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Updated: Aug 15, 2026
Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Mechanism of morphine in increasing plasma cyclic GMP level in male mice
Abstract:
Morphine given systemically or centrally increases the plasma concentration of cyclic GMP in male, ddY strain mice. Normorphine also increased the plasma cyclic GMP level, whereas the same dose of ketocyclazocine and SKF 10,047 had no effect. The effect of morphine on plasma cyclic GMP was mimicked by opioid peptides such as (D-Ala2, Met)-enkephalinamide, FK 33,824 or beta-endorphin. The effect of morphine and opioid peptides on plasma cyclic GMP was antagonized by naloxone, indicating the involvement of the opiate receptor. The increase in plasma cyclic GMP elicited by morphine was abolished by vagotomy and pretreatment with hexamethonium and atropine and was partly inhibited by pretreatment with phentolamine. Adrenalectomy and pretreatment with propranolol, which inhibited the increase in plasma cyclic AMP level elicited by morphine (Muraki et al., 1979), did not alter the cyclic GMP response to morphine. The development of tolerance to the cyclic GMP increase was observed in morphine-tolerant/dependent mice. These results suggest that morphine increases the plasma cyclic GMP level by activating the preganglionic parasympathetic tone via the stimulation of the opiate receptors, thereby increasing the generation of cyclic GMP through the muscarinic receptors on the effector cells.
Insights
Morphine and similar opioid peptides elevate plasma cyclic GMP levels in mice by activating opiate receptors. This effect is mediated through the parasympathetic nervous system, not the sympathetic system.
Area of Science:
- Pharmacology
- Neuroscience
- Biochemistry
Background:
- Opioid receptors are known to modulate various physiological processes.
- The role of cyclic GMP (cGMP) in opioid-mediated signaling is not fully understood.
- Previous research linked morphine to changes in cyclic AMP (cAMP) levels.
Purpose of the Study:
- To investigate the effect of morphine and related compounds on plasma cyclic GMP levels.
- To elucidate the receptor subtypes and signaling pathways involved in morphine-induced cGMP changes.
- To examine the development of tolerance to these effects.
Main Methods:
- Administration of morphine, normorphine, ketocyclazocine, SKF 10,047, and opioid peptides to male ddY mice.
- Measurement of plasma cyclic GMP concentrations.
- Use of antagonists (naloxone, phentolamine) and surgical/pharmacological interventions (vagotomy, hexamethonium, atropine, propranolol, adrenalectomy).
- Assessment of tolerance in morphine-tolerant/dependent mice.
Main Results:
- Morphine and normorphine significantly increased plasma cyclic GMP; ketocyclazocine and SKF 10,047 had no effect.
- Opioid peptides mimicked morphine's effect on cyclic GMP.
- Naloxone antagonized the cyclic GMP increase, confirming opiate receptor involvement.
- Vagotomy, hexamethonium, and atropine abolished the effect, indicating parasympathetic activation.
- Phentolamine partially inhibited the response, suggesting minor sympathetic involvement.
- Adrenalectomy and propranolol did not affect the cyclic GMP response.
- Tolerance to the cyclic GMP increase developed in tolerant mice.
Conclusions:
- Morphine elevates plasma cyclic GMP by stimulating opiate receptors.
- This elevation is mediated via activation of preganglionic parasympathetic tone.
- Muscarinic receptors on effector cells are involved in the increased cyclic GMP generation.
- The sympathetic nervous system and adrenal medulla are not significantly involved in this specific response.
