Effects of morphine metabolites on micturition in normal, unanaesthetized rats

Abstract

1 By means of continuous cystometry in normal, unanaesthetized rats, the effects on micturition of intrathecally (i.t.) administered morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), the two main metabolites of morphine, were studied and compared with those of i.t. morphine.2 Both M6G (0.01, 0.1, and 0.5 lg) and M3G (5 pg) were found to have significant effects on micturition. Like morphine (0.1, 0.5, and 10pg), M6G was able to inhibit the micturition reflex, and produce urinary retention and dribbling incontinence in a dose-dependent manner. The potency of M6G for inhibiting micturition was approximately 10 times higher than that of morphine, and the duration of its effect was longer. All effects of M6G could be reversed by naloxone.3 M3G (5 jig) facilitated the micturition reflex, resulting in decreases in bladder capacity and micturition volume, and an increase in spontaneous contractile activity. Pretreatment with naloxone (10 fig), which by itself had no effect on micturition, enhanced the facilitatory effects of M3G. In addition, M3G tended to counteract the inhibitory effects of both morphine and M6G on micturition. M3G (5 jg) also produced an excitatory behavioural syndrome. 4 It is concluded that in rats, i.t. M3G has excitatory effects on micturition and behaviour, probably not mediated via opioid receptors. I.t M6G has a potent inhibitory effect on micturition mediated by stimulation of opioid receptors. It may have effects on somatosensory afferent input in lower doses than those required for effects on micturition.

Synaptic Connections between Endomorphin 2-Immunoreactive Terminals and μ-Opioid Receptor-Expressing Neurons in the Sacral Parasympathetic Nucleus of the Rat

“…Bladder contractions may be inhibited by the MOR exogenous agonist morphine in an isovolumetric rat model, and this effect is abolished by the intravenous administration of the MOR antagonist naloxone [21], further suggesting that MOR in the spinal cord is involved in the regulation of bladder function. The EM2 effects on micturition are similar to those of morphine [20], [51] and other opioid peptides [31], [52], [53], [54], resulting in the inhibition of the micturition reflex and subsequent urinary retention. Upon EM2 binding to MOR, the interactions between the ligand-receptor may occur via the release of the peptide and the subsequent activation of a postsynaptic MOR, resulting in inhibition of MOR-expressing PPNs in the SPN.…”

Actions of tramadol on micturition in awake, freely moving rats

“…For morphine, this is consistent with results after i.t. administration, on micturition pressure in conscious rats (Igawa et al ., 1993) and urethral resistance in anaesthetised dogs (Drenger et al ., 1986). Hence, (±)‐tramadol probably does not impair urethral closure.…”

Pathophysiology, Clinical Importance, and Management of Neurogenic Lower Urinary Tract Dysfunction Caused by Suprasacral Spinal Cord Injury

“…Additionally, opioid receptor agonists and antagonists have been extensively investigated for treating neurogenic lower urinary tract dysfunction . Opioid receptors are widely distributed within central nervous system micturition pathways, including locations such as the spinal cord parasympathetic nucleus, pontine micturition center and periaqueductal gray.…”

“…These opioid‐induced effects on the lower urinary tract can lead to secondary complications including bladder overdistension and reduced contractility, urinary tract infections, autonomic responses, such as hypertension, bradycardia, and cardiac dysrhythmias, increased hospital stay and costs, as well as increased morbidity in human patients . Nonetheless, experimental and early clinical evidence suggests that opioids, such as tramadol which is a weak mu‐receptor agonist, U‐50488 which is a kappa‐receptor agonist and morphine which is a pure mu‐ and kappa‐receptor agonist, can mitigate detrusor overactivity and detrusor‐sphincter dyssynergia and improve voiding efficiency …”