Genetic differences in morphine sensitivity, tolerance and withdrawal in rats

Abstract

Significant genetic differences in the endogenous opioid system and in response to a variety of noxious stimuli are present in rodents. We now compared the response to noxious heat with the hot plate test, morphine sensitivity and the development of tolerance and dependence to morphine in spontaneously hypertensive (SHR), Wistar–Kyoto (WK) and Sprague–Dawley (SD) rats. Significant differences were observed in basal nociception among the three strains, where SHRs were hypoalgesic compared to WK and SD. The antinociceptive effect of morphine varied among strains (SD>SHR>WK) as did the rate of tolerance development (10 mg/kg morphine 2/day for 4 days) where WK>SD=SHR. SHR rats developed hyperalgesia following morphine administration during the course of tolerance development. Furthermore, although naloxone (2 mg/kg) precipitated withdrawal symptoms in all tolerant rats, the panorama of symptoms varied among the three strains. Thus, there are significant genetic differences in a variety of effect of opiates.

Introduction

Considerable interindividual variability in the perception of noxious stimuli is characteristic of pain in humans. A number of possible mechanisms underlying these differences may exist, such as gender, cultural differences of pain expression, as well as differences in the endogenous pain modulating system [see Ref. [17]for review]. Among the latter, genetic differences may have important impacts on pain sensitivity and the response to analgesics. For example, humans that lack the genetic polymorphic cytochrome P4502D6 enzyme (CYP2D6) are poor metabolizers of opiates [1]and have increased response to tonically painful stimuli [23]. Another genetic factor that influences pain sensitivity is the presence of essential hypertension. Hypertensive humans have decreased pain ratings compared to normotensives [32]and normotensive offspring of hypertensive parents, who are at risk to develop hypertension later in life, also exhibit hypoalgesia in a number of experimental pain models [20].

A number of animal models of genetic differences in response to brief noxious stimuli that induce acute or tonic pain have been described in rodents, using inbred strains, selective breeding, spontaneous and targeted mutations 17, 21. Spontaneously hypertensive rats (SHR), which were selectively bred from the normotensive Wistar–Kyoto (WK) strain [19], exhibit increased nociceptive threshold in a number of test paradigms 14, 22, 24, 30, 31, 33. Furthermore, hypoalgesia has been observed in young SHR rats prior to the development of sustained elevation in blood pressure 14, 24. SHR rats have an elevated level of opioid binding sites in the CNS 7, 8, 12, 16, 31, 33. The involvement of the endogenous opioid system in abnormal pain sensitivity in SHR rats has been demonstrated since hypoalgesia was reversed by naloxone 22, 24.

Abnormal pain sensitivity involving genetic factors also seems to be a major factor in the development of chronic pain states. In humans a large number of painful neuropathic conditions appear to have a major hereditary component [6]. In animals genetic factors are also important in the development and expression of neuropathic pain states. In the Wistar-derived Sabra rat the propensity to perform autotomy, a behavioral sign of neuropathic pain following peripheral nerve injury, is inherited as a recessive trait, perhaps involving a single gene [5]. Furthermore, the hypoalgesic SHR rats demonstrated less pain-related behaviors following injury to both peripheral nerve [28]and spinal cord [29]compared to Sprague–Dawley (SD) and WK rats.

Sensitivity to morphine-induced analgesia is also under genetic control in both mice [17]and rats [27]. For example, Fischer rats have been found to be more sensitive to morphine than Lewis rats [27]and there are differences in brain dynorphin and enkephalin levels under basal conditions and during morphine tolerance and withdrawal in these strains [18]. Dark–Agouti rats, which lack the enzyme P4502D1 (CYP2D1), which is analogous to CYP2D6 in humans, demonstrate less antinociception in the tail flick test following administration of a number of opiate ligands, compared to SDs [4]. SHR rats have been found to be more sensitive to morphine than WK in the hot plate [25]and tail flick [3]tests. Interestingly, morphine-induced analgesia has been found to have a different genetic background than morphine-induced tolerance in both mice [13]and rats [27]. Thus, Fischer and Lewis rats developed morphine-induced tolerance at the same rate [27]as did Swiss Webster mice selectively bred for different sensitivity to morphine and stress-induced analgesia [13].

The aim of the present study was to compare the sensitivity of SHR, WK and SD rats to acute morphine administration and to compare the rate of development of morphine tolerance. We also examined the expression of dependence in the three rat strains.