Morphine tolerance and nonspecific subsensitivity of the longitudinal muscle myenteric plexus preparation of the guinea-pig to inhibitory agonists

Abstract

1. The sensitivity of the longitudinal smooth muscle/myenteric plexus (LM/MP) to agonists which reduce the amplitude of neurogenic contractions was studied in preparations obtained from animals implanted with either placebo or morphine (75 mg/pellet) pellets 7 days prior. 2. Tolerance or subsensitivity to morphine was observed following chronic treatment with morphine and was revealed as a rightward shift of the concentration-response curve to morphine. The degree of tolerance decayed modestly with time after removal from a morphine containing environment suggesting a time dependence for the loss of subsensitivity to morphine. 3. LM/MP preparations from animals pretreated with morphine also developed subsensitivity to the inhibitory effects of the purine analogue, 2-chloroadenosine. Subsensitivity to 2-chloroadenosine was seen as a parallel rightward shift of the concentration-response curve in morphine-tolerant preparations. The magnitude of the loss in sensitivity was comparable to that observed to morphine. 4. A reduction in sensitivity of the LM/MP following chronic treatment with morphine was also observed to the inhibitory effects of the alpha2 adrenoceptor agonists, clonidine and xylazine. In contrast to the results obtained with morphine and 2-chloroadenosine, the development of subsensitivity to alpha2 adrenoceptor agonists was characterized by a marked reduction in slope and a depression of the maximum response. 5. These data suggest that myenteric neurons possess spare receptors for morphine and 2-chloroadenosine but not for clonidine and xylazine. Furthermore, the studies support the idea that tolerance is associated with a general cellular change or adaptation which impacts on all of these inhibitory substances in such a way as to reduce their efficacy.

Evidence for functional dissociation of dependence and tolerance in guinea‐pig isolated ileal segments following 20 hour exposure to morphine in vitro

“…Significantly, in both of these reports the ileal segments also exhibited evidence of tolerance, as judged by the reduction in either the potency of, and/or the maximum inhibition produced by, opiates against the electrically-evoked twitch response. Based upon these findings, and earlier reports of a close association between the development of opiate dependence and tolerance (see Collier, 1980), Johnson & Fleming (1989) proposed that the ability of naloxone to produce a contraction in the guinea-pig isolated ileum is a consequence of non-specific 'supersensitivity' within the myenteric plexus, which is associated with the development of tolerance to agents that inhibit acetylcholine release from cholinergic neurones (see also , Taylor et al, 1988).…”

Time Course of Altered Sensitivity to Inhibitory and Excitatory Agonist Responses in the Longitudinal Muscle–Myenteric Plexus and Analgesia in the Guinea Pig after Chronic Morphine Treatment

“…The LM/MP from treated animals was removed and isolated as previously (Taylor et al, 1988). Segments of the ileum were obtained from animals sacrificed by decapitation following isoflurane anesthesia.…”

“…Opioid tolerance in the guinea longitudinal muscle/myenteric plexus (LM/MP) is associated with the development of non-specific supersensitivity to excitatory agonists (Schulz and Goldstein, 1973; Johnson et al, 1978) and non-specific subsensitivity to inhibitory agents (Taylor et al, 1988; Leedham et al, 1992) that has been related to a partial membrane depolarization of the myenteric “S” neurons (Li et al, 2010). In addition, it appears that there may be an association between the time course over which the change in responsiveness and the reduction in the abundance of the alpha 3 subunit of the Na + /K + ATPase occurs in the LM/MP model (Li et al, 2010).…”

Involvement of Ca2+-dependent PKCs in the adaptive changes of μ-opioid pathways to sympathetic denervation in the guinea pig colon

“…13 In normal preparations, Ca ++ -dependent PKC activity significantly increased in the presence of the -opioid agonist, DAMGO 0. …”

“…Tolerance and dependence to the effect of opiates may represent an example of adaptive sensitivity change leading to altered function not only of opioid but also of a variety of other neuronal systems, including  2 -adrenoceptors, in the central nervous system and peripherally [11,12]. Several reports have described the occurrence of changes in  2 -adrenoceptor sensitivity after chronic morphine treatment in the enteric nervous system (ENS) [13][14][15], which represents a complex and integrative neuronal network suitable for the study of neuronal plasticity [16]. Adaptive changes involving inhibitory -opioid receptor and  2 -adrenoceptor pathways have been documented also after chronic ablation of the 5 sympathoadrenergic pathway innervating the guinea pig distal colon.…”