhibition of anterior pituitary function is altered in hypertension development. (Hypertension 1989;14:636‐644)

Endogenous opiate peptides, stress reactivity, and risk for hypertension.

Endogenous opiate peptides can regulate neuroendocrine and circulatory responses to behavioral stress and may be important in the pathogenic effects of sympathoadrenal reactivity. We tested this hypothesis by examining the effect of the opiate antagonist naloxone on blood pressure responses to behavioral stress in young adults with high, medium, or low casual blood pressures. Naloxone increased mean arterial pressure responses to stress in subjects with low casual pressure, but had no significant effect on responses in subjects with high casual pressure. These results suggest opioidergic inhibition of sympathetic nervous system responses may be deficient in persons at risk for essential hypertension.

Social influence and pain response in women and men

The purpose of this study was to examine the effects of social influence on responses to acute pain in women and men in a randomized experimental design. Sixty-eight undergraduates (32 women; 36 men) were randomly assigned to perform a cold pressor task either alone or in the presence of a same-sex friend. Expressions of pain were assessed with the short form of the McGill Pain Questionnaire. Overall social support was measured using the Krause social support assessment scale. The presence of a same-sex friend significantly increased pain reports in women, but not in men. Persons who reported high levels of social support on the Krause scale also reported greater cold pressor pain. Results suggest that the presence of a friend can increase pain report to an acute laboratory pain stimulus in women. These findings are consistent with models of social reinforcement in chronic pain syndromes.

Opioid dysfunction and risk for hypertension: naloxone and blood pressure responses during different types of stress.

&NA; Opioidergic inhibition of sympathetic nervous system responses may be deficient in persons at risk for essential hypertension (McCubbin et al: Hypertension 7:808, 1985). The opiate antagonist naloxone increases blood pressure responses during psychological stress in young adults with low causal blood pressure, but has no pressor effect in subjects with high casual blood pressure. The purpose of the present study was to determine the role of altered baroreflex function in the abnormal pressor effect of naloxone in persons at risk for hypertension development. We tested this by comparison of the effects of naloxone on responses to psychological stress with responses to orthostatic stress in persons with high and low casual blood pressure. The results suggest that abnormal opioidergic control of systolic blood pressure responses to psychological stress is not likely a result of altered baroreflex function. Persons at risk for hypertension show evidence of an opioid peptide lesion that can probably be localized either at the adrenal medullae or at levels of central autonomic control that are parallel with or rostral to baroreflex circuits.

Relaxation training and opioid inhibition of blood pressure response to stress

The present study was designed to determine the role of endogenous opioid mechanisms in the circulatory effects of relaxation training. Opioid mechanisms were assessed by examination of the effects of opioid receptor blockade with naltrexone on acute cardiovascular reactivity to laboratory stress before and after relaxation training. Thirty-two young men with mildly elevated casual arterial pressure were recruited for placebo-controlled naltrexone stress tests and relaxation training. The results indicated that relaxation training significantly reduced the diastolic pressure response to mental arithmetic stress. Opioid receptor blockade with naltrexone antagonized the effects of relaxation training. These findings suggest that some of the physiological effects of relaxation training are mediated by augmentation of inhibitory opioid mechanisms.

Opioid Analgesia in Persons at Risk for Hypertension

Objective: Acute pain sensitivity is reduced in clinical hypertension, but the precise relationship between pain perception and altered blood pressure control is not well-characterized. A negative correlation between resting blood pressure and pain sensitivity is observed throughout the normotensive range, suggesting links between basic mechanisms of blood pressure control and pain regulation. The opioid peptides are important endogenous analgesic mechanisms, but their role in the hypoalgesia of blood pressure elevations has not been well-established. The current study sought to examine the effects of endogenous opioids on blood pressure-associated hypoalgesia in young adults at risk for hypertension development. Methods: The effects of the opioid receptor antagonist, naltrexone, on cold pressor pain sensitivity were assessed in young adult men (n = 49) and women (n = 76) with mildly elevated casual blood pressure. Results: Results indicate interactions between hypertension risk and the effects of opioid blockade on pain sensitivity. Conclusions: These findings suggest exaggerated opioid analgesia in persons at enhanced risk for hypertension and point to important links between altered neuropeptide regulation of pain and altered blood pressure control mechanisms in the early stages of hypertension. HR = heart rate; SBP = systolic blood pressure; DBP = diastolic blood pressure; MAP = mean arterial pressure; HPA = hypothalamic pituitary adrenocortical; CRF = corticotropin-releasing factor.