Separation of Morphine Analgesia from Physical Dependence

Abstract

Intravenous infusion of morphine sulfate in rats for 24 hours produced marked opioid dependence, manifested by a series of well-documented signs appearing after injection of the opiate antagonist naloxone. Treatment of rats with naloxonazine significantly reduced the analgesia associated with the morphine infusions for more than 24 hours. Furthermore, 14 of 16 withdrawal signs observed in naloxonazine-treated rats were virtually identical to those in rats that received morphine alone. These results raise the possibility that different receptor mechanisms mediate morphine analgesia and many of the withdrawal signs associated with morphine dependence.

Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

“…These chronically morphine-treated mice were both tolerant and physically dependent, with naloxone precipitating a profound withdrawal syndrome (Fig. 3F) (4). Chronic IBNtxA dosing also produced tolerance, although it developed more slowly (Fig.…”

“…Tail-flick analgesia was assessed quantally as a doubling or greater of the baseline tail-flick latency, which ranged from 2 to 3 s, in the radiant heat tail-flick technique (2,4,42,43), with a maximal 10-s latency to minimize tissue damage (4,43). Analysis of the data using graded responses with %MPE yielded similar responses.…”

“…Most of the clinical opioids act through mu receptors, which mediate both analgesia and these side effects. Pharmacological studies have long suggested subtypes of mu receptors (1) and the possibility of dissociating analgesia from respiratory depression (2,3), physical dependence (4), and the inhibition of gastrointestinal transit (5,6). However, attempts to develop opiate analgesics that avoid these side effects have not been very fruitful.…”

“…Tolerance was induced by twice-daily injections with either morphine (6 mg/kg s.c.) or IBNtxA (1 mg/kg s.c.) or through the implantation of free-base morphine pellets (75 mg). Dependence was determined on day 3 after pellet implantation with either IBNtxA (1 mg/ kg s.c.) or naloxone (1 mg/kg s.c.) to precipitate withdrawal, and animals were evaluated for signs of diarrhea and jumping (4,15).…”

Splice variation of the mu-opioid receptor and its effect on the action of opioids

“…[9][10][11][12] Opioid receptor subtypes were first proposed in the 1980s when binding assays suggested the presence of multiple classes of binding site for opiates and enkephalins, 13 and subsequent pharmacological studies supported this possibility. [13][14][15][16][17][18] However, when the mu, delta and kappa opioid receptors were cloned in the early 1990s, they were found to originate from distinct opioid receptor genes, OPRM1, [19][20][21][22]24 and OPRK1, respectively. [25][26][27] This discovery left scientists wondering how a single MOR gene, OPRM1, could generate a protein product that enabled such variable clinical response.…”